Cobalt-catalyzed cross-coupling reactions of heterocyclic chlorides with arylmagnesium halides and of polyfunctionalized arylcopper reagents with aryl bromides, chlorides, fluorides and tosylates

Article abstract of DOI:10.1055/s-2006-950290

A range of aromatic organocopper or organomagnesium compounds undergo smooth cross-coupling reactions with aryl bromides, chlorides, fluorides and tosylates, leading to polyfunctionalized aromatics or heterocycles in the presence of cobalt salts (5-7.5 mol%) as catalysts. Very mild reaction conditions are needed and, in the case of cross-coupling with organocopper compounds, Bu₄NI (1 equiv) and 4-fluorostyrene (20 mol%) are essential as promoters for successful couplings. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950290

PAPER
3547
Cobalt-Catalyzed Cross-Coupling Reactions of Heterocyclic Chlorides with
Arylmagnesium Halides and of Polyfunctionalized Arylcopper Reagents with
Aryl Bromides, Chlorides, Fluorides and Tosylates
C
obalt-Catalyze
o
d
Cross-Cou
b
pling of
A
ry
i
l
H
alid
a
es
w
ith Ary
s
lmagnesium and
J
A
rylcopp
.
er Korn, Matthias A. Schade, Murthy N. Cheemala, Stefan Wirth, Simon A. Guevara, Gérard Cahiez,
Paul Knochel*
Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, 81377 München, Germany
Fax +49(89)218077680; E-mail: paul.knochel@cup.uni-muenchen.de
Received 25 April 2006; revised 26 June 2006
Dedicated with great scientific respect and friendship to Professor Martin F. Semmelhack on the occasion of his 65th birthday
that Fe(acac)3 catalyzes cross-coupling reactions between
Abstract: A range of aromatic organocopper or organomagnesium
arylcoppers and aryl iodides.11
compounds undergo smooth cross-coupling reactions with aryl bro-
mides, chlorides, fluorides and tosylates, leading to polyfunctional-
ized aromatics or heterocycles in the presence of cobalt salts (5–7.5
mol%) as catalysts. Very mild reaction conditions are needed and,
in the case of cross-coupling with organocopper compounds, Bu4NI
(1 equiv) and 4-fluorostyrene (20 mol%) are essential as promoters
for successful couplings.
The high reactivity of cheap cobalt catalysts for various
C–C bond-forming reactions was reported by Kharasch in
194312 and recently by Cahiez,13 Oshima14 and Gosmini.15
Many of these reactions show unprecedented coupling po-
tential, such as the cobalt-catalyzed coupling between ter-
tiary alkyl halides and allyl Grignard reagents, resulting in
facile formation of quaternary carbons,14c,e which has not
been possible with palladium, nickel, copper, or even iron
catalysts.
Key words: cross-coupling, transition metals, magnesium, hetero-
cycles, halides
Recently, we reported the cross-coupling of aryl Grignard
reagents with heterocyclic chlorides in the presence of
catalytic amounts of CoCl2 (5 mol%).16 We also found an
unprecedented C–C bond formation between arylcoppers
and carbocyclic aryl bromides, chlorides, fluorides and
even tosylates in the presence of Co(acac)2 (7.5 mol%)
and the reaction promoters Bu4NI (1 equiv) and 4-fluo-
rostyrene (20 mol%).17,18 Herein we wish to describe the
full details of these cobalt-catalyzed cross-coupling reac-
tions and demonstrate their scope and synthetic utility.
Transition metal catalyzed cross-coupling reactions are
important methods for forming new C–C bonds and catal-
ysis with palladium and nickel complexes, especially,
have occupied a central role.1 This methodology plays an
important role in the synthesis of fine chemicals and phar-
maceutically active compounds,2 and is implemented in a
multiplicity of total syntheses of target molecules of high
complexity.3 These catalysts have a wide scope and an ex-
cellent tolerance towards various functional groups. Yet,
they have some disadvantages associated with the high
cost of palladium and the required phosphine ligands, as
well as the high toxicity of nickel catalysts. Fortunately,
alternative catalysts are available in the form of simple but
highly effective iron and cobalt salts.
In preliminary experiments, 2-chloroquinoline (1a, 1
equiv) was treated with phenylmagnesium chloride (2a,
2.3 equiv) in the presence of Co(acac)3 (5 mol%) in a
manner similar to that reported by Fürstner using iron ca-
talysis.6a 2-Phenylquinoline (3a)16 could be isolated in
52% yield (Scheme 1).
The use of inexpensive and toxicologically benign iron
salts has attracted increasing attention since the pioneer-
ing work of Kochi,4 and the performance of iron-cata-
lyzed cross-coupling has recently been very actively
investigated and improved by Cahiez,5 Fürstner,6 Naka-
mura,7 Hayashi,8 Bedford9 and others.10 Although the
coupling of alkyl or aryl Grignard reagents with alkenyl
halides, aryl chlorides and sulfonates or primary and sec-
ondary alkyl halides, could be performed very efficiently,
iron-catalyzed cross-coupling between two aryl moieties
remained problematic due to extensive homo-coupling re-
actions of the arylmagnesium species. Recently, we found
Co(acac)3 (5 mol%)
PhMgCl
THF, –30 °C
N
Cl
N
Ph
1a
2a
3a: 52%
Scheme 1 Cobalt-catalyzed cross-coupling between 2-chloroquino-
line and phenylmagnesium chloride
SYNTHESIS 2006, No. 21, pp 3547–3574
x
x.
x
x
.
2
0
0
6
Advanced online publication: 12.10.2006
DOI: 10.1055/s-2006-950290; Art ID: T06906SS
© Georg Thieme Verlag Stuttgart · New York

3548
T. J. Korn et al.
PAPER
Table 1 Cobalt-Catalyzed Cross-Coupling between Functionalized
Arylmagnesium Halides and Heterocyclic Chlorides
Table 1 Cobalt-Catalyzed Cross-Coupling between Functionalized
Arylmagnesium Halides and Heterocyclic Chlorides (continued)
Entry Heteroaryl
Arylmagne- Product 3
sium halide 2 (°C, h)b
Yield
(%)a
Entry Heteroaryl
Arylmagne- Product 3
sium halide 2 (°C, h)b
Yield
(%)a
chloride 1
chloride 1
MgCl
N
1
84
N
N
Cl
11
12
1c
1c
2b
84
85
1a
2a
3a (–40, 5)
MgBr
OMe
3k (–40, 12)
N
2
1a
74
OMe
OMe
N
2b
3b (–40, 24)
2e
MgBr
3
4
5
1a
1a
1a
76
57
89
N
3l (–40, 48)
3c (–20, 34)
2c
13
14
2a
2b
75
55
N
N
Cl
MgBr
OMe
1d
OMe
3m (–40, 12)
N
2d
3d (25, 12)
N
1d
MgBr
OMe
3n (–40, 72)
N
3e (25, 12)
2e
15
16
17
1d
1d
2c
2e
2a
53
51
40
N
MgCl
3o (–40, 18)
6
7
1a
1a
N
74
82
OPiv
N
OPiv
3f (–20, 2)
2f
3p (25, 96)
S
MgCl
N
S
MeO
N
2g
2a
MeO
N
Cl
3g (–20, 4)
1e
3q (25, 39)
Cl
N
a Yield of analytically pure product.
b Reaction temperature and time.
8
9
36
91
N
1b
This result prompted us to further investigations. Optimi-
zation reactions revealed that among various cobalt salts
such as Co(acac)2, Co(OAc)2, Co(acac)3, Co(benzoylac)2
and CoCl2, the use of CoCl2 gave the best result, and 2-
phenylquinoline (3a) was obtained in 65% yield. When
we tested a range of solvents such as THF, toluene, diethyl
ether, and solvent mixtures such as THF–NMP (4:1),
Et2O–NMP (4:1) and toluene–NMP (4:1), diethyl ether
proved to be superior. Interestingly, in contrast to the
work of Cahiez5,13 the addition of NMP to diethyl ether
(1:4) did not improve the cross-coupling yield, and only
increased the reaction time. Finally, experiments were
undertaken in order to compare CoCl2, CoBr2 and CoI2 as
catalysts. Using the reaction of 2-chloroquinoline (1a)
3h (–20, 19)
N
N
2a
2c
Cl
1c
1c
3i (–40, 2)
N
10
74
3j (25, 12)
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PAPER
Cobalt-Catalyzed Cross-Coupling of Aryl Halides with Arylmagnesium and Arylcopper
3549
with phenylmagnesium chloride (2a) as a test reaction, we systems. The more electron-rich 2-chloro-6-methoxypyri-
found that the cross-coupling reaction using CoBr2 or dine (1d) was less prone to undergo the cross-coupling re-
CoI2 as catalysts (5 mol%) in diethyl ether were fast at action, and the desired cross-coupling product 3q16 was
–40 °C, leading to the desired product 3a in 76–80% obtained only in 40% yield after 39 hours reaction time at
yield. A somewhat slower reaction was obtained with room temperature (entries 1, 9, 13 and 17).
CoCl2 (5 h at –40 °C), but the GC analysis of the crude re-
action mixture indicated a cleaner reaction and the prod-
The cobalt-catalyzed cross-coupling could also be applied
to 2-chloropyrimidine (1f), albeit with lower yields, as
shown in Scheme 3. Thus, the reactions with phenylmag-
nesium chloride (2a) and 2b led to products 3r and 3s in
uct (3a) was isolated in a higher yield of 84% (Table 1,
entry 1).19 With these optimized reaction conditions, a
range of functionalized aryl magnesium reagents could be
reacted in good to excellent yields with chloroquinolines,
1-chloroisoquinoline and 2-chloropyridines (Scheme 2
28–42% yield (–40 °C, 12 h).
CoCl2 (5 mol%)
N
N
N
PhMgCl
and Table 1).
Et2O, –40 °C, 12 h
N
Cl
Cl
N
1f
2a
3r: 28%
CoCl2 (5 mol%)
ArMgX
Et2O, –40 to 25 °C,
1–96 h
MgBr
CoCl2 (5 mol%)
N
N
Cl
N
Ar
Et2O, –40 °C, 12 h
1
2
3: 36–91%
N
N
MeO
Scheme 2 Co(II)-catalyzed cross-coupling between heterocyclic
chlorides of type 1 and aryl and heteroarylmagnesium compounds of
type 2
OMe
1f
2b
3s: 42%
Scheme 3 Co(II)-catalyzed cross-coupling between 2-chloropyri-
midine (1f) and arylmagnesium compounds 2a and 2b
As shown in Table 1, a variety of substituted heterocycles
could be prepared by this method. Thus, p-methoxyphe-
nylmagnesium bromide (2b) and p-tolylmagnesium bro-
mide (2c) reacted with (1a) at –40 °C to –20 °C (24–34 h)
to furnish the corresponding quinolines 3b and 3c in 74–
76% yield (Table 1, entries 2 and 3). The use of an aryl-
magnesium reagent bearing a methoxy group in the ortho-
position (2d) led to a sharp rate decrease. In this case,
complete conversion was observed only after 12 hours at
room temperature to give 3d16 in 57% isolated yield (entry
4). Sterically hindered Grignard reagents, typified by 2e,
smoothly underwent the cross-coupling with 1a yielding
3e in 89% yield (entry 5). Interestingly, the presence of a
functional group, such as the ester20 in the arylmagnesium
halide 2f, was well tolerated and the cobalt-catalyzed
cross-coupling proceeded well at –20 °C, within two
hours, leading to the product 3f in 74% yield (entry 6).
Heterocyclic Grignard reagents reacted well with, for
example, 2-thienylmagnesium chloride (2g) reacting at
–20 °C, within four hours, to provide the expected product
3g16 in satisfactory yield (82%; entry 7). Besides 2-chlo-
roquinoline (1a), 4-chloroquinoline (1b) also coupled
with phenylmagnesium chloride (2a) within 19 hours at
–20 °C, to give 3h in a somewhat lower yield of 36% (en-
try 8). A higher reactivity was observed with 1-chloroiso-
quinoline (1c). In this case, 2a underwent the cross-
coupling reaction at –40 °C within two hours and led to
the product 3i16 in 91% yield (entry 9). Similarly, p-sub-
stituted arylmagnesium species reacted in satisfactory
yields (74–84%, entries 10 and 1116). The sterically hin-
dered mesitylmagnesium bromide (2e) underwent the
cross-coupling reaction at –40 °C within 48 hours leading
to the sterically hindered product 3l16 in 85% yield (entry
12). Finally, 2-chloropyridines 1d and 1e reacted in a sat-
isfactory way (entries 13–1716), although lower yields
were obtained compared to the quinoline and isoquinoline
In order to elucidate the mechanism of this cobalt-cata-
lyzed cross-coupling reaction, we attempted to use several
reduced cobalt species to initiate the cross-coupling. We
found that cobalt powder21 (5 mol%) was an excellent cat-
alyst for the cross-coupling reaction, although the reaction
of 2-chloroquinoline (1a) with 2a proceeded only at room
temperature in diethyl ether. An excellent yield (88%) of
1-phenylquinoline (3a) was obtained within four hours re-
action time. Using iron powder22 (5 mol%) instead, a
yield of 86% was obtained, but only after a reaction time
of 12 hours. A similar behavior was observed for the reac-
tion with 1-chloroisoquinoline (1c) (Scheme 4).
metal powder (5 mol%)
PhMgCl
Et2O, 25 °C
N
Cl
N
1a
2a
3a
metal = cobalt: 4 h, 88%
metal = iron: 12 h, 86%
metal powder (5 mol%)
Et2O, 25 °C
PhMgCl
N
N
Cl
1c
2a
3i
metal = cobalt: 1 h, 91%
metal = iron: 5 h, 89%
Scheme 4 Cross-coupling of 1a and 1c with 2a using different me-
tal powders.
If Co2(CO)8 was used as catalyst, 3a could be isolated in
78% yield after 13 hours at –40 °C. The reactions with
CpCo(CO)2 and CoCp2 as catalysts led, respectively, to
only traces of 3a or no product at all.
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3550
T. J. Korn et al.
PAPER
Br
MgCl
Cu(CN)MgCl
CO2Et
4a
CO2Et
CuCN·2LiCl
–20 °C, 10 min
Co(acac)2 (7.5 mol%)
DME–THF–DMPU (3:2:1)
Bu4NI (1 equiv)
2a
5a
6a: 77%
7 (20 mol%)
80 °C, 15 min
F
Scheme 5 Cobalt-catalyzed cross-coupling between phenylcopper (2a) and ethyl 2-bromobenzoate (5a).
As mentioned above, we have recently found that func- the scope of the reaction and found that a broad range of
tionalized arylcopper reagents smoothly undergo cross- arylcopper reagents of type 5 reacted with various aryl
coupling with aryl iodides in the presence of Fe(acac)3 bromides, bearing electron-withdrawing substituents
catalyst.11 However, in this study, only aryl iodides were (Scheme 6 and Table 2).
found to be effective, with neither aryl bromides nor chlo-
Br
Ar
rides reacting. In order to extend the scope of this cross-
coupling, we have examined other metal salts as catalysts.
Preliminary experiments showed that Co(acac)2 catalyzed
efficiently the cross-coupling between arylcopper deriva-
tives and aryl bromides. Other cobalt salts such as
Co(acac)3, Co(OAc)2, Co(benzoylac)2 and CoCl2, also
catalyzed this reaction, but proved to be inferior to
Co(acac)2. Interestingly, CoCl2, which was the best cata-
lyst for the coupling of organomagnesium compounds,
was the worst when arylcopper reagents were used. As a
test reaction, we examined the coupling of ethyl 2-bro-
mobenzoate (4a; 1 equiv) with phenylcopper (5a; 3
equiv),23 which was prepared by the reaction of 2a with
CuCN·2LiCl24 in a 2:1 DME:THF mixture at 80 °C. In the
absence of catalyst, no reaction was observed after four
hours, and the desired product 6a was only detected after
24 hours.25 By adding Co(acac)2 (10 mol%), a conversion
of 46% was observed after 15 minutes, but no further con-
version could be achieved and only 49% conversion was
observed after four hours of reaction time. A significant
improvement was accomplished by adding Bu4NI
(3 equiv)26 which led to a conversion of 81% after
21 hours. After also examining LiI, KI, Bu4NBr and
Bu4NCl as additives, we found that, whereas LiI and KI
were less effective than Bu4NI, Bu4NBr and Bu4NCl also
facilitated the cross-coupling. GC analysis, however, indi-
cated that Bu4NI gave optimal conversions. The addition
of p-fluorostyrene (7; 20 mol%) which is known to pro-
mote cross-coupling reactions27 was not effective alone,28
but in conjunction with Bu4NI, a conversion of 100% was
reached within 21 hours. A considerable rate improve-
ment was further obtained by adding DMPU29 as a co-sol-
vent. With these modifications, a conversion of 100% was
achieved after 15 minutes reaction time at 80 °C, leading
to the desired 6a17 as the sole product. Under optimized
reaction conditions [ethyl 2-bromobenzoate (4a; 1 equiv),
phenylcopper (5a; 1.7 equiv), Co(acac)2 (7.5 mol%),
Bu4NI (1 equiv), p-fluorostyrene (7; 20 mol%)], the ester
6a was isolated in 77% yield (Scheme 5).
Co(acac)2 (7.5 mol%)
FG
FG
ArCu(CN)MgX
DME–THF–DMPU (3:2:1)
Bu4NI (1 equiv)
4
5
6: 25–90%
7 (20 mol%)
F
25–80 °C, 15 min to 24 h
Scheme 6 Cobalt-catalyzed cross-coupling between arylbromides
of type 4 and arylcopper compounds of type 5
Thus, 4-methoxyphenylcopper (5b) underwent smooth
cross-coupling at 80 °C and afforded, as observed for 5a,
the desired biphenyl 6b17 in 79% (Table 2, entries 1 and
2). Ethyl 4-bromobenzoate (4b) showed a somewhat low-
er reactivity. It reacted with the organocopper species 5b
within 16 hours (80 °C) yielding 6c in 35% (entry 3).
Arylcopper species bearing electron-withdrawing groups,
such as 5c and 5d, coupled with 2-bromobenzophenone
(4c) at 80 °C (3 h) leading to the corresponding ketones
6d17 and 6e in 53–62% yield (entries 4 and 5). Similarly,
the bromo diester 4d reacted with various unactivated
arylcopper derivatives such as 5d–5f, providing the cross-
coupling products 6f–6h17 in 36–65% yield (entries 6–8).
Heterocyclic copper reagents such as 5g reacted readily
with 2-bromobenzophenone (4c) at 80 °C, leading to the
substituted pyridine 6i17 in 62% yield (entry 9). As seen
above, aryl bromides with electron-withdrawing groups in
the para-position displayed a lower reactivity. Neverthe-
less, the reactions between 4-bromobenzonitrile (4e) and
either 5a or 5b, led to the biaryls 6j–k in 43–52% yield at
80 °C (entries 10 and 11). Interestingly, the heterocyclic
bromide 4f coupled with 5b at 80 °C and 6l was obtained
in 40% yield (entry 12). As mentioned above, arylcopper
compounds bearing an electron-donating substituent dis-
played a high reactivity in these cross-couplings. Thus, 4-
methoxyphenylcopper (5b) reacted with 4c within one
hour at room temperature instead of 80 °C (89% yield; en-
try 1317). The para-substituted bromobenzophenone (4g)
also underwent complete conversion at 25 °C within 7.5
hours (73% yield; entry 1417). However, the meta-substi-
tuted bromoketone (4h) reacted only slowly (in contrast to
the ortho- and para-substituted analogues 4c and 4g),
The additives (Bu4NI and styrene 7) are also required in
the polar solvent mixture containing DMPU, since other-
wise only a partial conversion was observed. We studied
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Cobalt-Catalyzed Cross-Coupling of Aryl Halides with Arylmagnesium and Arylcopper
3551
leading to the expected product 6o17 in 25% yield after 24 19) reacted smoothly with 4c, providing ketones 6q–s17 in
hours at room temperature (see entries 13–15). Besides 74–90% yield. Finally, we found that the remarkable com-
5b, the sterically hindered copper reagent 5h also under- patibility with various functional groups could be extend-
went cross-coupling with 4g at room temperature, leading ed to an aldehyde function. Thus, 2-bromobenzaldehyde
to 6p in 31% yield (entry 16). Interestingly, the cyano- (4i) reacted readily with phenylcopper (5a), providing 2-
substituted arylcopper derivatives (5f and 5i,j; entries 17– phenylbenzaldehyde (6t)17 in 42% yield (entry 17).
Table 2 Cobalt-Catalyzed Cross-Coupling between Functionalized Arylcopper Reagents and Aryl Bromides
Entry
Aryl bromide 4
ArCu(CN)MgX 5 (X = Br, Cl)
Product 6 (°C, h)b
Yield (%)a
77
Br
Cu
EtO2C
CO2Et
1
6a (80, 0.25)
4a
4a
5a
Cu
EtO2C
2
79
MeO
OMe
6b (80, 0.25)
5b
Br
EtO2C
OMe
3
4
5b
35
62
6c (80, 0.25)
CO2Et
4b
Ph
O
Cu
Br
O
Ph
CF3
F3C
4c
4c
5c
6d (80, 3)
Ph
O
Cu
5
53
CO2Et
EtO2C
5d
6e (80, 3)
EtO2C
Br
Cu
CO2Et
CO2Et
6
7
8
65
54
36
F
F
CO2Et
5e
6f (80,0.5)
4d
EtO2C
CO2Et
4d
5d
EtO2C
6g (80, 18)
Cu
EtO2C
4d
4c
NC
CO2Et
CN
6h (80, 0.5)
5f
Ph
Cu
O
N
9
62
N
Br
Br
5g
6i (80, 16)
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3552
T. J. Korn et al.
PAPER
Table 2 Cobalt-Catalyzed Cross-Coupling between Functionalized Arylcopper Reagents and Aryl Bromides (continued)
Entry
10
Aryl bromide 4
ArCu(CN)MgX 5 (X = Br, Cl)
Product 6 (°C, h)b
Yield (%)a
43
Br
CN
5a
6j (80, 16)
CN
4e
MeO
CN
11
12
4e
5b
5b
52
40
6k (80, 21)
Br
O
CO2Et
O
MeO
CO2Et
6l (80, 16)
4f
Ph
O
13
4c
5b
5b
89
MeO
6m (25, 1)
O
Ph
MeO
COPh
COPh
14
15
73
25
Br
6n (25, 8)
4g
O
Br
Ph
5b
MeO
6o (25, 24)
4h
O
Cu
Ph
16
4g
31
5h
5f
6p (25, 17)
Ph
O
17
18
4c
4c
90
80
NC
6q (25, 0.5)
Ph
Cu
O
NC
CN
5i
6r (25, 0.5)
Ph
Cu
O
CN
19
20
4c
74
42
CN
5j
6s (25, 2.5)
Br
OHC
CHO
5a
6t (25, 0.25)
4i
a Yield of analytically pure product.
b Reaction temperature and time.
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Cobalt-Catalyzed Cross-Coupling of Aryl Halides with Arylmagnesium and Arylcopper
3553
Br
O
Ar
O
R
Besides copper reagents prepared by transmetalation of
organomagnesium compounds, copper reagents prepared
by transmetalation of organolithium compounds (both
with CuCN·2LiCl) could also be coupled with Co(acac)2
as catalyst. As seen in Scheme 7, 2-benzophenone (4c) re-
acted with benzofuranylcopper30 (8a; 80 °C, 17 h) and
ferrocenylcopper31 (8b; 25 °C, 21 h) yielding ketones 9a
and 9b in 30% and 45% yields, respectively.
Co(acac)2 (7.5 mol%)
R
ArCu(CN)MgX
DME–THF–DMPU (3:2:1)
Bu4NI (1 equiv)
10
5
11: 70–99%
7 (20 mol%)
F
25–80 °C, 15 min to 2 h
Scheme 8 Cobalt-catalyzed cross-coupling between 2-bromoaryl
alkylketones of type 10 and copper reagents of type 5
The methyl ketone group is an especially sensitive func-
tionality which can be readily deprotonated by numerous
organometallic reagents. Remarkably, we found that 2-
bromoacetophenone (10a) and aryl bromide 10b, bearing
a cyclohexyl moiety, reacted smoothly with various aryl-
copper reagents leading to polyfunctional ketones
(Scheme 8 and Table 3).
ficient copper reagents leading to the cross-coupling
products 11h–11k in 67–99% yield (entries 8–11).
Unfortunately, unlike 4-bromobenzophenone (4g) with 4-
methoxyphenylcopper (5b; Table 2, entry 14) the para-
substituted bromine, 4-bromoacetophenone (10c), did not
undergo the desired cross-coupling with phenylcopper
(5a). Even after 24 hours at 80 °C the corresponding ke-
tone 11l was not detected.
Thus, 2-bromoacetophenone (10a) underwent cobalt-cat-
alyzed cross-coupling with electron-rich copper reagents
such as phenylcopper (5a), 4-methoxyphenylcopper (5b)
or 4-dimethylaminophenylcopper (5k) at room tempera-
ture within 15–30 minutes, leading to the desired ketones
11a, 11b17 and 11c in excellent yields (90–96%; Table 3,
entries 1–3). Electron-deficient arylcopper compounds
such as 4-cyanophenylcopper (5f) and 3,4-dichlorophe-
nylcopper (5l) could also be successfully coupled with
10a, furnishing the products 11d17 and 11e in good yields
(77–88%; entries 4 and 5). Sterically demanding arylcop-
per reagents such as 5h and 5m were also well tolerated
under these conditions, furnishing the biaryls 11f17 and
11g17 in 70–75% yield (entries 6 and 7). Similarly, the ke-
tone 10b reacted with both electron-rich and electron-de-
Heterocyclic compounds are of great interest for academ-
ic as well as for industrial research since many natural
products, pharmaceuticals and materials contain hetero-
cycles.1,32 In order to delineate the reaction scope, we have
investigated the cross-coupling reactions with bromoke-
tones bearing heterocyclic substituents such as 12a–b. In
all cases, an efficient cross-coupling reaction took place
with a range of arylcopper compounds (Scheme 9 and
Table 4).
1) n-BuLi, Et2O
–80 °C
–10 °C, 2 h
Cu(CN)Li
O
2) CuCN·2LiCl
–20 °C, 10 min
O
O
8a
Co(acac)2 (7.5 mol%)
DME–THF–DMPU (3:2:1)
O
Br
O
O
Cu(CN)Li
Ph
Bu4NI (1 equiv)
Ph
7 (20 mol %)
4c
8a
F
9a: 30%
80 °C, 17 h
1) n-BuLi, THF
–80 °C 25 °C, 40 min
Sn(nBu)3
Cu(CN)Li
Fe
Fe
2) CuCN·2LiCl
–20 °C, 10 min
8b
Co(acac)2 (7.5 mol%)
DME–THF–DMPU (3:2:1)
Br
O
Fc
O
Cu(CN)Li
Fe
Ph
Ph
Bu4NI (1 equiv)
7 (20 mol %)
F
8b
4c
9b: 45%
25 °C, 21 h
Scheme 7 Cobalt-catalyzed cross-coupling between 2-bromobenzophenone (4c) and heteroarylcopper compounds 8a and 8b
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3554
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PAPER
Table 3 Cobalt-Catalyzed Cross-Coupling between Functionalized Arylcopper Reagents and Aryl Bromides Bearing Acidic Protons
Entry
1
Aryl bromide 10
ArCu(CN)MgX 5
(X = Br, Cl)
Product 11
Yield
(%)a
(°C, h)b
Me
Br
O
O
Me
5a
94
90
10a
10a
11a (25, 0.25)
Me
O
2
3
4
5
5b
MeO
11b (25, 0.5)
Cu
Me
O
10a
10a
10a
96
77
88
N
N
11c (25, 0.5)
5k
Me
O
5f
NC
11d (25, 2)
Me
Cu
O
Cl
Cl
Cl
Cl
5l
11e (25, 1)
Me
O
6
10a
10a
5h
70
11f (25, 0.25)
Me
O
Cu
7
8
9
75
67
99
5m
11g (25, 0.75)
Br
O
O
5f
NC
10b
11h (25, 0.5)
O
10b
5b
MeO
11i (25, 1)
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Cobalt-Catalyzed Cross-Coupling of Aryl Halides with Arylmagnesium and Arylcopper
3555
Table 3 Cobalt-Catalyzed Cross-Coupling between Functionalized Arylcopper Reagents and Aryl Bromides Bearing Acidic Protons
(continued)
Entry
10
Aryl bromide 10
ArCu(CN)MgX 5
(X = Br, Cl)
Product 11
Yield
(%)a
(°C, h)b
O
10b
5k
97
N
11j (25, 0.5)
O
11
12
10b
5l
87
Cl
Cl
11k (25, 1)
O
O
Me
Me
5a
0
Br
10c
11l (80, 24)
a Yield of analytically pure product.
b Reaction temperature and time.
The pyridine derivative 12a reacted efficiently with aryl-
copper reagents at room temperature. A variety of func-
tional groups including methoxy, cyano, and chloride
functionalities were well tolerated, allowing the synthesis
of biaryls 13a, 13b, 13c17 and 13d in 56–82% yield
(Table 4, entries 1–4). Ketone 12b, bearing a thienyl moi-
ety, could also be used as an electrophile in these cou-
plings. Thus, the reaction with 5k led to product 13e
within one hour at room temperature in 80% yield (entry
5). Cross-coupling with the heteroaromatic copper com-
pounds 5g and 5o required 80 °C for successful C–C bond
formation and the products 13f17 and 13g17 were obtained
in 74% and 88% yield, respectively (entries 6 and 7).
Br
O
Ar
O
HetAr
Co(acac)2 (7.5 mol%)
HetAr
ArCu(CN)MgX
DME–THF–DMPU (3:2:1)
Bu4NI (1 equiv)
12
5
13: 56–88%
7 (20 mol %)
F
25–80 °C, 15 min to 17 h
Scheme 9 Cobalt-catalyzed cross-coupling between 2-bromoaryl
heteroarylketones of type (12) and copper reagents of type 5
Table 4 Cobalt-Catalyzed Cross-Coupling between Functionalized Arylcopper Reagents and Heterocyclic Aryl Bromides
Entry
Aryl bromide 12
ArCu(CN)MgX 5
(X = Br, Cl)
Product 13
Yield
(%)a
(°C, h)b
OMe
Cu
MeO
OMe
O
Br
O
1
60
56
MeO
OMe
N
Cl
OMe
12a
N
Cl
5n
13a (25, 4)
CN
O
2
12a
5f
N
Cl
13b (25, 5)
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3556
T. J. Korn et al.
PAPER
Table 4 Cobalt-Catalyzed Cross-Coupling between Functionalized Arylcopper Reagents and Heterocyclic Aryl Bromides (continued)
Entry
Aryl bromide 12
ArCu(CN)MgX 5
(X = Br, Cl)
Product 13
Yield
(%)a
(°C, h)b
NC
O
3
12a
5i
5l
82
60
N
Cl
13c (25, 17)
Cl
Cl
O
4
5
12a
N
Cl
13d (25, 15)
N
Br
O
S
5k
80
O
S
12b
13e (25, 1)
Br
N
O
6
7
12b
12b
5g
74
88
S
13f (80, 1)
S
Cu
O
S
S
5o
13g (80, 0.25)
a Yield of analytically pure product.
b Reaction temperature and time.
The cobalt-catalyzed cross-coupling reaction could also While aryl iodides and activated aryl bromides can be
be extended to the aryl bromides 14 and 15, which contain converted using standard palladium and nickel salts, the
ferrocene or bromoferrocene substituents, respectively. transformation of aryl chlorides requires the use of recent-
Both aryl bromides reacted with arylcoppers leading to ly developed stabilizing ligands.34 The excellent reactivity
ketones 16a–d and 17 in good yields (63–95%; of aryl bromides bearing an electron-withdrawing group
Schemes 10 and 11). In the case of the cross-coupling be- in the cobalt-catalyzed cross-coupling, led us to examine
tween 15 and 5a, three equivalents of this arylcopper re- cross-coupling reactions with aryl chlorides. To our de-
agent and 10 mol% of Co(acac)2 were required light, several activated aryl chlorides reacted with various
(Scheme 11).
arylcopper reagents under our typical reaction conditions
(Scheme 13 and Table 5).
An interesting reaction was accomplished when 2,4-di-
bromobenzophenone (18) was used. The first cross-cou- The reaction of 2-chlorobenzophenone (21a) with the
pling with phenylcopper (5a) or 4-cyanophenylcopper arylcopper compounds 5a, 5b and 5i proceeded smoothly
(5f) took place exclusively in ortho-position,33 and the at 25 °C within 15 minutes to two hours and furnished the
products 19a and 19b were obtained in 51–85% yield expected ketones 22a,17 22b17 and 22c17 in almost quanti-
(Scheme 12). A second coupling occurred readily at tative yield (95–98%; Table 5, entries 1–3). The heterocy-
80 °C, furnishing the terphenyls 20a–c in 44–48% yield.
clic aryl chloride 21b also underwent the cross-coupling
at room temperature with 5l and 5p and the products, 22d
and 22e, were isolated in 53–70% yield (entries 4 and 5).
In the case of the reaction between ethyl 2-chlorobenzoate
Aryl chlorides are cheaper and commercially more readily
available than the corresponding aryl bromides or iodides.
Synthesis 2006, No. 21, 3547–3574 © Thieme Stuttgart · New York

PAPER
Cobalt-Catalyzed Cross-Coupling of Aryl Halides with Arylmagnesium and Arylcopper
3557
R1
R2
Br
O
Cu(CN)MgX
O
Co(acac)2 (7.5 mol%)
Fe
Fe
DME–THF–DMPU (3:2:1)
Bu4NI (1 equiv), 25 °C
R2
R1
14
5a: R1 = H; R2 = H
5b: R1 = OMe; R2 = H
5f: R1 = CN; R2 = H
5l: R1 = Cl; R2 = Cl
16a: R1 = H; R2 = H; 0.5 h; 95%
16b: R1 = OMe; R2 = H; 3 h; 82%
16c: R1 = CN; R2 = H; 2 h; 63%
16d: R1 = Cl; R2 = Cl; 1 h; 74%
7 (20 mol%)
F
Scheme 10 Cobalt-catalyzed cross-coupling between 2-bromophenyl ferrocenylketone(14) and copper reagents 5a, 5b, 5f and 5l.
O
O
Cl
O
Ar
O
R
Cu(CN)MgX
Co(acac)2 (10 mol%)
Co(acac)2 (7.5 mol%)
Ph
Ph
R
ArCu(CN)MgX
Fe
Fe
Br
Ph
DME–THF–DMPU (3:2:1)
Bu4NI (1 equiv)
DME–THF–DMPU (3:3.5:1)
Bu4NI (1 equiv), 25 °C, 2 h
21
5
22: 53–98%
15
5a
17: 69%
7 (20 mol%)
F
7 (20 mol%)
F
25–80 °C, 15 min to 26 h
Scheme 11 Cobalt-catalyzed cross-coupling between 2-bromofer-
rocenyl phenylketone(15) and phenylcopper reagent 5.
Scheme 13 Cobalt-catalyzed cross-coupling of arylchlorides of
type 21 and copper reagents of type 5.
the inherent strength of the C–F bond, metal insertion into
this bond is a very difficult process.36 However, the acti-
vation of C–F bonds is of utmost importance because this
transformation contributes to a fundamental understand-
ing of the reactivity of very stable bonds. Therefore, we
examined whether aryl fluorides could be used in the co-
balt-catalyzed cross-couplings. In preliminary experi-
ments, we examined the coupling of 2-
fluorobenzophenone (23a; 1 equiv) with 4-methoxyphe-
nylcopper (5b; 3 equiv). Interestingly, a C–C bond forma-
tion did take place under the same conditions employed
for aryl bromides and aryl chlorides (see above),37 and the
(21c) and phenylcopper (5a), an elevated temperature was
needed. The biphenyl 22f17 was obtained in 66% yield af-
ter 26 hours at 80 °C (entry 6). Interestingly, when 2-chlo-
roacetophenone (21d) was reacted with the copper
reagent 5a, only a complex reaction mixture was obtained.
No desired cross-coupling product 22g could be detected
(entry 7). However, with the tert-butyl-substituted aryl
chloride 21e, a cobalt-catalyzed arylation with 5a and 5n
occurred smoothly (81–94%, entries 8 and 918).
While aryl iodides, bromides and, recently, even
chlorides34 have found widespread applications, aryl fluo-
ride electrophiles35 are much less frequently used. Due to
R1
Br
O
Co(acac)2 (7.5 mol%)
DME–THF–DMPU (3:2:1)
Cu(CN)MgCl
Ph
O
Bu4NI (1 equiv), 3 h
Br
R1
5a: R1 = H
5f: R1 = CN
Ph
18
7 (20 mol%)
Br
F
19a: R1 = H; 25 °C; 85%
19b: R1 = CN; 80 °C; 51%
R1
R1
O
O
Cu(CN)MgCl
Co(acac)2 (7.5 mol%)
Ph
Ph
DME–THF–DMPU (3:2:1)
Bu4NI (1 equiv), 80 °C
Br
R2
R2
5b: R2 = OMe
5k: R2 = NMe2
19a: R1 = H
19b: R1 = CN
7 (20 mol%)
20a: R1 = H; R2 = OMe; 5 h; 48%
20b: R1 = H; R2 = NMe2; 0.25 h; 44%
20c: R1 = CN; R2 = OMe; 19 h; 45%
F
Scheme 12 Cobalt-catalyzed diarylation of 18 with arylcopper compounds 5a, 5f, 5b and 5k.
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T. J. Korn et al.
PAPER
Table 5 Cobalt-Catalyzed Cross-Coupling between Functionalized Arylcopper Reagents and Aryl Chlorides
Entry
1
Aryl chloride 21
ArCu(CN)MgX 5
(X = Br, Cl)
Product 22
Yield
(°C, h)b
(%)a
Ph
Cl
O
O
Ph
5a
5b
95
21a
21a
22a (25, 0.25)
Ph
O
2
3
98
96
MeO
22b (25, 1)
Ph
O
21a
5i
NC
22c (25, 2)
O
Cl
O
O
O
4
5
5l
70
53
Cl
21b
Cl
22d (25, 0.5)
Cu
O
O
21b
F
F
5p
22e (25, 1)
Cl
EtO2C
CO2Et
6
7
5a
5a
66
0
22f (80, 26)
21c
Me
O
Cl
O
Me
21d
22g (25, 1)
Cl
O
O
8
9
5a
5n
94
81
21e
21e
22h (25, 1)
MeO
MeO
MeO
O
22i (80, 0.5)
a Yield of analytically pure product.
b Reaction temperature and time.
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Cobalt-Catalyzed Cross-Coupling of Aryl Halides with Arylmagnesium and Arylcopper
3559
OMe
F
O
O
MgBr
Cu(CN)MgBr
23a
Ph
CuCN·2LiCl
Ph
–20 °C, 10 min
Co(acac)2 (7.5 mol%)
DME–THF–DMPU (3:3.5:1)
Bu4NI (1 equiv), r.t., 2 h
OMe
OMe
24a: 98%
2b
5b
7 (20 mol%)
F
Scheme 14 Co(II)-catalyzed cross-coupling between 4-methoxyphenylcopper (5b) and 2-fluorobenzophenone (23a).
desired product 24a17 was obtained in 98% yield to give the polyfunctional ketone 24c18 in 72% yield (en-
(Scheme 14).
try 3). The reaction between the copper reagent 5q and
more electron-rich fluoroketones, substituted in the para-
position with a methoxy (23c) or a dimethylamine group
(23d), proceeded much faster (3 h instead of 16 h) and the
coupling products 24d18 and 24e18 were isolated in 95–
98% yield (entries 4 and 5). Remarkably, arylcopper re-
agents bearing an electron-withdrawing cyano substituent
in the meta- (5i) or para-position (5f) gave the fastest re-
actions and reacted within 15 minutes at room tempera-
ture with the fluorobenzophenones 23b and 23c to give
the ketones 24f18 and 24g18 in 52% and 87% yield, respec-
tively (entries 6 and 7). Elevated temperatures were re-
quired for the coupling of heterocyclic copper reagents
with fluoroketones. 3-Benzo[b]thienylcopper (5r)
smoothly underwent the cross-coupling with 2-fluoroben-
zophenone (23a) at 80 °C, yielding the desired product
24h18 in 94% yield (entry 8). Similarly, 3-thienylcopper
(5o) reacted with 23d, providing ketone 24i18 in 42% yield
(entry 9). Finally, alkyl substituted ketones such as 23e
and ethyl 2-fluorobenzoate (23f) reacted with the elec-
tron-rich arylcopper reagents 5n and 5b at 80 °C yielding
ketones 24j18 and 24k18 in 71% and 51% yield, respective-
ly (entries 10 and 11).
To explore the scope of this cross-coupling, we examined
the reactions of a range of arylcopper reagents of type 5
with aryl fluorides bearing electron-withdrawing substitu-
ents (Scheme 15 and Table 6).
F
O
Ar
O
Co(acac)2 (7.5 mol%)
R
R
ArCu(CN)MgX
DME–THF–DMPU (3:3.5:1)
Bu4NI (1 equiv)
23
5
24: 42–98%
7 (20 mol%)
F
25–80 °C, 15 min to 16 h
Scheme 15 Co-catalyzed cross-coupling between arylfluorides of
type 23 and copper reagents of type 5.
2-Fluorobenzophenone (23a) reacted even faster with 3,4-
dichlorophenylcopper (5l) (0.5 h at r.t.) and the corre-
sponding ketone 24b18 was obtained in 87% yield
(Table 6, entry 2). Interestingly, functionalized fluoroben-
zophenones underwent the cobalt-catalyzed cross-cou-
pling reaction as well. Thus, the fluorobenzophenone
derivative 23b, bearing a pivaloate substituent, reacted
with arylcopper 5q at room temperature within 16 hours
Table 6 Cobalt-Catalyzed Cross-Coupling between Functionalized Arylcopper Reagents and Aryl Fluorides
Entry
1
Aryl fluoride 23
ArCu(CN)MgX 5
(X = Br, Cl)
Product 24
Yield
(%)a
(°C, h)b
Ph
F
O
O
Ph
5b
98
87
MeO
23a
23a
24a (25, 2)
Ph
O
2
3
5l
Cl
Cl
24b (25, 0.5)
O
O
Cu
F
O
O
72
O
O
OPiv
23b
OPiv
5q
24c (25, 16)
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3560
T. J. Korn et al.
PAPER
Table 6 Cobalt-Catalyzed Cross-Coupling between Functionalized Arylcopper Reagents and Aryl Fluorides (continued)
Entry
Aryl fluoride 23
ArCu(CN)MgX 5
(X = Br, Cl)
Product 24
Yield
(°C, h)b
(%)a
O
O
F
O
4
5q
98
O
OMe
23c
OMe
24d (25, 3)
O
O
F
O
O
5
5q
95
NMe2
NMe2
23d
24e (25, 3)
CN
O
6
7
23b
5i
52
87
OPiv
24f (25, 0.25)
CN
O
23c
23a
5f
OMe
24g (25, 0.25)
S
Cu
O
8
9
94
42
Ph
S
5r
24h (80, 1)
S
O
23d
5o
NMe2
24i (80, 1)
F
O
MeO
MeO
O
10
11
5n
5b
71
51
23e
MeO
24j (80, 1)
F
EtO2C
CO2Et
MeO
24k (80, 0.25)
23f
a Yield of analytically pure product.
b Reaction temperature and time.
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Cobalt-Catalyzed Cross-Coupling of Aryl Halides with Arylmagnesium and Arylcopper
3561
Remarkably, a two-fold, cobalt-catalyzed cross-coupling (48 h), furnishing the ketone 28e18 in 54% yield (entry 5).
was possible with the pentafluorinated benzophenone 25. 3-Thienylcopper (5o) smoothly underwent the cross-cou-
Thus, the reactions between 25 and arylcoppers 5l and 5i pling with 27b at 80 °C within 15 minutes yielding the de-
proceeded smoothly at room temperature, within sired product 28f18 in 74% yield (entry 6).
30 minutes, and furnished the expected ketones 26a18 and
Finally, phenylcopper (5a) reacted with tosylate 27c,
which bears a toluenesulfonyl group meta to two ester
26b18 in acceptable yields (39–50%, Scheme 16).38
functions. After two hours at 80 °C, biaryl 28g was isolat-
ed in 24% yield (entry 7).
Cl
Cl
Cl
Cl
Cu(CN)MgCl
In summary, we have reported new cobalt(II) catalyzed
cross-coupling reactions of heteroaryl chlorides with aryl-
magnesium reagents and of polyfunctionalized arylcopper
reagents with aryl bromides, chlorides, fluorides and tosy-
lates. Due to the low cost of cobalt compared to palladium
or even nickel, these cross-coupling reactions may find
practical applications. The remarkable functional group
compatibility of organocopper reagents with esters, ke-
tones and even aldehydes should make this cross-coupling
especially attractive in multi-step syntheses and should
avoid the extensive use of protecting groups. Extension of
the reaction scope and further mechanistic studies are cur-
rently being investigated in our laboratories.
(5l: 6 equiv)
O
Co(acac)2 (15 mol%)
DME–THF–DMPU (3:7:1)
Bu4NI (1 equiv), r.t., 0.5 h
F
Ph
Cl
F
F
O
F
F
26a: 50%
7 (40 mol%)
Cl
F
F
F
Ph
NC
NC
F
Cu(CN)MgCl
25
(5i: 6 equiv)
O
Co(acac)2 (15 mol%)
DME–THF–DMPU (3:7:1)
Bu4NI (1 equiv), r.t., 0.5 h
F
F
Ph
F
7 (40 mol%)
F
26b: 39%
CN
All reactions were carried out under an argon atmosphere in dried
glassware. Commercially available starting materials were used
without further purification. Melting points were uncorrected and
measured on Dr. Tottoli (Büchi B-540) apparatus. NMR spectra
were recorded on Bruker ARX 200, AC 300, WH 400, and WH 600
instruments. IR spectra were recorded on a Nicolet 510 or a Perkin-
Elmer 281 spectrometer. Mass spectra were recorded on a Varian
CH 7A, and high-resolution mass spectra (HRMS) on a Varian
MAT 711 spectrometer. The following substrates were prepared ac-
cording to literature procedures: 2-bromobenzophenone (4c),40 2-
bromobenzoylferrocene (14),41 ethyl 5-bromo-2-furoate (4f),42 di-
ethyl 4-bromoisophthalate (4d),43 2,4-dibromo-1-iodobenzene44
and tri-n-butyltinferrocene.31 THF was continuously refluxed and
freshly distilled from sodium benzophenone ketyl under nitrogen.
DME was distilled from sodium benzophenone ketyl under nitro-
gen. DMPU was refluxed for 6 h over CaH and distilled. Yields re-
fer to isolated yields of compounds estimated to be >95% pure as
determined by 1H NMR and capillary GC.
Scheme 16 Cobalt-catalyzed diarylation of 25 by the arylcopper
compounds 5l and 5i.
Since aryl tosylates are easily available from phenols and
are more stable and less expensive than the corresponding
triflates, they are very attractive reagents for cross-cou-
plings.39 We found that cobalt-catalyzed aryl–aryl cross-
coupling reactions between aryl tosylates and arylcopper
reagents proceeded readily (Scheme 17 and Table 7).
Thus, various copper reagents such as 5b or 5e underwent
cross-coupling efficiently with tosylate 27a, furnishing
the corresponding ketones 28a18 and 28b18 after
three hours at room temperature in 82% and 78% yield,
respectively (Table 7, entries 1 and 2). Interestingly, an
alkoxy substituent accelerated the cobalt-catalyzed reac-
tion and the ketones 28c18 and 28d18 were obtained in 78–
96% yield after only 15 minutes at room temperature (en-
tries 3 and 4). The presence of ortho-substituents in the
copper reagent, such as the two methyl groups in mesityl-
The characterization data and spectra for the following compounds
have been reported previously: [4c, 4h, 6a, 6b, 6d, 6f, 6g, 6i, 6m,
6n, 6o, 6q, 6r, 6s, 6t, 11b, 11d, 11f, 11g, 12a, 12b, 13c, 13f, 13g,
22a, 22b, 22c, 22f],17 [22i, 23b, 23d, 23e, 24a–k, 26a–b, 27a–b,
28a–f].18
copper (5t), required an elevated reaction temperature and Cobalt-Catalyzed Cross-Coupling Reaction of Arylmagnesium
Halides with Heterocyclic Chlorides; General Procedure (GP 1)
A 25-mL Schlenk tube, equipped with a magnetic stirring bar and a
septum, was charged with the appropriate heterocyclic chloride (1.0
a longer reaction time. Thus, the reaction between the
copper reagent 5t and tosylate 27a proceeded at 80 °C
OTs O
Ar
O
R1
R1
Co(acac)2 (7.5 mol%)
ArCu(CN)MgX
DME–THF–DMPU (3:3.5:1)
Bu4NI (1 equiv)
R2
R2
27
5
28: 24–96%
7 (20 mol%)
F
25–80 °C, 15 min to 48 h
Scheme 17 Cobalt-catalyzed cross-coupling of aryltosylates of type 27 and copper reagents of type 5.
Synthesis 2006, No. 21, 3547–3574 © Thieme Stuttgart · New York

3562
T. J. Korn et al.
PAPER
Table 7 Cobalt-Catalyzed Cross-Coupling of Functionalized Arylcopper Reagents and Aryl Tosylates
Entry
1
Aryl tosylate 27
ArCu(CN)MgX 5
(X = Br, Cl)
Product 28
Yield
(%)a
(°C, h)b
Ph
OTs O
Ph
O
5b
5e
82
78
MeO
27a
27a
28a (25, 3)
Ph
O
2
3
F
28b (25, 3)
Ph
OTs O
O
Ph
5f
78
NC
EtO
OEt
27b
28c (25, 0.25)
Ph
Cu
O
4
5
27b
27a
27b
96
54
Cl
Cl
OEt
5s
28d (25, 0.25)
Ph
Cu
O
5t
28e (80, 48)
Ph
O
6
7
5o
74
24
S
OEt
28f (25, 0.25)
CO2Me
OTs
5a
MeO2C
CO2Me
CO2Me
27c
28g (80, 2)
a Yield of analytically pure product.
b Reaction temperature and time.
equiv), CoCl2 (5.0 mol%) and Et2O (3.0 mL). The solution was
cooled to –40 °C and the corresponding arylmagnesium halide (2.3
equiv) was added dropwise. The reaction mixture was stirred at the
temperature stated in each experiment. After full conversion
(checked by GC analysis) the suspension was quenched with EtOH
(2.0 mL) and filtered through a pad of silica gel. The silica gel was
washed with Et2O (350 mL) and the solvent was concentrated in
vacuo. Flash chromatography on silica gel furnished the analytical-
ly pure products.
ate temperature, and the aryl bromide was added. The reaction mix-
ture was stirred at the same temperature or higher (as stated in the
experiment) until full completion of the Br–Mg exchange had oc-
curred (checked by GC analysis). Subsequently, a solution of
CuCN·2LiCl was added at –20 °C. After stirring for an additional
10 min, the corresponding acid chloride was added. The reaction
mixture was stirred at –10 °C and, after full conversion (checked by
GC analysis), the suspension was quenched with sat. aq NH4Cl–
NH3 (9:1, 50 mL). The organic fraction was washed a second time
with sat. aq NH4Cl–NH3 (9:1, 50 mL) and the combined aqueous
phases were extracted with EtOAc (4 × 100 mL). The organic frac-
tions were washed with brine (100 mL), dried over Mg2SO4, filtered
and the solvent was evaporated in vacuo. Flash chromatography on
silica gel furnished the analytically pure products.
Preparation of Bromo and Chloro Ketones from Aryl Magne-
sium Halides and Acid Chlorides; General Procedure (GP 2)
A 100-mL Schlenk tube, equipped with a magnetic stirring bar and
a septum, was charged with i-PrMgCl·LiCl, cooled to the appropri-
Synthesis 2006, No. 21, 3547–3574 © Thieme Stuttgart · New York

PAPER
Cobalt-Catalyzed Cross-Coupling of Aryl Halides with Arylmagnesium and Arylcopper
3563
Cobalt-Catalyzed Cross-Coupling Reaction of Polyfunctional-
ized Arylcopper Reagents with Aryl Bromides or Chlorides;
General Procedure (GP 3)
21.00 mmol), CuCN·2LiCl (1.00 M in THF, 22.00 mL,
22.00 mmol) and cyclohexanecarbonyl chloride (3.80 g,
25.98 mmol). The i-PrMgCl·LiCl solution was added at –15 °C and
the halogen–Mg exchange was complete after 3 h at –15 °C. The re-
action time for coupling with the acid chloride was 15 h. Purifica-
tion by flash chromatography on silica gel (pentane–Et2O, 49:1)
yielded product 10b.
A 25-mL Schlenk tube, equipped with a magnetic stirring bar and a
septum, was charged with the appropriate Grignard reagent (1.7
mmol), cooled to –20 °C and a solution of CuCN·2LiCl (1 M in
THF, 1.9 mL, 1.9 mmol) was added. After stirring for 10 min at
–20 °C DME (6.0 mL), DMPU (2.0 mL), Bu4NI (370 mg,
1.00 mmol), 4-fluorostyrene (25 mg, 0.20 mmol), Co(acac)2
(19.3 mg, 0.075 mmol) and the corresponding aryl bromide or chlo-
ride (1.00 mmol) were added. The reaction mixture was stirred at
r.t. or heated to 80 °C. After full conversion (checked by GC analy-
sis) the suspension was quenched with sat. aq NH4Cl–NH3 (9:1, 50
mL). The organic fraction was washed a second time with sat. aq
NH4Cl–NH3 (9:1, 50 mL) and the combined aqueous phases were
extracted with EtOAc (3 × 40 mL). The organic fractions were
washed with brine (50 mL), dried over Mg2SO4, filtered and the sol-
vent was evaporated in vacuo. Flash chromatography on silica gel
furnished the analytically pure products.
Yield: 3.70 g (69%); colorless oil.
IR (KBr): 3065 (vw), 2931 (vs), 2854 (m), 1699 (vs), 1588 (w),
1449 (m), 1244 (w), 1206 (w), 1026 (w), 973 (m), 762 (m), 736 (m)
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.59–7.56 (m, 1 H), 7.36–7.27 (m,
3 H), 3.02 (tt, J = 11.1, 3.1 Hz, 1 H), 2.03–1.15 (m, 10 H).
13C NMR (75 MHz, CDCl3): d = 207.9, 142.2, 133.3, 130.9, 128.1,
127.2, 118.6, 49.9, 28.4, 25.8, 25.6.
MS (70 eV, EI): m/z (%) = 266 (12) [M+], 187 (15), 185 (100), 183
(100), 157 (12), 155 (12), 55 (15), 37 (11).
HRMS: m/z calcd for C13H15BrO: 266.0306; found: 266.0280.
Cobalt-Catalyzed Cross-Coupling Reaction of Polyfunctional-
ized Arylcopper Reagents with Aryl Bromides or Chlorides;
General Procedure (GP 4)
(2,4-Dibromophenyl)(phenyl)methanone (18)
Prepared according to GP 2 from 2,4-dibromo-1-iodobenzene
(5.43 g, 15.01 mmol), i-PrMgCl (0.98 M in THF, 16.00 mL,
15.68 mmol), CuCN·2LiCl (1.00 M in THF, 16.50 mL,
16.50 mmol) and benzoyl chloride (2.74 g, 19.50 mmol). The
i-PrMgCl solution was added at –20 °C and the halogen–Mg
exchange was complete after 2 h at –20 °C. The reaction time for
coupling with the acid chloride was 3 h. Purification by flash chro-
matography on silica gel (pentane–Et2O, 39:1) yielded product 18.
A 25-mL Schlenk tube, equipped with a magnetic stirring bar and a
septum, was charged with i-PrMgCl or i-PrMgCl·LiCl, cooled to
the appropriate temperature and the aryl halide (1.70 mmol) was
added. The reaction mixture was stirred at the same temperature or
higher (as stated in the experiment) until full completion of the halo-
gen–Mg exchange had occurred (checked by GC analysis). Subse-
quently, a solution of CuCN·2LiCl (1 M in THF, 1.9 mL, 1.9 mmol)
was added at –20 °C. After stirring for additional 10 min, DME
(6.0 mL), DMPU (2.0 mL), Bu4NI (370 mg, 1.00 mmol), 4-fluo-
rostyrene (25 mg, 0.20 mmol), Co(acac)2 (19.3 mg, 0.075 mmol)
and the corresponding aryl bromide or chloride (1.00 mmol) were
added. The reaction mixture was stirred at r.t. or heated to 80 °C.
After full conversion (checked by GC analysis) the suspension was
quenched with sat. aq NH4Cl–NH3 (9:1, 50 mL). The organic frac-
tion was washed a second time with sat. aq NH4Cl–NH3 (9:1,
50 mL) and the combined aqueous phases were extracted with
EtOAc (3 × 40 mL). The organic fractions were washed with brine
(50 mL), dried over Mg2SO4, filtered and the solvent was evaporat-
ed in vacuo. Flash chromatography on silica gel furnished the ana-
lytically pure products.
Yield: 4.49 g (88%); colorless solid; mp 51.5–53.9 °C.
IR (KBr): 3082 (vw), 1673 (vs), 1574 (s), 1449 (m), 1365 (m), 1282
(vs), 1154 (m), 1076 (m), 1044 (m), 926 (s), 825 (m), 765 (m), 699
(m), 650 (m), 584 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.83–7.77 (m, 3 H), 7.63–7.44 (m,
4 H), 7.22 (d, J = 8.0 Hz, 1 H). 13C NMR (75 MHz, CDCl3):
d = 194.9, 139.5, 135.8, 135.7, 133.9, 130.5, 130.1, 128.7, 124.4.
MS (70 eV, EI): m/z (%) = 338 (16) [M+], 265 (13), 263 (26), 261
(13), 105 (100), 77 (28).
HRMS: m/z calcd for C13H8Br2O: 337.8942; found: 337.8931.
Preparation of NeophylCuLi
Cobalt-Catalyzed Cross-Coupling Reaction of Polyfunctional-
ized Arylcopper Reagents with Aryl Fluorides or Tosylates;
General Procedure (GP 5)
To a suspension of CuCN (107 mg, 1.20 mmol) in THF (6.0 mL),
neophyllithium (1.34 M in THF, 1.80 mL, 2.40 mmol) was added at
–78 °C. The reaction mixture was warmed to r.t. and stirred for 15
min. This solution was directly used in the following procedure.
A 25-mL Schlenk flask, equipped with a magnetic stirring bar and
a septum, was charged with the appropriate Grignard reagent (3.00
mmol), cooled to –20 °C and a solution of CuCN·2LiCl (1 M in
THF, 3.2 mL, 3.2 mmol) was added. After stirring for 10 min at
–20 °C, DME (6.0 mL), DMPU (2.0 mL), Bu4NI (370 mg,
1.00 mmol), 4-fluorostyrene (25 mg, 0.20 mmol), Co(acac)2
(19.3 mg, 0.075 mmol) and the corresponding aryl fluoride or tosy-
late (1.00 mmol) were added. The reaction mixture was stirred at r.t.
or heated to 80 °C. After full conversion (checked by GC analysis)
the suspension was quenched with sat. aq NH4Cl–NH3 (9:1, 50 mL).
The organic fraction was washed a second time with sat. aq NH4Cl–
NH3 (9:1, 50 mL) and the combined aqueous phases were extracted
with EtOAc (3 × 40 mL). The organic fractions were washed with
brine (50 mL), dried over Mg2SO4, filtered and the solvent was
evaporated in vacuo. Flash chromatography on silica gel furnished
the analytically pure products.
2-Benzoyl-1-bromoferrocene (15)
A 25-mL Schlenk tube, equipped with a magnetic stirring bar and a
septum, was charged with 1,2-dibromoferrocene (344 mg, 1.00
mmol) and THF (5.0 mL), cooled to –78 °C and a solution of Neo-
phylCuLi (0.308 M in THF, 7.80 mL, 2.40 mmol; prepared as de-
scribed above) was added dropwise. After stirring for 2 h at 25 °C
full completion of the Br–Mg exchange was observed (checked by
GC analysis). Benzoyl chloride (0.24 mL, 2.00 mmol) was then
added and the reaction mixture was stirred at r.t overnight. After full
conversion, the suspension was quenched with sat. aq NH4Cl–NH3
(9:1, 50 mL). The organic fraction was washed a second time with
sat. aq NH4Cl–NH3 (9:1, 50 mL) and the combined aqueous phases
were extracted with EtOAc(3 × 40 mL). The organic fractions were
washed with brine (50 mL), dried over Mg2SO4, filtered and the sol-
vent was evaporated in vacuo. Purification by flash chromatography
on silica gel (pentane–Et2O, 10:1) yielded product 15.
[4¢-Methoxy(1,1¢-biphenyl)-2-yl](phenyl)methanone (10b)
Prepared according to GP 2 from 1,2-dibromobenzene (4.81 g,
20.39 mmol), i-PrMgCl·LiCl (2.00 M in THF, 10.50 mL,
Yield: 258 mg (70%); red oil.
Synthesis 2006, No. 21, 3547–3574 © Thieme Stuttgart · New York

3564
T. J. Korn et al.
PAPER
IR (KBr): 3853 (w), 3099 (w), 1648 (s), 1423 (m), 1257 (m), 864
(m) cm–1.
1H NMR (300 MHz, C6D6): d = 7.74–7.84 (m, 2 H), 6.80–7.10 (m,
3 H), 4.26–4.41 (m, 1 H), 4.16–4.24 (m, 1 H), 3.97 (s, 5 H), 3.76–
3.81 (m, 1 H).
13C NMR (75 MHz, C6D6): d = 197.8, 139.2, 132.0, 128.7, 128.2,
80.1, 73.2, 72.7, 72.3, 71.5.
mixture was poured onto ice (50 g) and EtOAc (100 mL) and HCl
(2 M, 30 mL) were added. The phases were separated and the aque-
ous phase was extracted with EtOAc (4 × 100 mL). The organic
phases were washed with HCl (2 M, 30 mL), sat. NaHCO3 (50 mL),
brine (50 mL), dried over Mg2SO4, filtered and concentrated in vac-
uo. Recrystallization (CH2Cl2) yielded product 27c.
Yield: 3.64 g (100%); colorless solid; mp 131.0–132.7 °C.
IR (KBr): 3094 (vw), 2956 (vw), 1724 (vs), 1597 (w), 1434 (m),
1377 (m), 1321 (s), 1261 (vs), 1180 (m), 1092 (w), 985 (m), 915
(w), 798 (m), 765 (s), 666 (m), 564 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.55 (t, J = 1.3 Hz, 1 H), 7.84 (d,
J = 1.8 Hz, 2 H), 7.72 (d, J = 8.4 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 2 H),
3.91 (s, 6 H), 2.44 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 164.8, 149.5, 145.9, 132.3, 131.9,
130.0, 129.1, 128.4, 127.6, 52.6, 21.7.
MS (70 eV, EI): m/z (%) = 364 (25) [M+], 333 (14), 155 (100), 91
(69).
MS (70 eV, EI): m/z (%) = 367 (59) [M+], 288 (100), 260 (89), 204
(61).
HRMS: m/z calcd for C17H13BrFeO: 367.9498; found: 367.9508.
(2-Chlorophenyl)(2-furyl)methanone (21b)
Prepared according to GP 2 from 1-bromo-2-chlorobenzene
(3.83 g, 20.01 mmol), i-PrMgCl·LiCl (1.00 M in THF, 21.00 mL,
21.00 mmol), CuCN·2LiCl (1.00 M in THF, 22.00 mL,
22.00 mmol) and 2-furoyl chloride (3.58 g, 27.43 mmol). The i-
PrMgCl·LiCl solution was added at –15 °C and the halogen–Mg ex-
change was complete after 2.5 h at –15 °C. The reaction time for
coupling with the acid chloride was 6 h. Purification by flash chro-
matography on silica gel (pentane–Et2O, 6:1) yielded product 21b.
HRMS: m/z calcd for C17H16O7S: 364.0617; found: 364.0643.
2-Phenylquinoline (3a)
Method A:
Yield: 3.77 g (91%); light-brown solid; mp 55.7–57.6 °C.
IR (KBr): 3152 (vw), 3130 (vw), 1649 (vs), 1562 (m), 1462 (s),
1394 (m), 1314 (m), 1144 (w), 1060 (m), 1022 (m), 952 (m), 890
(m), 780 (m), 764 (m), 652 (w), 595 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.68 (dd, J = 1.8, 0.9 Hz, 1 H),
7.47–7.31 (m, 4 H), 7.05 (dd, J = 3.5, 0.9 Hz, 1 H), 6.56 (dd,
J = 3.5, 1.3 Hz, 1 H).
Prepared according to GP 1 from 2-chlorochinoline (1a) (223 mg,
1.36 mmol), CoCl2 (10.0 mg, 0.077 mmol) and phenylmagnesium
chloride (1.86 M in THF, 1.60 mL, 2.98 mmol). The reaction time
for the cross-coupling was 5 h at –40 °C. Purification by flash chro-
matography on silica gel (pentane–Et2O, 13:1) yielded product 3a
as a colorless solid (234 mg, 1.14 mmol, 84%).
13C NMR (75 MHz, CDCl3): d = 181.9, 152.1, 147.9, 137.5, 131.6,
130.2, 129.2, 126.5, 121.4, 112.6.
Method B:
Prepared according to GP 1 from 2-chlorochinoline (1a) (141 mg,
0.86 mmol), Co powder (2.1 mg, 0.036 mmol) and phenylmagne-
sium chloride (1.76 M in THF, 1.10 mL, 1.94 mmol). The reaction
time for the cross-coupling was 4 h at 25 °C. Purification by flash
chromatography on silica gel (pentane–Et2O, 13:1) yielded product
3a as a colorless solid (133 mg, 0.65 mmol, 75%).
MS (70 eV, EI): m/z (%) = 206 (96) [M+], 178 (15), 141 (26), 139
(85), 111 (27), 95 (100), 75 (19). HRMS: m/z calcd for
C11H7ClO2:206.0135; found: 206.0127.
1-(2-Chlorophenyl)-2,2-dimethyl-1-propanone (21e)
Prepared according to GP 2 from 1-bromo-2-chlorobenzene
(3.81 g, 19.90 mmol), i-PrMgCl·LiCl (1.10 M in THF, 19.10 mL,
21.90 mmol), CuCN·2LiCl (1.10 M in THF, 22.00 mL,
22.00 mmol) and 2,2-dimethylpropanoyl chloride (3.12 g,
26.50 mmol). The i-PrMgCl·LiCl solution was added at –15 °C and
the halogen–Mg exchange was complete after 2.5 h at –15 °C. The
reaction time for coupling with the acid chloride was 20 h. Purifica-
tion by flash chromatography on silica gel (pentane–Et2O, 19:1)
yielded product 21e.
Method C:
Prepared according to GP 1 from 2-chlorochinoline (1a) (288 mg,
1.76 mmol), Fe powder (5.0 mg, 0.090 mmol) and phenylmagne-
sium chloride (1.76 M in THF, 2.30 mL, 4.05 mmol). The reaction
time for the cross-coupling was 12 h at 25 °C. Purification by flash
chromatography on silica gel (pentane–Et2O, 13:1) yielded product
3a as a colorless solid (312 mg, 1.52 mmol, 86%).
Mp 82.4–83.7 °C.
Yield: 3.69 g (94%); colorless oil.
IR (KBr): 3057 (vw), 1597 (m), 1492 (m), 1320 (w), 1126 (w), 1026
(w), 831 (m), 773 (vs), 692 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.28–8.20 (m, 3 H), 8.12 (d,
J = 9.9 Hz, 1 H), 7.83–7.70 (m, 3 H), 7.59–7.46 (m, 4 H).
IR (KBr): 2972 (m), 2871 (w), 1699 (vs), 1592 (w), 1479 (m), 1432
(m), 1366 (w), 1283 (w), 1195 (w), 1063 (m), 965 (m), 742 (m)
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.40–7.35 (m, 1 H), 7.33–7.23 (m,
2 H), 7.15–7.10 (m, 1 H), 1.26 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 157.0, 148.1, 139.5, 136.5, 129.5,
129.4, 129.1, 128.6, 127.4, 127.3, 127.0, 126.0, 118.7.
13C NMR (75 MHz, CDCl3): d = 211.5, 140.5, 129.9, 129.7, 129.4,
MS (70 eV, EI): m/z (%) = 205 (100) [M+], 204 (70).
126.2, 126.1, 45.2, 26.9.
HRMS: m/z calcd for C15H11N: 205.0891; found: 205.0884.
MS (70 eV, EI): m/z (%) = 196 (1) [M+], 139 (100), 111 (10).
2-(4-Methoxyphenyl)quinoline (3b)45a
HRMS: m/z calcd for C11H13ClO: 196.0655; found: 196.0631.
Prepared according to GP 1 from 2-chlorochinoline (1a) (241 mg,
1.47 mmol), CoCl2 (10.0 mg, 0.077 mmol) and 4-methoxyphenyl-
magnesium bromide (0.95 M in THF, 3.50 mL, 3.33 mmol). The re-
action time for the cross-coupling was 24 h at –40 °C. Purification
by flash chromatography on silica gel (pentane–Et2O, 5:1) yielded
product 3b.
Dimethyl 5-{[(4-Methylphenyl)sulfonyl]oxy}isophthalate (27c)
A 100-mL round-bottom flask, equipped with a magnetic stirring
bar, was charged with dimethyl 5-hydroxyisophthalate (2.10 g,
9.98 mmol) and dry pyridine (20 mL) was added. The solution was
cooled to 0 °C and 4-methylbenzenesulfonyl chloride (2.48 g,
13.02 mmol) was added in portions. On completion of the addition,
the reaction mixture was stirred for additional 15 min at 0 °C and
was then allowed to warm to r.t. and stirred overnight. The reaction
Yield: 256 mg (74%); colorless solid; mp 124.1–125.2 °C.
Synthesis 2006, No. 21, 3547–3574 © Thieme Stuttgart · New York

PAPER
Cobalt-Catalyzed Cross-Coupling of Aryl Halides with Arylmagnesium and Arylcopper
3565
1H NMR (300 MHz, CDCl3): d = 8.18–8.12 (m, 4 H), 7.84–7.78 (m,
2 H), 7.70 (ddd, J = 8.9, 6.6, 1.3 Hz, 1 H), 7.49 (ddd, J = 8.0, 6.6,
0.9 Hz, 1 H), 7.05 (d, J = 8.9 Hz, 2 H), 3.88 (s, 3 H).
2,2-Dimethylpropanoic Acid 4-(2-Quinolinyl)phenyl Ester (3f)
2,2-Dimethylpropanoic acid 4-iodophenyl ester (610 mg,
2.00 mmol) was charged in a dry, nitrogen-flushed, 25-mL flask
equipped with a rubber septum and a magnetic stirring bar. Dry
Et2O (4.0 mL) was added and the solution was cooled to –20 °C. i-
PrMgCl (0.95 M in THF, 2.40 mL, 2.28 mmol) was added slowly
and the reaction mixture was stirred at this temperature until the ex-
change reaction was complete (1 h, checked by GC analysis of re-
action aliquots). 2-Chloroquinoline (1a) (135 mg, 0.83 mmol) and
anhyd CoCl2 (6.00 mg; 0.05 mmol) were added and the resulting
suspension was stirred at –20 °C until the cross-coupling reaction
was complete (2 h, checked by GC analysis of reaction aliquots).
The reaction mixture was then quenched with EtOH (2.0 mL) and
filtered through a pad of silica gel. The silica gel was washed with
Et2O (350 mL) and the solvent was concentrated in vacuo. The res-
idue was purified by flash column chromatography (pentane–Et2O,
7:1) affording product 3f.
2-(4-Methylphenyl)quinoline (3c)45a
Prepared according to GP 1 from 2-chlorochinoline (1a) (259 mg,
1.58 mmol), CoCl2 (10.0 mg, 0.077 mmol) and 4-methylphenyl-
magnesium bromide (1.40 M in THF, 2.60 mL, 3.64 mmol). The re-
action time for the cross-coupling was 34 h at –20 °C. Purification
by flash chromatography on silica gel (pentane–Et2O, 20:1) yielded
product 3c.
Yield: 256 mg (76%); colorless solid; mp 82.2–84.4 °C.
1H NMR (300 MHz, CDCl3): d = 8.20–8.15 (m, 2 H), 8.08 (d,
J = 8.0 Hz, 2 H), 7.86 (d, J = 8.9 Hz, 1 H), 7.81 (dd, J = 8.0, 1.3 Hz,
1 H), 7.71 (ddd, J = 8.4, 6.6, 1.3 Hz, 1 H), 7.50 (ddd, J = 8.0, 6.6,
1.3 Hz, 1 H), 7.24 (d, J = 8.4 Hz, 2 H), 2.43 (s, 3 H).
Yield: 187 mg (74%); colorless solid; mp 107.0–109.5 °C.
2-(2-Methoxyphenyl)quinoline (3d)
Prepared according to GP 1 from 2-chlorochinoline (1a) (223 mg,
1.36 mmol), CoCl2 (10.0 mg, 0.077 mmol) and 2-methoxyphenyl-
magnesium bromide (2.20 M in THF, 1.42 mL, 3.12 mmol). The re-
action time for the cross-coupling was 12 h at 25 °C. Purification by
flash chromatography on silica gel (pentane–Et2O, 13:1) yielded
product 3d.
IR (KBr): 3061 (vw), 2972 (w), 1747 (s), 1598 (w), 1497 (m), 1279
(w), 1203 (m), 1169 (s), 1121 (vs), 899 (w), 834 (w), 755 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.23–8.15 (m, 4 H), 7.87–7.71 (m,
2 H), 7.72 (ddd, J = 8.4, 6.6, 1.8 Hz, 1 H), 7.52 (ddd, J = 8.0, 6.6,
1.3 Hz, 1 H), 7.22 (d, J = 8.8 Hz, 2 H), 1.39 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 176.9, 156.4, 152.3, 148.2, 136.9,
129.8, 129.6, 128.7, 127.5, 127.1, 126.3, 121.9, 118.8, 39.2, 27.2.
Yield: 183 mg (57%); light-yellow oil.
IR (KBr): 3058 (w), 2937 (w), 2836 (w), 1599 (vs), 1492 (vs), 1462
(s), 1316 (m), 1258 (s), 1127 (m), 1024 (s), 833 (m), 759 (vs), 620
(w) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.19–8.12 (m, 2 H), 7.90–7.81 (m,
3 H), 7.70 (ddd, J = 8.4, 6.6, 1.3 Hz, 1 H), 7.52 (ddd, J = 8.0, 6.6,
1.3 Hz, 1 H), 7.42 (ddd, J = 8.4, 6.6, 1.8 Hz, 1 H), 7.16–7.10 (m,
1 H), 7.04 (dd, J = 8.4, 0.9 Hz, 1 H), 3.86 (s, 3 H).
MS (70 eV, EI): m/z (%) = 305 (11) [M+], 221 (63), 220 (24), 208
(24), 207 (100), 192 (11), 191 (20), 133 (12), 73 (14), 57 (20), 44
(16), 41 (11).
HRMS: m/z calcd for C20H19NO2: 305.1416; found: 305.1415.
2-(2-Thienyl)quinoline (3g)45b,16
2-Iodothiophene (475 mg, 2.26 mmol) was charged in a dry, nitro-
gen-flushed, 25 mL flask equipped with a rubber septum and a mag-
netic stirring bar. Dry Et2O (4.0 mL) was added and the solution
was cooled to –20 °C. i-PrMgCl (0.70 M in THF, 3.60 mL,
2.52 mmol) was added slowly and the reaction mixture was stirred
at this temperature until the exchange reaction was complete (1 h,
checked by GC analysis of reaction aliquots). 2-Chloroquinoline
(1a) (151 mg, 0.92 mmol) and anhyd CoCl2 (7.00 mg, 0.054 mmol)
were added and the resulting suspension was stirred at –20 °C until
the cross-coupling reaction was complete (4 h, checked by GC anal-
ysis of reaction aliquots). The reaction mixture was then quenched
with EtOH (2.0 mL) and filtered through a pad of silica gel. The sil-
ica gel was washed with Et2O (350 mL) and the solvent was concen-
trated in vacuo. The residue was purified by flash column
chromatography (pentane–Et2O, 13:1) affording product 3g.
13C NMR (75 MHz, CDCl3): d = 157.2, 157.1, 148.3, 135.1, 131.5,
130.3, 129.7, 129.6, 129.2, 127.4, 127.0, 126.1, 123.4, 121.3, 111.5,
55.6.
MS (70 eV, EI): m/z (%) = 235 (100) [M+], 234 (85), 206 (27), 205
(30), 204 (52), 130 (32).
HRMS: m/z calcd for C16H13NO: 235.0997; found: 235.1000.
2-(2,4,6-Trimethylphenyl)quinoline (3e)
Prepared according to GP 1 from 2-chlorochinoline (1a) (252 mg,
1.54 mmol), CoCl2 (10.0 mg, 0.077 mmol) and 2,4,6-trimethylphe-
nylmagnesium bromide (0.85 M in THF, 4.20 mL, 3.57 mmol). The
reaction time for the cross-coupling was 12 h at 25 °C. Purification
by flash chromatography on silica gel (pentane–Et2O, 6:1) yielded
product 3e.
Yield: 159 mg (82%); colorless solid; mp 130.4–133.0 °C.
Yiled: 336 mg (89%); colorless oil.
1H NMR (300 MHz, CDCl3): d = 8.14 (d, J = 8.9 Hz, 1 H), 8.09 (d,
J = 8.4 Hz, 1 H), 7.81–7.66 (m, 4 H), 7.51–7.45 (m, 2 H), 7.16 (dd,
J = 4.9, 3.5 Hz, 1 H).
IR (KBr): 3056 (w), 2919 (m), 2857 (w), 1598 (vs), 1489 (m), 1424
(m), 1305 (w), 1047 (m), 835 (s), 758 (s), 616 (w), 476 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.20 (d, J = 8.4 Hz, 1 H), 8.17 (d,
J = 8.4 Hz, 1 H), 7.87 (dd, J = 8.4, 1.3 Hz, 1 H), 7.73 (ddd, J = 8.4,
6.6, 1.8 Hz, 1 H), 7.57 (ddd, J = 8.0, 6.6, 1.3 Hz, 1 H), 7.36 (d,
J = 8.4 Hz, 1 H), 6.96 (s, 2 H), 2.33 (s, 3 H), 2.04 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 161.0, 148.5, 138.1, 136.6, 136.0,
129.9, 129.5, 128.8, 128.0, 127.1, 126.8, 123.3, 21.5, 20.5.
4-Phenylquinoline (3h)45c
Prepared according to GP 1 from 4-chlorochinoline (1b) (200 mg,
1.22 mmol), CoCl2 (9.0 mg, 0.069 mmol) and phenylmagnesium
chloride (1.40 M in THF, 2.10 mL, 2.94 mmol). The reaction time
for the cross-coupling was 19 h at –20 °C. Purification by flash
chromatography on silica gel (pentane–Et2O, 2:1) yielded product
3h.
MS (70 eV, EI): m/z (%) = 247 (30) [M+], 246 (100), 231 (16), 230
(12).
Yield: 90 mg (36%); light-yellow oil.
HRMS: m/z calcd for C18H17N: 247.1361; found: 247.1369.
1H NMR (300 MHz, CDCl3): d = 8.94 (d, J = 4.4 Hz, 1 H), 8.18
(dd, J = 8.4, 1.3 Hz, 1 H), 7.92 (dd, J = 8.4, 1.3 Hz, 1 H), 7.72 (ddd,
J = 8.4, 6.6, 1.3 Hz, 1 H), 7.55–7.45 (m, 6 H), 7.34 (d, J = 4.4 Hz,
1 H).
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PAPER
1-Phenylisoquinoline (3i)45d,16
Method A:
(dd, J = 5.8, 0.9 Hz, 1 H), 7.53 (ddd, J = 8.4, 6.6, 1.3 Hz, 1 H), 7.06
(d, J = 8.9 Hz, 2 H), 3.89 (s, 3 H).
Prepared according to GP 1 from 1-chloroisochinoline (1c)
(208 mg, 1.27 mmol), CoCl2 (8.0 mg, 0.062 mmol) and phenylmag-
nesium chloride (1.40 M in THF, 2.20 mL, 3.08 mmol). The reac-
tion time for the cross-coupling was 2 h at –40 °C. Purification by
flash chromatography on silica gel (pentane–Et2O, 3:1) yielded
product 3i as a colorless solid (236 mg, 1.15 mmol, 91%).
13C NMR (75 MHz, CDCl3): d = 160.3, 160.0, 142.1, 136.9, 132.0,
131.3, 129.9, 127.7, 127.0, 126.9, 126.7, 119.5, 113.8, 55.4.
MS (70 eV, EI): m/z (%) = 235 (78) [M+], 234 (100), 220 (13), 219
(23), 204 (36), 192 (17), 191 (54), 190 (14).
HRMS: m/z calcd for C16H13NO: 235.0997; found: 235.0982.
Method B:
1-(2,4,6-Trimethylphenyl)isoquinoline (3l)
Prepared according to GP 1 from 1-chloroisochinoline (1c)
(223 mg, 1.36 mmol), Co powder (4.0 mg, 0.068 mmol) and phe-
nylmagnesium chloride (1.76 M in THF, 1.80 mL, 3.17 mmol). The
reaction time for the cross-coupling was 1 h at 25 °C. Purification
by flash chromatography on silica gel (pentane–Et2O, 3:1) yielded
product 3i as a colorless solid (255 mg, 1.24 mmol, 91%).
Prepared according to GP 1 from 1-chloroisochinoline (1c)
(250 mg, 1.53 mmol), CoCl2 (10.0 mg, 0.077 mmol) and 2,4,6-tri-
methylphenylmagnesium bromide (0.85 M in THF, 4.20 mL,
3.57 mmol). The reaction time for the cross-coupling was 48 h at
–40 °C. Purification by flash chromatography on silica gel (pen-
tane–Et2O, 1:1) yielded product 3l.
Method C:
Yield: 321 mg (85%); colorless oil.
Prepared according to GP 1 from 1-chloroisochinoline (1c)
(210 mg, 1.28 mmol), Fe powder (3.5 mg, 0.063 mmol) and phenyl-
magnesium chloride (1.76 M in THF, 1.70 mL, 2.99 mmol). The re-
action time for the cross-coupling was 5 h at 25 °C. Purification by
flash chromatography on silica gel (pentane–Et2O, 3:1) yielded
product 3i as a colorless solid (234 mg, 1.14 mmol, 89%).
IR (KBr): 3049 (m), 2918 (s), 1613 (s), 1558 (s), 1436 (s), 1378 (s),
1317 (m), 1139 (w), 1016 (w), 977 (m), 827 (vs), 751 (s), 690 (m),
592 (w), 424 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.63 (d, J = 5.8 Hz, 1 H), 7.88 (d,
J = 8.4 Hz, 1 H), 7.69–7.63 (m, 2 H), 7.54 (d, J = 8.0 Hz, 1 H), 7.44
(ddd, J = 8.4, 6.6, 1.3 Hz, 1 H), 6.97 (s, 2 H), 2.37 (s, 3 H), 1.86 (s,
6 H).
Mp 95.5–97.8 °C.
1H NMR (300 MHz, CDCl3): d = 8.61 (d, J = 5.8 Hz, 1 H), 8.10
(dd, J = 8.4, 0.9 Hz, 1 H), 7.87 (d, J = 8.4 Hz, 1 H), 7.72–7.61 (m,
4 H), 7.56–7.48 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 161.6, 142.6, 137.6, 136.2, 136.2,
135.5, 130.1, 128.2, 127.7, 127.3, 126.9, 126.9, 119.5, 21.2, 19.7.
MS (70 eV, EI): m/z (%) = 247 (39) [M+], 246 (100), 245 (13), 231
(18), 230 (15), 115 (10).
1-(4-Methylphenyl)isoquinoline (3j)
HRMS: m/z calcd for C18H17N: 247.1361; found: 247.1351.
Prepared according to GP 1 from 1-chloroisochinoline (1c)
(214 mg, 1.31 mmol), CoCl2 (9.0 mg, 0.069 mmol) and 4-meth-
ylphenylmagnesium bromide (1.40 M in THF, 2.10 mL,
2.94 mmol). The reaction time for the cross-coupling was 12 h at
25 °C. Purification by flash chromatography on silica gel (pentane–
Et2O, 3:1) yielded product 3j.
2-Phenylpyridine (3m)
Prepared according to GP 1 from 2-chloropyridine (1d) (169 mg,
1.49 mmol), CoCl2 (10.0 mg, 0.077 mmol) and phenylmagnesium
chloride (1.86 M in THF, 1.80 mL, 3.35 mmol). The reaction time
for the cross-coupling was 12 h at –40 °C. Purification by flash
chromatography on silica gel (pentane–Et2O, 1:1) yielded product
3m.
Yield: 212 mg (74%); light-yellow oil.
IR (KBr): 3050 (w), 2920 (vw), 2865 (vw), 1618 (w), 1553 (m),
1498 (w), 1453 (vw), 1386 (m), 1356 (m), 975 (w), 824 (vs), 751
(m), 678 (m), 577 (w), 496 (w), 422 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.60 (d, J = 5.8 Hz, 1 H), 8.15–
8.11 (m, 1 H), 7.87 (d, J = 8.0 Hz, 1 H), 7.70–7.49 (m, 5 H), 7.34
(dd, J = 8.4, 0.9 Hz, 2 H), 2.46 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 160.8, 142.1, 138.5, 136.9, 136.6,
129.9, 129.8, 129.0, 127.7, 127.0, 126.9, 126.7, 119.7, 21.3.
MS (70 eV, EI): m/z (%) = 219 (52) [M+], 218 (100), 217 (20), 216
(19), 205 (16), 204 (100), 203 (13), 109 (16).
Yield: 174 mg (75%); colorless oil.
IR (KBr): 3063 (w), 2928 (vw), 1587 (m), 1468 (s), 1450 (s), 1425
(m), 1152 (w), 1074 (w), 1021 (w), 800 (w), 746 (vs), 694 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.70 (d, J = 4.9 Hz, 1 H), 8.01–
7.97 (m, 2 H), 7.75–7.71 (m, 2 H), 7.55–7.33 (m, 3 H), 7.25–7.20
(m, 1 H).
13C NMR (75 MHz, CDCl3): d = 157.5, 149.6, 139.3, 136.8, 128.9,
128.7, 126.9, 122.1, 120.6.
MS (70 eV, EI): m/z (%): 155 (100) [M+], 154 (83).
HRMS: m/z calcd for C16H13N: 219.1048; found: 219.1027.
HRMS: m/z calcd for C11H9N: 155.0735; found: 155.0726.
1-(4-Methoxyphenyl)isoquinoline (3k)
2-(4-methoxyphenyl)pyridine (3n)45e
Prepared according to GP 1 from 1-chloroisochinoline (1c)
(241 mg, 1.47 mmol), CoCl2 (10.0 mg, 0.077 mmol) and 4-meth-
oxyphenylmagnesium bromide (1.10 M in THF, 3.10 mL,
3.41 mmol). The reaction time for the cross-coupling was 12 h at
–40 °C. Purification by flash chromatography on silica gel (pen-
tane–Et2O, 3:1) yielded product 3k.
Prepared according to GP 1 from 2-chloropyridine (1d) (169 mg,
1.49 mmol), CoCl2 (10.0 mg, 0.077 mmol) and 4-methoxyphenyl-
magnesium bromide (1.10 M in THF, 3.60 mL, 3.42 mmol). The re-
action time for the cross-coupling was 72 h at –40 °C. Purification
by flash chromatography on silica gel (pentane–Et2O, 3:1) yielded
product 3n.
Yield: 292 mg (84%); colorless solid; mp 55.4–56.4 °C.
Yield: 152 mg (55%); colorless solid; mp 53.0–54.0 °C.
IR (KBr): 3049 (w), 2933 (vw), 2836 (w), 1610 (s), 1514 (m), 1454
(w), 1385 (m), 1355 (m), 1302 (m), 1250 (vs), 1177 (m), 1033 (m),
974 (w), 826 (m), 752 (w), 677 (w), 588 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.58 (d, J = 5.8 Hz, 1 H), 8.16–
8.12 (m, 1 H), 7.86 (d, J = 8.0 Hz, 1 H), 7.70–7.64 (m, 3 H), 7.60
1H NMR (300 MHz, CDCl3): d = 8.65–8.63 (m, 1 H), 7.95 (d,
J = 8.9 Hz, 2 H), 7.72–7.63 (m, 2 H), 7.15 (ddd, J = 7.1, 4.9,
1.8 Hz, 1 H), 6.99 (d, J = 8.9 Hz, 2 H), 3.84 (s, 3 H).
Synthesis 2006, No. 21, 3547–3574 © Thieme Stuttgart · New York

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Cobalt-Catalyzed Cross-Coupling of Aryl Halides with Arylmagnesium and Arylcopper
3567
2-(4-Methylphenyl)pyridine (3o)45f
2-(4-Methoxyphenyl)pyrimidine (3s)45h
Prepared according to GP 1 from 2-chloropyridine (1d) (230 mg,
2.03 mmol), CoCl2 (13.0 mg, 0.100 mmol) and 4-methylphenyl-
magnesium bromide (1.00 M in THF, 4.60 mL, 4.60 mmol). The re-
action time for the cross-coupling was 18 h at –40 °C. Purification
by flash chromatography on silica gel (pentane–Et2O, 3:1) yielded
product 3o.
Prepared according to GP 1 from 2-chloropyrimidine (1f) (147 mg,
1.28 mmol), CoCl2 (8.0 mg, 0.062 mmol) and 4-methoxyphenyl-
magnesium bromide (0.95 M in THF, 3.00 mL, 2.85 mmol). The re-
action time for the cross-coupling was 24 h at –40 °C. Purification
by flash chromatography on silica gel (pentane–Et2O, 1:1) yielded
product 3s.
Yield: 181 mg (53%); colorless oil.
Yield: 101 mg (42%); colorless solid; mp 66.1–67.0 °C.
1H NMR (300 MHz, CDCl3): d = 8.69–8.66 (m, 1 H), 7.90 (d,
J = 8.0 Hz, 2 H), 7.71–7.69 (m, 2 H), 7.28 (dd, J = 8.4, 0.9 Hz,
2 H), 7.20–7.16 (m, 1 H), 2.40 (s, 3 H).
1H NMR (300 MHz, CDCl3): d = 8.74 (d, J = 4.9 Hz, 2 H), 8.39 (d,
J = 8.8 Hz, 2 H), 7.11–7.08 (m, 1 H), 6.99 (d, J = 8.4 Hz, 2 H), 3.86
(s, 3 H).
2-(2,4,6-Trimethylphenyl)pyridine (3p)
Ethyl 4¢-Methoxy[1,1¢-biphenyl]-4-carboxylate (6c)46a
Prepared according to GP 1 from 2-chloropyridine (1d) (230 mg,
2.03 mmol), CoCl2 (13.0 mg, 0.100 mmol) and 2,4,6-trimethylphe-
nylmagnesium bromide (0.85 M in THF, 5.50 mL, 4.68 mmol). The
reaction time for the cross-coupling was 96 h at 25 °C. Purification
by flash chromatography on silica gel (pentane–Et2O, 3:1) yielded
product 3p.
Prepared according to GP 3 from ethyl 4-bromobenzoate (4b)
(229 mg, 1.00 mmol) and (4-methoxyphenyl)magnesium bromide
(0.80 M in THF, 2.13 mL, 1.70 mmol). The reaction time for the
cross-coupling was 16 h at 80 °C. Purification by flash chromatog-
raphy on silica gel (pentane–Et2O, 19:1) yielded product 6c.
Yield: 90 mg (35%); colorless solid; mp 102.0–103.3 °C.
Yield: 203 mg (51%); colorless oil.
1H NMR (300 MHz, CDCl3): d = 8.08 (d, J = 8.8 Hz, 2 H), 7.63–
7.54 (m, 4 H), 6.99 (d, J = 8.8 Hz, 2 H), 4.39 (q, J = 7.4 Hz, 2 H),
3.85 (s, 3 H), 1.40 (t, J = 7.4 Hz, 3 H).
IR (KBr): 3003 (w), 2920 (m), 1614 (m), 1587 (vs), 1563 (m), 1665
(vs), 1433 (m), 1147 (w), 1028 (w), 851 (m), 792 (m), 751 (m), 624
(w), 581 (w) cm–1.
Ethyl 2¢-Benzoyl[1,1¢-biphenyl]-3-carboxylate (6e)
1H NMR (300 MHz, CDCl3): d = 8.71–8.69 (m, 1 H), 7.73 (td,
J = 8.0, 1.8 Hz, 1 H), 7.25–7.19 (m, 2 H), 6.92 (s, 2 H), 2.31 (s,
3 H), 2.01 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 160.1, 149.6, 137.7, 137.3, 136.1,
135.6, 128.2, 124.6, 121.4, 21.1, 20.1.
MS (70 eV, EI): m/z (%) = 197 (42) [M+], 196 (100), 181 (22), 180
(10).
Prepared according to GP 4 from 2-bromobenzophenone (4c)
(259 mg, 0.99 mmol), ethyl 3-iodobenzoate (470 mg, 1.70 mmol)
and i-PrMgCl (0.83 M in THF, 2.15 mL, 1.79 mmol). The i-
PrMgCl solution was added at –20 °C and the I–Mg exchange was
complete after 0.5 h at –20 °C. The reaction time for the cross-cou-
pling was 3 h at 80 °C. Purification by flash chromatography on sil-
ica gel (pentane–Et2O, 19:1) yielded product 6e.
Yield: 174 mg (53%); light-yellow oil.
HRMS: m/z calcd for C14H15N: 197.1204; found: 197.1150.
IR (KBr): 3062 (w), 2981 (w), 1717 (vs), 1667 (s), 1597 (m), 1449
(m), 1368 (w), 1284 (s), 1236 (vs), 1112 (m), 1032 (m), 929 (m),
746 (s), 695 (m), 639 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.96 (t, J = 1.8 Hz, 1 H), 7.84 (dt,
J = 7.5, 1.3 Hz, 1 H), 7.66–7.38 (m, 8 H), 7.29–7.23 (m, 3 H), 4.31
(q, J = 7.1 Hz, 2 H), 1.32 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 198.4, 166.2, 140.4, 140.2, 138.9,
137.4, 133.3, 132.9, 130.5, 130.1, 129.9, 129.9, 128.9, 128.4, 128.2,
128.2, 127.4, 125.6, 60.9, 14.2.
MS (70 eV, EI): m/z (%) = 330 (100) [M+], 329 (30), 301 (18), 285
(38), 258 (12), 257 (45), 256 (16), 255 (41), 253 (27), 229 (14), 228
(22), 226 (12), 208 (12), 207 (77), 181 (20), 152 (26), 151 (18), 105
(68), 77 (37).
2-Methoxy-6-phenylpyridine (3q)
Prepared according to GP 1 from 2-chloro-6-methoxypyridine (1e)
(181 mg, 1.26 mmol), CoCl2 (8.0 mg, 0.62 mmol) and phenylmag-
nesium chloride (1.86 M in THF, 1.60 mL, 2.98 mmol). The reac-
tion time for the cross-coupling was 39 h at 25 °C. Purification by
flash chromatography on silica gel (pentane–Et2O, 49:1) yielded
product 3q.
Yield: 94 mg (40%); colorless oil.
IR (KBr): 2947 (vw), 1576 (vs), 1467 (s), 1450 (vs), 1431 (s), 1326
(m), 1255 (vs), 1151 (w), 1019 (w), 879 (w), 806 (w), 763 (s), 693
(m) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.08–8.04 (m, 2 H), 7.65–7.60 (m,
1 H), 7.55–7.33 (m, 4 H), 6.70 (d, J = 8.8 Hz, 1 H), 4.05 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 163.7, 154.6, 139.1, 139.0, 128.8,
128.6, 126.7, 112.7, 109.2, 53.2.
HRMS: m/z calcd for C22H18O3: 330.1256; found: 330.1227.
Diethyl 4¢-Cyano[1,1¢-biphenyl]-2,4-dicarboxylate (6h)
MS (70 eV, EI): m/z (%) = 185 (71) [M+], 184 (100), 156 (27), 155
(31), 154 (56), 127 (11).
Prepared according to GP 4 from diethyl 4-bromoisophthalate (4d)
(302 mg, 1.00 mmol), 4-bromobenzonitrile (309 mg, 1.70 mmol)
and i-PrMgCl·LiCl (0.78 M in THF, 2.17 mL, 1.70 mmol). The i-
PrMgCl·LiCl solution was added at –20 °C and the Br–Mg ex-
change was complete after 2 h at 0 °C. The reaction time for the
cross-coupling was 0.5 h at 80 °C. Purification by flash chromatog-
raphy on silica gel (pentane–Et2O, 4:1) yielded product 6h.
HRMS: m/z calcd for C12H11NO: 185.0841; found: 185.0842.
2-Phenylpyrimidine (3r)45g
Prepared according to GP 1 from 2-chloropyrimidine (1f) (149 mg,
1.30 mmol), CoCl2 (10.0 mg, 0.077 mmol) and phenylmagnesium
chloride (1.86 M in THF, 1.60 mL, 2.98 mmol). The reaction time
for the cross-coupling was 12 h at –40 °C. Purification by flash
chromatography on silica gel (pentane–Et2O, 1:1) yielded product
3r.
Yield: 116 mg (36%); colorless oil.
IR (KBr): 2983 (m), 2229 (s), 1724 (vs), 1607 (m), 1367 (s), 1304
(vs), 1248 (vs), 1096 (s), 1025 (s), 840 (s), 771 (s), 573 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.56 (d, J = 1.8 Hz, 1 H), 8.21
(dd, J = 8.0, 1.8 Hz, 1 H), 7.70 (d, J = 8.0 Hz, 2 H), 7.43–7.37 (m,
3 H), 4.43 (q, J = 7.1 Hz, 2 H), 4.14 (q, J = 7.1 Hz, 2 H), 1.42 (t,
J = 7.1 Hz, 3 H), 1.08 (t, J = 7.1 Hz, 3 H).
Yield: 57 mg (28%); colorless solid; mp 39.0–41.0 °C.
1H NMR (300 MHz, CDCl3): d = 8.78 (d, J = 4.9 Hz, 2 H), 8.46–
8.43 (m, 2 H), 7.49–7.47 (m, 3 H), 7.15 (t, J = 4.9 Hz, 1 H).
Synthesis 2006, No. 21, 3547–3574 © Thieme Stuttgart · New York

3568
T. J. Korn et al.
PAPER
13C NMR (150 MHz, CDCl3): d = 166.8, 165.3, 145.5 144.9 132.3,
131.8, 131.5, 130.9, 130.7, 130.6, 129.1, 118.6, 111.6, 61.5, 61.5,
14.3, 13.8.
13C NMR (75 MHz, CDCl3): d = 196.4, 145.2, 137.7, 137.7, 136.6,
132.5, 131.4, 130.7, 130.6, 130.2, 130.2, 130.1, 130.0, 128.8, 128.4,
127.7, 127.0, 127.0, 126.7, 126.6, 123.0, 122.6.
MS (70 eV, EI): m/z (%) = 323 (41) [M+], 295 (15), 279 (20), 278
MS (70 eV, EI): m/z (%) = 358 (100) [M+], 281 (34), 253 (24), 252
(100), 267 (15), 251 (11), 250 (41), 206 (14), 178 (12), 177 (19).
(31), 105 (12).
HRMS: m/z calcd for C19H17NO4: 323.1158; found: 323.1152.
HRMS: m/z calcd for C27H18O: 358.1358; found: 358.1363.
[1,1¢-Biphenyl]-4-carbonitrile (6j)46b
[2-(1-Benzofuran-2-yl)phenyl](phenyl)methanone (9a)
Prepared according to GP 3 from 4-bromobenzonitrile (4e)
(182 mg, 1.00 mmol) and phenylmagnesium chloride (1.20 M in
THF, 1.42 mL, 1.70 mmol). The reaction time for the cross-cou-
pling was 16 h at 80 °C. Purification by flash chromatography on
silica gel (pentane–Et2O, 9:1) yielded product 6j.
A 25-mL Schlenk flask, equipped with a magnetic stirring bar and
a septum, was charged with benzofuran (176 mg, 1.49 mmol) and
Et2O (2.0 mL), cooled to –78 °C and n-BuLi (1.60 M in hexane,
0.99 mL, 1.50 mmol) was added dropwise. The reaction mixture
was stirred at –10 °C for 2 h and then cooled to –20 °C. Subsequent-
ly, a solution of CuCN·2LiCl (1.00 M in THF, 1.67 mL, 1.67 mmol)
was added and, after stirring for additional 10 min, DME (6.0 mL),
DMPU (2.0 mL), Bu4NI (327 mg, 0.88 mmol), 4-fluorostyrene
(22 mg, 0.18 mmol), Co(acac)2 (17.0 mg, 0.066 mmol) and 2-bro-
mobenzophenone (2.30 mg, 0.88 mmol) were added. The reaction
mixture was stirred at 80 °C for 17 h. After full conversion (checked
by GC analysis) the suspension was quenched with sat. aq NH4Cl–
NH3 (9:1, 50 mL). The organic fraction was washed a second time
with sat. aq NH4Cl–NH3 (9:1, 50 mL) and the combined aqueous
phases were extracted with EtOAc (3 × 40 mL). The organic frac-
tions were washed with brine (50 mL), dried over Mg2SO4, filtered
and the solvent was evaporated in vacuo. Purification by flash chro-
matography on silica gel (pentane–Et2O, 40:1) yielded product 9a.
Yield: 77 mg (43%); colorless solid; mp 86.9–87.9 °C.
1H NMR (300 MHz, CDCl3): d = 7.73 (d, J = 8.9 Hz, 2 H), 7.68 (d,
J = 8.9 Hz, 2 H), 7.60–7.56 (m, 2 H), 7.51–7.39 (m, 3 H).
4¢-Methoxy[1,1¢-biphenyl]-4-carbonitrile (6k)46c
Prepared according to GP 3 from 4-bromobenzonitrile (4e)
(182 mg, 1.00 mmol) and (4-methoxyphenyl)magnesium bromide
(0.80 M in THF, 2.13 mL, 1.70 mmol). The reaction time for the
cross-coupling was 21 h at 80 °C. Purification by flash chromatog-
raphy on silica gel (pentane–Et2O, 9:1) yielded product 6k.
Yield: 108 mg (52%); colorless solid; mp 101.5–102.5 °C.
1H NMR (300 MHz, CDCl3): d = 7.68 (d, J = 8.4 Hz, 2 H), 7.63 (d,
J = 8.9 Hz, 2 H), 7.53 (d, J = 8.9 Hz, 2 H), 6.99 (d, J = 8.9 Hz, 2 H),
3.85 (s, 3 H).
Yield: 79 mg (30%); light-yellow solid; mp 92.5–93.7 °C.
IR (KBr): 3084 (vw), 2922 (w), 1660 (m), 1594 (w), 1447 (w), 1259
(m), 1105 (w), 1000 (w), 926 (m), 818 (m), 759 (m), 704 (s), 635
(m), 533 (w), 518 (vs) cm–1.
Ethyl 5-(4-Methoxyphenyl)-2-furoate (6l)
Prepared according to GP 3 from ethyl 5-bromo-2-furoate (4f)
(220 mg, 1.01 mmol) and 4-methoxyphenylmagnesium bromide
(0.80 M in THF, 2.13 mL, 1.70 mmol). The reaction time was 8 h at
80 °C. Purification by flash chromatography on silica gel (pentane–
Et2O, 9:1) yielded product 6l.
1H NMR (300 MHz, CDCl3): d = 7.93–7.91 (m, 1 H), 7.81–7.77 (m,
2 H), 7.62–7.56 (m, 1 H), 7.50–7.40 (m, 4 H), 7.35–7.26 (m, 3 H),
7.20–7.09 (m, 2 H), 6.79 (d, J = 0.9 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 198.2, 154.7, 153.6, 137.9, 137.1,
133.2, 130.0, 129.6, 128.7, 128.6, 128.4, 128.3, 128.2, 127.5, 124.5,
122.8, 121.0, 111.0, 105.2.
MS (70 eV, EI): m/z (%) = 298 (100) [M+], 297 (22), 281 (17), 270
(19), 269 (30), 241 (13), 239 (11), 221 (18), 165 (30), 163 (11), 105
(17), 77 (23).
Yield: 100 mg (40%); colorless oil.
IR (KBr): 2981 (w), 2838 (w), 1715 (s), 1614 (m), 1488 (vs), 1373
(w), 1303 (s), 1256 (s), 1139 (s), 835 (m), 795 (m), 759 (m), 616 (w)
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.70 (d, J = 8.8 Hz, 2 H), 7.21 (d,
J = 3.5 Hz, 1 H), 6.93 (d, J = 9.9 Hz, 2 H), 6.59 (d, J = 3.5 Hz, 1 H),
4.37 (q, J = 7.1 Hz, 2 H), 3.83 (s, 3 H), 1.38 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 160.2, 158.9, 157.7, 143.3, 126.4,
122.5, 120.0, 114.2, 105.3, 60.7, 55.3, 14.4.
MS (70 eV, EI): m/z (%) = 246 (100) [M+], 218 (33), 203 (21), 201
(10), 174 (17), 145 (17).
HRMS: m/z calcd for C21H14O2: 298.0994; found: 298.1006.
[2-(Ferrocen-1-yl)phenyl](phenyl)methanone (9b)
A 25-mL Schlenkflask, equipped with a magnetic stirring bar and a
septum, was charged with tri-n-butyltinferrocene (808 mg, 1.70
mmol) and THF (2.0 mL), cooled to –78 °C and n-BuLi (1.60 M in
hexane, 1.18 mL, 1.80 mmol) was added dropwise. The reaction
mixture was stirred at –78 °C for 0.5 h, then for 10 min at 25 °C.
Subsequently, a solution of CuCN·2LiCl (1.00 M in THF, 1.90 mL,
1.90 mmol) was added at –20 °C. After stirring for additional
10 min, DME (6.0 mL), DMPU (2.0 mL), Bu4NI (370 mg,
1.00 mmol), 4-fluorostyrene (25 mg, 0.20 mmol), Co(acac)2
(19.3 mg, 0.075 mmol) and 2-bromobenzophenone (2.61 mg,
1.00 mmol) were added. The reaction mixture was stirred at 25 °C
for 21 h. After full conversion (checked by GC analysis) the suspen-
sion was quenched with sat. aq NH4Cl–NH3 (9:1, 50 mL). The or-
ganic fraction was washed a second time with sat. aq NH4Cl–NH3
(9:1, 50 mL) and the combined aqueous phases were extracted with
EtOAc (3 × 40 mL). The organic fractions were washed with brine
(50 mL), dried over Mg2SO4, filtered and the solvent was evaporat-
ed in vacuo. Purification by flash chromatography on silica gel
(pentane–Et2O, 40:1) yielded product 9b.
HRMS: m/z calcd for C14H14O4: 246.0892; found: 246.0888.
[4-(9-Phenanthryl)phenyl](phenyl)methanone (6p)
Prepared according to GP 4 from 4-bromobenzophenone (4g)
(263 mg, 1.01 mmol), 9-bromophenanthrene (438 mg, 1.70 mmol)
and i-PrMgCl·LiCl (0.96 M in THF, 2.86 mL, 1.79 mmol). The i-
PrMgCl·LiCl solution was added at –20 °C and the Br–Mg ex-
change was complete after 17 h at 25 °C. The reaction time for the
cross-coupling was 1 h at 80 °C. Purification by flash chromatogra-
phy on silica gel (pentane–Et2O, 19:1) yielded product 6p.
Yield: 110 mg (31%); colorless solid; mp 137.7–143.5 °C.
IR (KBr): 3077 (vw), 3057 (vw), 1657 (vs), 1604 (m), 1448 (m),
1308 (m), 1282 (s), 924 (m), 851 (w), 754 (m), 701 (s), 656 (w)
cm–1.
Yield: 163 mg (45%); dark-red resin.
1H NMR (300 MHz, CDCl3): d = 8.80 (d, J = 8.0 Hz, 1 H), 8.74 (d,
J = 8.0 Hz, 1 H), 7.99–7.90 (m, 6 H), 7.72–7.50 (m, 10 H).
Synthesis 2006, No. 21, 3547–3574 © Thieme Stuttgart · New York

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Cobalt-Catalyzed Cross-Coupling of Aryl Halides with Arylmagnesium and Arylcopper
3569
IR (KBr): 3063 (w), 2923 (w), 1665 (vs), 1595 (w), 1446 (m), 1256
(m), 1152 (w), 1014 (w), 926 (m), 816 (w), 770 (m), 740 (m), 704
(m), 633 (w) cm–1.
1H NMR (300 MHz, C6D6): d = 7.81–7.77 (m, 2 H), 7.72–7.69 (m,
1 H), 7.23–7.16 (m, 2 H), 7.03–6.89 (m, 4 H), 4.32 (dd, J = 2.0,
2.0 Hz, 2 H), 3.83–3.79 (m, 7 H).
13C NMR (75 MHz, C6D6): d = 198.4, 139.6, 138.0, 132.8, 130.2,
130.0, 129.3, 128.4, 128.1, 127.9, 126.1, 85.6, 70.0, 69.7, 68.9.
MS (70 eV, EI): m/z (%): 366 (100) [M+], 302 (20), 301 (97), 215
(25), 139 (12).
HRMS: m/z calcd for C14H10Cl2O: 264.0109; found: 264.0101.
2¢-(Cyclohexylcarbonyl)(1,1¢-biphenyl)-4-carbonitrile (11h)
Prepared according to GP 4 from (2-bromophenyl)(cyclohex-
yl)methanone (10b) (267 mg, 1.00 mmol), 4-bromobenzonitrile
(309 mg, 1.70 mmol) and i-PrMgCl·LiCl (1.00 M in THF, 1.79 mL,
1.79 mmol). The i-PrMgCl·LiCl solution was added at –20 °C and
the Br–Mg exchange was complete after 2 h at 0 °C. The reaction
time for the cross-coupling was 0.5 h at 25 °C. Purification by flash
chromatography on silica gel (pentane–Et2O, 9:1) yielded product
11h.
Yield: 193 mg (67%); colorless oil.
HRMS: m/z calcd for C23H18FeO: 366.0707; found: 366.0688.
IR (KBr): 060 (vw), 2931 (vs), 2854 (m), 2229 (m), 1689 (vs), 1608
(m), 1450 (m), 1369 (w), 1311 (w), 1243 (w), 1205 (m), 973 (m),
843 (m), 763 (m), 573 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.69 (d, J = 8.4 Hz, 2 H), 7.55–
7.33 (m, 6 H), 2.32 (tt, J = 11.1, 3.1 Hz, 1 H), 1.68–1.55 (m, 5 H),
1.37–0.93 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 209.6, 145.7, 140.1, 138.3, 132.2,
130.5, 130.1, 129.5, 128.4, 128.1, 118.7, 111.4, 49.9, 28.9, 25.6,
25.6.
1-[1,1¢-Biphenyl]-2-ylethanone (11a)47
Prepared according to GP 3 from 2-bromoacetophenone (10a)
(198 mg, 1.00 mmol) and phenylmagnesium bromide (1.20 M in
THF, 1.42 mL, 1.70 mmol). The reaction time was 0.25 h at 25 °C.
Purification by flash chromatography on silica gel (pentane–Et2O,
9:1) yielded product 11a.
Yield: 183 mg (94%); colorless oil.
1H NMR (300 MHz, CDCl3): d = 7.56–7.32 (m, 9 H), 2.00 (s, 3 H).
MS (70 eV, EI): m/z (%): 289 (14) [M+], 207 (14), 206 (100), 178
(11).
1-{4¢-(Dimethylamino)[1,1¢-biphenyl]-2-yl}ethanone (11c)
Prepared according to GP 3 from 2-bromoacetophenone (10a)
(199 mg, 1.00 mmol) and [4-(dimethylamino)phenyl]magnesium
bromide (0.62 M in THF, 2.74 mL, 1.70 mmol). The reaction time
was 0.5 h at 25 °C. Purification by flash chromatography on silica
gel (pentane–Et2O, 9:1) yielded product 11c.
HRMS: m/z calcd for C20H19NO: 289.1467; found: 289.1455.
Cyclohexyl[4¢-methoxy(1,1¢-biphenyl)-2-yl]methanone (11i)
Prepared according to GP 3 from (2-bromophenyl)(cyclohex-
yl)methanone (10b) (267 mg, 1.00 mmol) and 4-methoxyphenyl-
magnesium bromide (0.93 M in THF, 1.83 mL, 1.70 mmol).
Reaction time: 1 h at 25 °C. Purification by flash chromatography
on silica gel (pentane–Et2O, 29:1) yielded product 11i.
Yield: 230 mg (96%); yellow oil.
IR (KBr): 2889 (w), 2804 (w), 1683 (s), 1612 (vs), 1527 (s), 1477
(m), 1442 (m), 1356 (s), 1226 (m), 1063 (w), 946 (w), 821 (m), 764
(m), 596 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.51–7.44 (m, 2 H), 7.39–7.30 (m,
2 H), 7.21 (d, J = 8.8 Hz, 2 H), 6.78 (d, J = 8.4 Hz, 2 H), 3.00 (s,
6 H), 2.01 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 205.9, 150.1, 140.8, 140.7, 130.6,
129.9, 129.7, 127.8, 126.4, 40.5, 30.4.
MS (70 eV, EI): m/z (%) = 239 (100) [M+], 238 (51), 224 (28), 222
(12), 152 (13).
Yield: 291 mg (99%); colorless oil.
IR (KBr): 3062 (vw), 1690 (vs), 1462 (s), 1356 (m), 1247 (m), 1134
(m), 1030 (m), 826 (m), 763 (s), 679 (w), 596 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.48–7.41 (m, 1 H), 7.37–7.34 (m,
3 H), 7.25 (d, J = 8.8 Hz, 2 H), 6.94 (d, J = 8.8 Hz, 2 H), 3.84 (s,
3 H), 2.16 (tt, J = 11.1, 3.5 Hz, 1 H), 1.63–1.48 (m, 5 H), 1.29–0.83
(m, 5 H).
13C NMR (75 MHz, CDCl3): d = 212.0, 159.4, 140.7, 139.3, 133.1,
130.0, 129.8, 127.8, 126.8, 114.1, 55.4, 50.1, 28.9, 25.7, 25.6.
HRMS: m/z calcd for C16H17NO: 239.1310; found: 239.1330.
MS (70 eV, EI): m/z (%) = 294 (20) [M+], 212 (16), 211 (100), 168
(10).
1-[3¢,4¢-Dichloro(1,1¢-biphenyl)-2-yl]ethanone (11e)
Prepared according to GP 4 from 2-bromoacetophenone (10a)
(199 mg, 1.00 mmol), 4-bromo-1,2-dichlorobenzene (385 mg,
1.70 mmol) and i-PrMgCl·LiCl (1.30 M in THF, 1.37 mL,
1.79 mmol). The i-PrMgCl·LiCl solution was added at –20 °C and
the Br–Mg exchange was complete after 1 h at 25 °C. The reaction
time for the cross-coupling was 1 h at 25 °C. Purification by flash
chromatography on silica gel (pentane–Et2O, 9:1) yielded product
11e.
HRMS: m/z calcd for C20H22O2: 294.1620; found: 294.1595.
Cyclohexyl[4¢-(dimethylamino)(1,1¢-biphenyl)-2-yl]methanone
(11j)
Prepared according to GP 3 from (2-bromophenyl)(cyclohex-
yl)methanone (10b) (267 mg, 1.00 mmol) and [4-(dimethylami-
no)phenyl]magnesium bromide (0.65 M in THF, 2.62 mL,
1.70 mmol). Reaction time: 0.5 h at 25 °C. Purification by flash
chromatography on silica gel (pentane–Et2O, 9:1) yielded product
11j.
Yiled: 233 mg (88%); colorless oil.
IR (KBr): 2932 (s), 2853 (m), 1688 (s), 1611 (s), 1517 (s), 1475 (m),
1442 (m), 1248 (vs), 1179 (s), 1037 (m), 974 (m), 835 (m), 762 (s),
578 (w) cm–1.
Yield: 299 mg (97%); yellow oil.
IR (KBr): 2930 (s), 2853 (s), 2803 (w), 1686 (s), 1612 (vs), 1527 (s),
1477 (m), 1442 (m), 1356 (m), 1199 (m), 1062 (w), 973 (m), 946
(w), 821 (m), 762 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.46–7.27 (m, 4 H), 7.20 (d,
J = 8.8 Hz, 2 H), 6.76 (d, J = 8.4 Hz, 2 H), 2.98 (s, 6 H), 2.20 (tt,
J = 11.5, 3.1 Hz, 1 H), 1.62–1.45 (m, 5 H), 1.31–0.83 (m, 5 H).
1H NMR (300 MHz, CDCl3): d = 7.59 (dd, J = 7.5, 1.3 Hz, 1 H),
7.54–7.41 (m, 4 H), 7.31 (dd, J = 7.5, 1.3 Hz, 1 H), 7.12 (dd,
J = 8.0, 2.2 Hz, 1 H), 2.18 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 203.2, 140.9, 140.1, 138.1, 132.7,
132.1, 131.0, 130.4, 130.3, 128.2, 128.2, 30.3.
MS (70 eV, EI): m/z (%) = 264 (44) [M+], 252 (11), 251 (63), 250
(14), 249 (100), 214 (13), 188 (20), 186 (63), 151 (17), 150 (16).
13C NMR (75 MHz, CDCl3): d = 212.6, 150.1, 140.4, 139.8, 129.9,
129.6, 129.6, 127.9, 126.2, 50.0, 40.6, 29.0, 25.8, 25.6.
Synthesis 2006, No. 21, 3547–3574 © Thieme Stuttgart · New York

3570
T. J. Korn et al.
PAPER
MS (70 eV, EI): m/z (%): 307 (78) [M+], 225 (17), 224 (100).
HRMS: m/z calcd for C21H25NO: 307.1936; found: 307.1923.
1H NMR (300 MHz, CDCl3): d = 8.47 (d, J = 2.7 Hz, 1 H), 7.93
(dd, J = 8.4, 2.7 Hz, 1 H), 7.70–7.63 (m, 1 H), 7.60–7.52 (m, 4 H),
7.48 (d, J = 7.5 Hz, 1 H), 7.34 (d, J = 8.4 Hz, 2 H), 7.30 (d, J = 8.8
Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 195.1, 155.7, 151.5, 144.4, 139.4,
139.0, 137.3, 132.3, 131.6, 131.4, 130.2, 129.6, 129.2, 128.6, 124.3,
118.3, 111.7.
MS (70 eV, EI): m/z (%) = 318 (89) [M+], 317 (60), 291 (16), 289
(41), 283 (16), 207 (14), 206 (100), 178 (27), 177 (27), 151 (30),
142 (13), 140 (44), 112 (23).
Cyclohexyl(3¢,4¢-dichloro[1,1¢-biphenyl]-2-yl)methanone (11k)
Prepared according to GP 4 from (2-bromophenyl)(cyclohex-
yl)methanone (10b) (267 mg, 1.00 mmol), 4-bromo-1,2-dichlo-
robenzene (384 mg, 1.70 mmol) and i-PrMgCl·LiCl (1.30 M in
THF, 1.37 mL, 1.79 mmol). The i-PrMgCl·LiCl solution was added
at –20 °C and the Br–Mg exchange was complete after 1 h at 25 °C.
The reaction time for the cross-coupling was 1 h at 80 °C. Purifica-
tion by flash chromatography on silica gel (pentane–Et2O, 39:1)
yielded product 11k.
HRMS: m/z calcd for C19H11ClN2O: 318.0560; found: 318.0549.
Yield: 290 mg (87%); colorless solid; mp 56.2–57.9 °C.
(6-Chloro-3-pyridinyl)[3¢,4¢-dichloro(1,1¢-biphenyl)-2-yl]meth-
anone (13d)
IR (KBr): 2930 (m), 2856 (w), 1691 (vs), 1461 (m), 1374 (w), 1311
(w), 1202 (w), 1133 (w), 1030 (w), 972 (m), 888 (w), 824 (w), 758
(m), 695 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.52–7.39 (m, 5 H), 7.34–7.31 (m,
1 H), 7.13 (dd, J = 8.4, 2.2 Hz, 1 H), 2.34 (tt, J = 11.5, 3.5 Hz, 1 H),
1.69–1.54 (m, 5 H), 1.35–0.96 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 210.1, 140.8, 140.2, 137.5, 132.7,
131.9, 130.5, 130.4, 130.4, 130.0, 128.1, 128.0, 50.0, 28.9, 25.7,
25.6.
MS (70 eV, EI): m/z (%) = 332 (9) [M+], 253 (11), 252 (10), 251
(66), 250 (14), 249 (100), 214 (11), 188 (20), 186 (60), 181 (10),
169 (11), 151 (13), 131 (15), 119 (14), 69 (36), 55 (44), 40 (16).
Prepared according to GP 4 from (2-bromophenyl)(6-chloro-3-py-
ridinyl)methanone (12a) (297 mg, 1.00 mmol), 4-bromo-1,2-
dichlorobenzene (374 mg, 1.66 mmol) and i-PrMgCl·LiCl (1.10 M
in THF, 1.62 mL, 1.79 mmol). The i-PrMgCl·LiCl solution was
added at –20 °C and the Br–Mg exchange was complete after 1 h at
25 °C. The reaction time for the cross-coupling was 15 h at 25 °C.
Purification by flash chromatography on silica gel (pentane–Et2O,
6:1) yielded product 13d.
Yield: 216 mg (60%); light-yellow solid; mp 99.6–101.0 °C.
IR (KBr): 3052 (vw), 2965 (vw), 1906 (vw), 1664 (vs), 1578 (vs),
1461 (s), 1375 (m), 1282 (s), 1262 (s), 1101 (vs), 1031 (m), 926
(vs), 828 (m), 762 (s), 521 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.47 (d, J = 2.7 Hz, 1 H), 7.91
(dd, J = 8.4, 2.2 Hz, 1 H), 7.67–7.28 (m, 7 H), 7.04 (dd, J = 8.4,
2.2 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 195.4, 155.6, 151.3, 139.6, 138.9,
138.7, 137.3, 132.8, 132.2, 131.5, 130.7, 130.5, 130.2, 130.1, 129.1,
128.3, 128.2, 124.3.
HRMS: m/z calcd for C19H18Cl2O: 332.0735; found: 332.0724.
(6-Chloro-3-pyridinyl)[3¢,4¢,5¢-trimethoxy(1,1¢-biphenyl)-2-
yl]methanone (13a)
Prepared according to GP 3 from (2-bromophenyl)(6-chloro-3-py-
ridinyl)methanone (12a) (297 mg, 1.00 mmol) and (3,4,5-tri-
methoxyphenyl)magnesium bromide (0.90 M in THF, 1.89 mL,
1.70 mmol). Reaction time: 4 h at 25 °C. Purification by flash chro-
matography on silica gel (pentane–Et2O, 3:1) yielded product 13a.
MS (70 eV, EI): m/z (%) = 361 (100) [M+], 326 (51), 249 (65), 186
(49), 140 (27).
Yield: 230 mg (60%); yellow oil.
HRMS: m/z calcd for C18H10Cl3NO: 360.9828; found: 360.9809.
IR (KBr): 3059 (vw), 3002 (vw), 2938 (w), 2837 (vw), 1666 (s),
1582 (vs), 1456 (s), 1411 (s), 1346 (s), 1293 (m), 1242 (s), 1128
(vs), 1104 (s), 1005 (w), 929 (m), 762 (s), 683 (w) cm–1.
{4¢-(Dimethylamino)[1,1¢-biphenyl]-2-yl}(2-thienyl)methanone
(13e)
Prepared according to GP 3 from (2-bromophenyl)(2-thienyl)meth-
anone (12b) (184 mg, 0.99 mmol) and [4-(dimethylamino)phe-
nyl]magnesium bromide (0.65 M in THF, 2.62 mL, 1.70 mmol).
Reaction time: 1 h at 25 °C. Purification by flash chromatography
on silica gel (pentane–Et2O, 9:1) yielded product 13e.
1H NMR (300 MHz, CDCl3): d = 8.37 (d, J = 1.8 Hz, 1 H), 7.81
(dd, J = 8.4, 2.7 Hz, 1 H), 7.65–7.49 (m, 4 H), 7.17 (dd, J = 8.4 Hz,
1 H), 6.40 (s, 2 H), 3.74 (s, 6 H), 3.72 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 196.5, 154.8, 153.2, 150.9, 141.0,
138.4, 137.8, 137.7, 135.2, 131.8, 131.4, 129.5, 128.9, 127.8, 123.7,
106.8, 60.8, 56.2.
Yield: 246 mg (80%); yellow oil.
IR (KBr): 3084 (vw), 2884 (w), 2801 (w), 1641 (s), 1611 (vs), 1527
(m), 1479 (m), 1441 (m), 1410 (m), 1355 (m), 1291 (m), 1043 (w),
946 (w), 845 (m), 819 (m), 763 (m), 733 (m), 527 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.55–7.45 (m, 4 H), 7.38–7.33 (m,
1 H), 7.26–7.19 (m, 3 H), 6.93 (dd, J = 4.9, 3.5 Hz, 1 H), 6.64 (d,
J = 8.0 Hz, 2 H), 2.90 (s, 6 H).
13C NMR (150 MHz, CDCl3): d = 191.2, 149.7, 144.8, 140.7, 138.5,
135.1, 134.2, 130.2, 129.9, 129.6, 128.3, 128.0, 127.8, 125.9, 112.3,
40.3.
MS (70 eV, EI): m/z (%) = 383 (100) [M+], 368 (25), 340 (5), 282
(4), 140 (5).
HRMS: m/z calcd for C21H18ClNO4: 383.0924; found: 383.0943.
2¢-[(6-Chloro-3-pyridinyl)carbonyl](1,1¢-biphenyl)-4-carboni-
trile (13b)
Prepared according to GP 4 from (2-bromophenyl)(6-chloro-3-py-
ridinyl)methanone (12a) (301 mg, 1.02 mmol), 4-bromobenzoni-
trile (309 mg, 1.70 mmol) and i-PrMgCl·LiCl (0.95 M in THF,
1.88 mL, 1.79 mmol). The i-PrMgCl·LiCl solution was added at
–20 °C and the Br–Mg exchange was complete after 2 h at 0 °C. The
reaction time for the cross-coupling was 5 h at 25 °C. Purification
by flash chromatography on silica gel (pentane–Et2O, 4:1) yielded
product 13b.
MS (70 eV, EI): m/z (%) = 307 (100) [M+], 306 (39).
HRMS: m/z calcd for C19H17NOS: 307.1031; found: 307.1011.
[(1,1¢-Biphenyl)-2-yl](ferrocenyl)methanone (16a)
Prepared according to GP 3 from (2-bromophenyl)(ferroce-
nyl)methanone (14) (369 mg, 1.00 mmol) and phenylmagnesium
chloride (1.65 M in THF, 1.10 mL, 1.82 mmol). Reaction time:
0.5 h at 25 °C. Purification by flash chromatography on silica gel
(pentane–Et2O, 9:1) yielded product 16a.
Yield: 180 mg (56%); colorless solid; mp 129.0–130.7 °C.
IR (KBr): 3069 (vw), 2226 (m), 1669 (vs), 1581 (s), 1458 (w), 1364
(s), 1294 (m), 1103 (s), 930 (m), 850 (m), 772 (m), 568 (w), 521 (w)
cm–1.
Synthesis 2006, No. 21, 3547–3574 © Thieme Stuttgart · New York

PAPER
Cobalt-Catalyzed Cross-Coupling of Aryl Halides with Arylmagnesium and Arylcopper
3571
Yield: 348 mg (95%); dark-red resin.
THF, 1.50 mL, 1.80 mmol). The i-PrMgCl·LiCl solution was added
at –20 °C and the Br–Mg exchange was complete after 1 h at 25 °C.
The reaction time for the cross-coupling was 0.5 h at 25 °C. Purifi-
cation by flash chromatography on silica gel (pentane–Et2O, 9:1)
yielded product 16d.
IR (KBr): 3032 (vw), 3019 (vw), 1636 (s), 1444 (m), 1373 (w),
1288 (s), 1178 (w), 1104 (w), 1027 (w), 1003 (w), 820 (m), 766 (m),
710 (vs), 697 (s), 665 (s) cm–1.
1H NMR (300 MHz, C6D6): d = 7.70 (dd, J = 7.1, 1.3 Hz, 1 H),
7.45–7.42 (m, 2 H), 7.29–7.12 (m, 3 H), 7.05–7.00 (m, 2 H), 6.94–
6.89 (m, 1 H), 4.46 (dd, J = 2.0, 2.0 Hz, 2 H), 3.89 (dd, J = 2.0,
2.0 Hz, 2 H), 3.85 (s, 5 H).
13C NMR (75 MHz, C6D6): d = 201.1, 141.4, 141.0, 140.3, 130.2,
129.7, 129.6, 128.5, 128.4, 127.6, 127.1, 80.3, 72.0, 71.1, 70.2.
MS (70 eV, EI): m/z (%) = 366 (100) [M+], 302 (12), 301 (63), 209
(20).
Yield: 323 mg (74%); dark-red solid; mp 128.2–130.1 °C.
IR (KBr): 1647 (vs), 1558 (w), 1461 (w), 1436 (m), 1374 (w), 1336
(w), 1269 (m), 1135 (w), 1024 (m), 948 (w), 879 (w), 822 (s), 790
(vs), 734 (m), 672 (s) cm–1.
1H NMR (300 MHz, C6D6): d = 7.64–7.61 (m, 1 H), 7.44 (d,
J = 2.2 Hz, 1 H), 7.16–7.11 (m, 2 H), 7.00–6.95 (m, 2 H), 6.86 (d,
J = 8.4 Hz, 1 H), 4.38 (dd, J = 2.0, 2.0 Hz, 2 H), 3.90 (dd, J = 2.0,
2.0 Hz, 2 H), 3.83 (s, 5 H).
13C NMR (75 MHz, C6D6): d = 200.5, 141.1, 140.9, 137.8, 132.6,
132.0, 131.1, 130.3, 130.0, 129.8, 129.1, 128.5, 128.1, 79.9, 72.3,
71.1, 70.2.
HRMS: m/z calcd for C23H18FeO: 366.0707; found: 366.0715.
[4¢-Methoxy(1,1¢-biphenyl)-2-yl](ferrocenyl)methanone (16b)
Prepared according to GP 3 from (2-bromophenyl)(ferroce-
nyl)methanone (14) (369 mg, 1.00 mmol) and 4-methoxyphenyl-
magnesium bromide (0.80 M in THF, 2.25 mL, 1.80 mmol).
Reaction time: 3 h at 25 °C. Purification by flash chromatography
on silica gel (pentane–Et2O, 7:1) yielded product 16b.
MS (70 eV, EI): m/z (%) = 434 (100) [M+], 371 (13), 369 (19), 215
(26), 213 (20), 151 (12).
HRMS: m/z calcd for C23H16FeCl2O: 433.9928; found: 433.9912.
Yield: 325 mg (82%); dark-red solid; mp 106.2–108.1 °C.
1-Benzoyl-2-phenylferrocene (17)
A 25-mL Schlenk flask, equipped with a magnetic stirring bar and
a septum, was charged with phenylmagnesium chloride (1.44 M in
THF, 1.04 mL, 1.50 mmol), cooled to –20 °C and a solution of
CuCN·2LiCl (1.00 M in THF, 1.60 mL, 1.60 mmol) was added. Af-
ter stirring for 10 min at –20 °C, DME (6.0 mL), DMPU (2.0 mL),
Bu4NI (185 mg, 0.50 mmol), 4-fluorostyrene (13.0 mg, 0.10 mmol),
Co(acac)2 (12.8 mg, 0.050 mmol) and 2-benzoyl-1-bromoferrocene
(15) (0.50 M in THF, 1.00 mL, 0.50 mmol) were added. The reac-
tion mixture was stirred at r.t. for 2 h. After full conversion (checked
by GC analysis), the suspension was quenched with sat. aq NH4Cl–
NH3 (9:1, 50 mL). The organic fraction was washed a second time
with sat. aq NH4Cl–NH3 (9:1, 50 mL) and the combined aqueous
phases were extracted with EtOAc (3 × 40 mL). The organic frac-
tions were washed with brine (50 mL), dried over Mg2SO4, filtered
and the solvent was evaporated in vacuo. Purification by flash chro-
matography on silica gel (pentane–Et2O, 20:1) yielded product 17.
IR (KBr): 3109 (vw), 2934 (vw), 2840 (vw), 1632 (m), 1516 (w),
1454 (m), 1375 (w), 1290 (m), 1247 (m), 1182 (m), 1103 (m), 1026
(m), 825 (m), 765 (s), 703 (m), 660 (w), 518 (vs) cm–1.
1H NMR (300 MHz, C6D6): d = 7.72 (dd, J = 7.5, 1.8 Hz, 1 H), 7.38
(d, J = 8.9 Hz, 2 H), 7.33–7.13 (m, 3 H), 6.64 (d, J = 8.9 Hz, 2 H),
4.50 (dd, J = 2.0, 2.0 Hz, 2 H), 3.91 (dd, J = 2.0, 2.0 Hz, 2 H), 3.88
(s, 5 H), 3.11 (s, 3 H).
13C NMR (75 MHz, C6D6): d = 201.4, 159.6, 141.3, 140.0, 133.3,
130.7, 130.1, 129.7, 128.4, 126.6, 114.1, 80.3, 72.0, 71.1, 70.2,
54.5.
MS (70 eV, EI): m/z (%) = 396 (100) [M+], 332 (13), 331 (57), 288
(14).
HRMS: m/z calcd for C24H20FeO2: 396.0813; found: 396.0809.
2¢-[(Ferrocenyl)carbonyl](1,1¢-biphenyl)-4-carbonitrile (16c)
Prepared according to GP 4 from (2-bromophenyl)(ferroce-
nyl)methanone (14) (369 mg, 1.00 mmol), 4-bromobenzonitrile
(309 mg, 1.70 mmol) and i-PrMgCl·LiCl (1.20 M in THF, 1.50 mL,
1.80 mmol). The i-PrMgCl·LiCl solution was added at –20 °C and
the Br–Mg exchange was complete after 2 h at 0 °C. The reaction
time for the cross-coupling was 2 h at 25 °C. Purification by flash
chromatography on silica gel (pentane–Et2O, 4:1) yielded product
16c.
Yield: 126 mg (69%); dark-red solid; mp 121.0–122.0 °C
IR (KBr): 3929 (w), 3026 (m), 2925 (m), 1645 (s), 1410 (s), 1247
(s), 763 (s), 698 (s) cm–1.
1H NMR (300 MHz, C6D6): d = 8.08–7.98 (m, 2 H), 7.70–7.64 (m,
2 H), 7.24–7.04 (m, 6 H), 4.65–459 (m, 2 H), 4.24 (t, J = 2.7, 1 H),
4.15 (s, 5 H).
13C NMR (75 MHz, C6D6): d = 197.6, 140.3, 138.5, 132.3, 130.3,
129.8, 128.5, 128.3, 127.2, 91.6, 89.4, 81.5, 73.5, 72.8, 72.8, 69.8.
Yield: 247 mg (63%); dark-red solid; mp 214.5–215.9 °C.
MS (70 eV, EI): m/z (%) = 366 (100) [M+], 367 (30), 215 (19), 202
(9).
IR (KBr): 3731 (vw), 2968 (vw), 2220 (m), 1738 (m), 1634 (w),
1436 (w), 1374 (m), 1288 (w), 1217 (m), 852 (w), 829 (w), 766 (m),
668 (vs) cm–1.
HRMS: m/z calcd for C23H18FeO: 366.0702; found: 366.0697.
1H NMR (300 MHz, C6D6): d = 7.67–7.64 (m, 1 H), 7.16–6.96 (m,
5 H), 6.88 (d, J = 8.4 Hz, 2 H), 4.37 (dd, J = 2.0, 2.0 Hz, 2 H), 3.92
(dd, J = 2.0, 2.0 Hz, 2 H), 3.84 (s, 5 H).
13C NMR (75 MHz, C6D6): d = 200.4, 144.8, 141.1, 138.6, 131.9,
130.0, 129.9, 129.8, 128.6, 128.1, 118.5, 109.9, 79.9, 72.3, 71.1,
70.3.
[5-Bromo(1,1¢-biphenyl)-2-yl](phenyl)methanone (19a)
Prepared according to GP 3 from (2,4-dibromophenyl)(phe-
nyl)methanone (18) (340 mg, 1.00 mmol) and phenylmagnesium
chloride (1.60 M in THF, 1.06 mL, 1.70 mmol). Reaction time: 3 h
at 25 °C. Purification by flash chromatography on silica gel (pen-
tane–Et2O, 59:1) yielded product 19a.
MS (70 eV, EI): m/z (%) = 391 (100) [M+], 326 (24), 234 (12).
Yield: 285 mg (85%); colorless oil.
IR (KBr): 3060 (w), 1667 (vs), 1582 (s), 1550 (m), 1447 (m), 1385
(w), 1280 (vs), 1150 (m), 1082 (m), 927 (s), 829 (m), 771 (m), 741
(m), 697 (vs), 594 (w), 533 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.64–7.58 (m, 4 H), 7.43–7.37 (m,
2 H), 7.29–7.15 (m, 7 H).
HRMS: m/z calcd for C24H17FeNO: 391.0660; found: 391.0669.
[3¢,4¢-Dichloro(1,1¢-biphenyl)-2-yl](ferrocenyl)methanone (16d)
Prepared according to GP 4 from (2-bromophenyl)(ferroce-
nyl)methanone (14) (369 mg, 1.00 mmol), 4-bromo-1,2-dichlo-
robenzene (384 mg, 1.70 mmol) and i-PrMgCl·LiCl (1.20 M in
Synthesis 2006, No. 21, 3547–3574 © Thieme Stuttgart · New York

3572
T. J. Korn et al.
PAPER
13C NMR (75 MHz, CDCl3): d = 197.7, 143.1, 138.7, 137.7, 137.0,
IR (KBr): 3056 (vw), 2891 (vw), 2808 (vw), 1662 (m), 1597 (vs),
1529 (s), 1446 (m), 1360 (m), 1283 (m), 1205 (w), 928 (w), 815 (m),
699 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.70–7.54 (m, 7 H), 7.42–7.37 (m,
1 H), 7.32–7.14 (m, 7 H), 6.84 (d, J = 8.4 Hz, 2 H), 3.02 (s, 6 H).
133.0, 132.9, 130.3, 130.1, 129.8, 128.8, 128.4, 128.1, 127.9, 124.6.
MS (70 eV, EI): m/z (%): 336 (100) [M+], 335 (81), 261 (62), 259
(63), 257 (56), 228 (20), 180 (56), 152 (87), 151 (24), 128 (30), 105
(86), 77 (55).
HRMS: m/z calcd for C19H13BrO: 336.0150; found: 336.0124.
13C NMR (75 MHz, CDCl3): d = 198.6, 150.1, 143.3, 141.9, 140.6,
137.8, 136.4, 132.6, 132.5, 129.9, 129.7, 129.0, 128.2, 128.0, 127.9,
127.8, 127.2, 124.5, 112.8, 40.6.
2¢-Benzoyl-5¢-bromo(1,1¢-biphenyl)-4-carbonitrile (19b)
Prepared according to GP 4 from (2,4-dibromophenyl)(phe-
nyl)methanone (18) (680 mg, 2.00 mmol), 4-bromobenzonitrile
(616 mg, 3.40 mmol) and i-PrMgCl·LiCl (1.30 M in THF, 2.75 mL,
3.57 mmol). The i-PrMgCl·LiCl solution was added at –20 °C and
the Br–Mg exchange was complete after 2 h at 0 °C. The reaction
time for the cross-coupling was 3 h at 80 °C. Purification by flash
chromatography on silica gel (pentane–Et2O, 6:1) yielded product
19b.
MS (70 eV, EI): m/z (%) = 377 (100) [M+], 376 (12), 300 (13).
HRMS: m/z calcd for C27H23NO: 377.1780; found: 377.1772.
4¢-Benzoyl-4-methoxy[1,1¢;3¢,1¢¢]terphenyl-4¢¢-carbonitrile (20c)
Prepared according to GP 3 from 2¢-benzoyl-5¢-bromo(1,1¢-biphe-
nyl)-4-carbonitrile (19a) (104 mg, 0.29 mmol) and 4-methoxyphe-
nylmagnesium chloride (0.93 M in THF, 0.53 mL, 0.49 mmol).
Reaction time: 19 h at 80 °C. Purification by flash chromatography
on silica gel (pentane–Et2O, 6:1) yielded product 20c.
Yield: 369 mg (51%); colorless solid; mp 110.2–112.8 °C.
IR (KBr): 3058 (vw), 2228 (m), 1664 (vs), 1582 (s), 1448 (m), 1278
(s), 1151 (w), 1082 (w), 1029 (w), 926 (s), 841 (m), 703 (s), 561 (m)
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.67–7.60 (m, 4 H), 7.53–7.45 (m,
3 H), 7.42 (d, J = 8.4 Hz, 1 H), 7.36–7.30 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 196.8, 143.5, 141.3, 137.6, 136.8,
133.6, 132.9, 132.1, 131.2, 130.7, 129.8, 129.5, 128.5, 125.0, 118.4,
111.8.
Yield: 51 mg (45%); light-yellow solid; mp 150.4–151.6 °C.
IR (KBr): 3064 (vw), 2937 (vw), 2226 (m), 1660 (vs), 1599 (s),
1519 (s), 1447 (w), 1382 (s), 1255 (s), 1182 (m), 1036 (w), 927 (w),
824 (m), 704 (m), 567 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.71–7.31 (m, 14 H), 7.02 (d,
J = 8.9 Hz, 2 H), 3.87 (s, 3 H).
13C NMR (150 MHz, CDCl3): d = 197.6, 160.0, 145.2, 143.4, 140.3,
137.3, 136.8, 133.2, 132.0, 131.9, 130.1, 129.9, 129.7, 128.4, 128.3,
128.3, 126.1, 118.7, 114.5, 111.2, 55.4.
MS (70 eV, EI): m/z (%) = 361 (65) [M+], 360 (24), 286 (56), 284
(56), 282 (53), 205 (24), 177 (60), 141 (27), 105 (100), 77 (46).
MS (70 eV, EI): m/z (%) = 389 (100) [M+], 388 (10), 313 (13), 312
(56), 105 (14).
HRMS: m/z calcd for C20H12BrNO: 361.0102; found: 361.0068.
HRMS: m/z calcd for C27H19NO2: 389.1416; found: 389.1378.
(4-Methoxy-[1,1¢;3¢,1¢¢]terphenyl-4¢-yl)phenylmethanone (20a)
Prepared according to GP 3 from [5-bromo(1,1¢-biphenyl)-2-
yl](phenyl)methanone (19a) (1.00 M in THF, 1.00 mL, 1.00 mmol)
and 4-methoxyphenylmagnesium chloride (0.80 M in THF,
2.13 mL, 1.70 mmol). Reaction time: 5 h at 80 °C. Purification by
flash chromatography on silica gel (pentane–Et2O, 9:1) yielded
product 20a.
[3¢,4¢-Dichloro(1,1¢-biphenyl)-2-yl](2-furyl)methanone (22d)
Prepared according to GP 4 from (2-chlorophenyl)(2-furyl)metha-
none (21b) (206 mg, 1.00 mmol), 4-bromo-1,2-dichlorobenzene
(384 mg, 1.70 mmol) and i-PrMgCl·LiCl (1.10 M in THF, 1.62 mL,
1.79 mmol). The i-PrMgCl·LiCl solution was added at –20 °C and
the Br–Mg exchange was complete after 1 h at 25 °C. The reaction
time for the cross-coupling was 0.5 h at 25 °C. Purification by flash
chromatography on silica gel (pentane–Et2O, 9:1) yielded product
22d.
Yield: 174 mg (48%); colorless solid; mp 130.0–132.8 °C.
IR (KBr): 3055 (w), 2938 (vw), 2840 (vw), 1659 (vs), 1602 (s),
1518 (m), 1450 (w), 1284 (s), 1247 (s), 1178 (m), 1026 (m), 928
(m), 824 (s), 745 (w), 699 (vs) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.71–7.57 (m, 7 H), 7.44–7.38
(m, 1 H), 7.34–7.14 (m, 7 H), 7.02 (d, J = 8.8 Hz, 2 H), 3.86 (s,
3 H).
13C NMR (75 MHz, CDCl3): d = 198.5, 159.7, 142.8, 141.9, 140.3,
137.5, 137.0, 132.7, 132.4, 129.8, 129.6, 129.0, 128.3, 128.3, 128.2,
128.0, 127.3, 125.1, 114.4, 55.3.
Yield: 223 mg (70%); light-orange solid; mp 99.4–100.9 °C.
IR (KBr): 3118 (vw), 1650 (vs), 1596 (w), 1564 (m), 1461 (vs),
1376 (w), 1305 (m), 1132 (w), 1018 (m), 880 (m), 763 (s), 695 (w)
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.61–7.40 (m, 5 H), 7.32 (d,
J = 8.4 Hz, 2 H), 7.10 (dd, J = 8.4, 2.2 Hz, 1 H), 6.91 (dd, J = 3.5,
0.9 Hz, 1 H), 6.42 (dd, J = 3.5, 1.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 184.7, 152.4, 147.4, 140.2, 138.7,
137.7, 132.4, 131.7, 130.9, 130.5, 130.2, 130.1, 128.9, 128.2, 127.8,
120.7, 112.4.
MS (70 eV, EI): m/z (%) = 364 (100) [M+], 363 (35), 288 (13), 287
(64), 215 (12).
HRMS: m/z calcd for C26H20O2: 364.1463; found: 364.1439.
MS (70 eV, EI): m/z (%) = 316 (100) [M+], 299 (24), 287 (22), 252
(42), 218 (32), 186 (42), 141 (22).
(4-Dimethylamino[1,1¢;3¢,1¢¢]terphenyl-4¢-yl)phenylmethanone
(20b)
HRMS: m/z calcd for C17H10Cl2O2: 316.0058; found: 316.0050.
Prepared according to GP 3 from [5-bromo(1,1¢-biphenyl)-2-
yl](phenyl)methanone (19a) (1.00 M in THF, 1.00 mL, 1.00 mmol)
and [4-(dimethylamino)phenyl]magnesium bromide (0.62 M in
THF, 2.74 mL, 1.70 mmol). Reaction time: 0.25 h at 80 °C. Purifi-
cation by flash chromatography on silica gel (pentane–Et2O, 19:1)
yielded product 20b.
[4¢-Fluoro(1,1¢-biphenyl)-2-yl](2-furyl)methanone (22e)
Prepared according to GP 4 from (2-chlorophenyl)(2-furyl)metha-
none (21b) (206 mg, 1.00 mmol), 1-bromo-4-fluorobenzene
(298 mg, 1.70 mmol) and i-PrMgCl·LiCl (1.20 M in THF, 1.49 mL,
1.79 mmol). The i-PrMgCl·LiCl solution was added at –20 °C and
the Br–Mg exchange was complete after 3 h at 25 °C. The reaction
time for the cross-coupling was 1 h at 25 °C. Purification by flash
Yield: 166 mg (44%); yellow solid; mp 123.4–124.4 °C.
Synthesis 2006, No. 21, 3547–3574 © Thieme Stuttgart · New York

PAPER
Cobalt-Catalyzed Cross-Coupling of Aryl Halides with Arylmagnesium and Arylcopper
3573
chromatography on silica gel (pentane–Et2O, 9:1) yielded product
(4) (a) Tamura, M.; Kochi, J. K. J. Am. Chem. Soc. 1971, 93,
22e.
1487. (b) Tamura, M.; Kochi, J. K. Synthesis 1971, 93, 303.
(c) Kochi, J. K. Acc. Chem. Res. 1974, 7, 351.
Yield: 142 mg, 53%; colorless oil.
(d) Neumann, S.; Kochi, J. K. J. Org. Chem. 1975, 40, 599.
(e) Smith, R. S.; Kochi, J. K. J. Org. Chem. 1976, 41, 502.
(5) (a) Cahiez, G.; Marquais, S. Pure Appl. Chem. 1996, 68,
669. (b) Cahiez, G.; Marquais, S. Tetrahedron Lett. 1996,
37, 1773. (c) Cahiez, G.; Avedissian, H. Synthesis 1998,
1199. (d) Cahiez, G.; Chaboche, C.; Mahuteau-Betzer, F.;
Ahr, M. Org. Lett. 2005, 7, 1943.
IR (KBr): 4009 (vw), 3132 (w), 3065 (w), 2926 (vw), 2852 (vw),
1897 (vw), 1762 (w), 1652 (vs), 1564 (s), 1514 (vs), 1443 (vs), 1392
(s), 1307 (s), 1224 (vs), 1022 (s), 839 (s), 763 (vs) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.59–7.53 (m, 2 H), 7.47–7.42 (m,
3 H), 7.30–7.23 (m, 2 H), 6.99–6.91 (m, 2 H), 6.82 (dd, J = 3.5,
0.9 Hz, 1 H), 6.36 (dd, J = 3.5, 1.3 Hz, 1 H).
(6) (a) Fürstner, A.; Leitner, A.; Méndez, M.; Krause, H. J. Am.
Chem. Soc. 2002, 124, 13856. (b) Fürstner, A.; Leitner, A.
Angew. Chem. Int. Ed. 2002, 41, 609. (c) Fürstner, A.;
Leitner, A. Angew. Chem. Int. Ed. 2003, 42, 308.
(d) Scheiper, B.; Bonnekessel, M.; Krause, H.; Fürstner, A.
J. Org. Chem. 2004, 69, 3943. (e) Martin, R.; Fürstner, A.
Angew. Chem. Int. Ed. 2004, 43, 3955. (f) Fürstner, A.;
Martin, R.; Majima, K. J. Am. Chem. Soc. 2005, 127, 12236.
(7) (a) Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem.
Soc. 2001, 122, 978. (b) Nakamura, M.; Matsuo, K.; Ito, S.;
Nakamura, E. J. Am. Chem. Soc. 2004, 126, 3686.
(c) Nakamura, M.; Ito, S.; Matsuo, K.; Nakamura, E. Synlett
2005, 1794.
(8) (a) Nagano, T.; Hayashi, T. Org. Lett. 2004, 6, 1297.
(b) Nagano, T.; Hayashi, T. Org. Lett. 2005, 7, 491.
(9) (a) Bedford, R. B.; Bruce, D. W.; Frost, R. M.; Goodby, J.
W.; Hird, M. Chem. Commun. 2004, 2822. (b) Bedford, R.
B.; Bruce, D. W.; Frost, R. M.; Hird, M. Chem. Commun.
2005, 4161.
13C NMR (75 MHz, CDCl3): d = 185.4, 162.2 (q, J = 246.9 Hz),
152.5, 147.1, 140.0, 137.9, 136.2 (q, J = 3.2 Hz), 130.7, 130.4 (q,
J = 8.1 Hz), 130.1, 128.7, 127.2, 120.5, 115.3 (q, J = 21.6 Hz),
112.2.
MS (70 eV, EI): m/z (%) = 266 (100) [M+], 249 (34), 237 (42), 221
(20), 209 (27), 199 (15), 170 (32).
HRMS: m/z calcd for C17H11FO2: 266.0743; found: 266.0744.
Prepared according to GP 5 from dimethyl 5-{[(4-methylphe-
nyl)sulfonyl]oxy}isophthalate (27c) (372 mg, 1.02 mmol) and phe-
nylmagnesium chloride (1.60 M in THF, 1.88 mL, 3.00 mmol).
Reaction time: 2 h at 80 °C. Purification by flash chromatography
on silica gel (pentane–Et2O, 9:1) yielded product 28g.
Yield: 66 mg (24%); colorless solid; mp 90.9–92.4 °C.
IR (KBr): 2952 (vw) 1716 (s), 1428 (m), 1336 (m), 1237 (vs), 1128
(w), 1072 (w), 993 (m), 7.40 (vs), 696 (s) cm–1.
(10) (a) For a review on iron-catalyzed reactions, see: Bolm, C.;
Legros, J.; Le Paih, J.; Zani, L. Chem. Rev. 2004, 104, 6217.
(b) Molander, G.; Rahn, B.; Shubert, D. C.; Bonde, S. E.
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Cahiez, G.; Knochel, P. Synlett 2001, 1901. (d) Hojo, M.;
Murakami, Y.; Aihara, H.; Sakuragi, R.; Baba, Y.; Hosomi,
A. Angew. Chem. Int. Ed. 2001, 40, 621. (e) Fakhfakh, M.
A.; Franck, X.; Hocquemiller, R.; Figadère, B. J.
Organomet. Chem. 2001, 624, 131. (f) Hölzer, B.;
Hoffmann, R. W. Chem. Commun. 2003, 732.
1H NMR (300 MHz, CDCl3): d = 8.64 (t, J = 1.3 Hz, 1 H), 7.45 (d,
J = 1.8 Hz, 2 H), 7.66–7.62 (m, 2 H), 7.50–7.36 (m, 3 H), 3.96 (s,
6 H).
13C NMR (75 MHz, CDCl3): d = 166.2, 141.9, 139.0, 132.2, 131.1,
129.3, 129.0, 128.2, 127.1, 52.4.
MS (70 eV, EI): m/z (%) = 270 (100) [M+], 240 (16), 239 (89), 211
(23), 196 (19), 152 (21), 151 (10).
HRMS: m/z calcd for C16H14O4: 270.0892; found: 270.0906.
(g) Shinokubo, H.; Oshima, K. Eur. J. Org. Chem. 2004,
2081.
Acknowledgment
(11) Sapountzis, I.; Lin, W.; Kofink, C. C.; Despotopoulou, C.;
Knochel, P. Angew. Chem. Int. Ed. 2005, 44, 1654.
(12) (a) Kharasch, M. S.; Fuchs, C. F. J. Am. Chem. Soc. 1943,
65, 504. (b) Kharasch, M. S.; Fuchs, C. F. J. Org. Chem.
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(14) (a) For a review, see: Shinokubo, H.; Oshima, K. Eur. J.
Org. Chem. 2004, 2081. (b) Fujioka, T.; Nakamura, T.;
Yorimitsu, H.; Oshima, K. Org. Lett. 2002, 4, 2257.
(c) Tsuji, T.; Yorimitsu, H.; Oshima, K. Angew. Chem. Int.
Ed. 2002, 41, 4137. (d) Wakabayashi, K.; Yorimitsu, H.;
Oshima, K. J. Am. Chem. Soc. 2001, 123, 5374.
We thank the Fonds der Chemischen Industrie, the Deutsche For-
schungs-gemeinschaft (DFG) and Merck Research Laboratories
(MSD) for financial support. T.J.K. thanks the DFG and CNRS for
a fellowship (KN 347/5-2). We also thank Chemetall GmbH
(Frankfurt), Degussa AG (Hanau) and BASF AG (Ludwigshafen)
for the generous gift of chemicals.
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Synthesis 2006, No. 21, 3547–3574 © Thieme Stuttgart · New York