New Cobalt-Catalyzed Cross-Coupling Reactions of Heterocyclic Chlorides with Aryl and Heteroaryl Magnesium Halides

Article abstract of DOI:10.1055/s-2003-41460

New cobalt-catalyzed cross-coupling between arylmagnesium halides and 2-chloropyridines and related heterocycles occur at low temperature leading to 2-arylated heterocycles in good yields.

Full text of DOI:10.1055/s-2003-41460

1892
LETTER
New Cobalt-Catalyzed Cross-Coupling Reactions of Heterocyclic Chlorides
with Aryl and Heteroaryl Magnesium Halides
New
C
obalt-C
a
o
b
s-Coupling R
i
eaction
a
s
s J. Korn,a Gérard Cahiez,b Paul Knochel*a
a
Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, 81377 München, Germany
Fax +49(89)218077680; E-mail: Paul.Knochel@cup.uni-muenchen.de
b
Département de Chimie, ESCOM, 13, Boulevard de l’Hautil, 95092 Cergy-Pontoise, France
Fax +33(1)34257071; E-mail: Gerard.Cahiez@chim.u-cergy.fr
Received 7 July 2003
using CoBr2 or CoI2 as catalysts (5 mol%) in ether are fast
at –40 °C leading to the desired product 3a in 76–80%
yield. A somewhat slower reaction is obtained with CoCl2
(5 h at –40 °C), but the GC-analysis of the crude reaction
mixture indicated a cleaner reaction and a higher yield of
84% of 2-phenylquinoline (3a) was isolated (entry 1 of
Table 1). Similarly, p-tolylmagnesium bromide reacts
with 1a at –20 °C (34 h) to furnish the corresponding
quinoline 3b in 76% yield (entry 2). The use of an aryl-
magnesium reagent bearing a methoxy group in ortho-po-
sition leads to a sharp rate decrease and complete
conversion is observed only at room temperature after 12
hours reaction time (entry 3). Interestingly, the presence
of a functional group like an ester10 in the arylmagnesium
halide is well tolerated and the Co-catalyzed cross-cou-
pling proceeds well at –20 °C within 2 hours leading to
the product 3d in 74% yield. Heterocyclic Grignard re-
agents react well and for example 2-thienylmagnesium
chloride reacts at –20 °C (4 h) and provides the expected
product 3e in satisfactory yield (82%; see entry 5). A
higher reactivity is observed with 1-chloro-isoquinoline
(1b). In this case, PhMgCl undergoes the cross-coupling
reaction at –40 °C within 2 hours and leads to the product
3f in 91% yield (entry 6). Similarly, para-substituted aryl-
magnesium species react in satisfactory yields (74–84%;
entries 7 and 8). Interestingly, the sterically hindered mes-
itylmagnesium bromide undergoes the cross-coupling re-
action at –40 °C within 48 hours leading to the sterically
hindered product 3i in 85% yield (entry 9). Finally, 2-
chloropyridines 1c and 1d react in a satisfactory way (en-
tries 10–13), although lower yields are obtained compared
to the quinoline and isoquinoline systems. The more elec-
tron-rich pyridine, 2-chloro-6-methoxypyridine (1d) is
less prone to undergo the cross-coupling reaction and the
desired cross-coupling product 3m is obtained only in
40% yield after 39 hours reaction time at room tempera-
ture (compare entries 1, 6, 10, and 13). In order to eluci-
date the mechanism of this cobalt cross-coupling reaction,
we have attempted to use several reduced cobalt species to
initiate the cross-coupling. We have found that cobalt
powder11 is an excellent catalyst-source for the cross-cou-
pling reaction although the reaction of 2-chloro-quinoline
(1a) with PhMgCl proceeds only at room temperature in
diethyl ether. An excellent yield of 1-phenyl-quinoline
(3a; 88%) is obtained within 4 hours reaction time. By
using iron powder12 (5 mol%) instead, a yield of 86% is
Abstract: New cobalt-catalyzed cross-coupling between arylmag-
nesium halides and 2-chloropyridines and related heterocycles oc-
cur at low temperature leading to 2-arylated heterocycles in good
yields.
Key words: cobalt-catalysis, cross-coupling, organomagnesium
reagents, arylation, heterocycles
The performance of transition metal catalyzed cross-cou-
pling reactions between Csp2-centers is a very active field
of research since it allows the preparation of a range of
polyfunctional heterocycles which are of interest for phar-
maceutical and agrochemical purposes.1 Cross-coupling
reactions using chloro-substituted heterocycles as sub-
strates are especially important, since many of these com-
pounds are readily prepared or commercially available.2
Most transition metal cross-coupling reactions have been
performed using Pd- or Ni-catalysis which give excellent
results, but require the use of expensive catalysts1,3 or
toxic nickel salts.4 Recently, a number of iron-5,6 and
cobalt-7,8 catalyzed cross-coupling reactions have been
reported. Herein, we wish to report our results on a new
cobalt-catalyzed cross-coupling reaction between chloro-
substituted heterocycles of type 1 and arylmagnesium
reagents 2 leading to the cross-coupling products 3 under
remarkably mild reaction conditions (Scheme 1 and
Table 1).9
CoCl2 (5 mol %)
ArMgX
Et2O, –40 °C,
N
Cl
N
Ar
1–96 h
1
2
3
Scheme 1
Preliminary experiments show that among various sol-
vents like THF, DME, toluene or diethyl ether, the use of
diethyl ether gives the best results. The choice of the co-
balt(II) salt as catalyst was also important. Using the reac-
tion of 2-chloroquinoline (1a) with PhMgCl as a test
reaction, we have found that the cross-coupling reaction
SYNLETT 2003, No. 12, pp 1892–1894
2
9
.0
9
.2
0
0
3
Advanced online publication: 19.09.2003
DOI: 10.1055/s-2003-41460; Art ID: G16003ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
New Cobalt-Catalyzed Cross-Coupling Reactions
1893
Table 1 Cobalt(II)-catalyzed Cross-coupling between 2-Halogenoheterocycles and Arylmagnesium Halides in Diethyl Ether
Entry
1
Chloro-heterocycle
ArMgX (Ar)
Ph
Conditions (°C, h)
–40, 5
Product of type 3
Yield (%)a
84
3a: R = Ph
1a
1a
2
3
4
4-MeC6H4
–20, 34
r.t., 12
–20, 2
3b: R = 4-MeC6H4
76
57
74
1a
1a
1a
2-MeOC6H4
4-PivOC6H4
3c: R = 2-MeOC6H4
3d: R = 4-PivOC6H4
3e: R = 2-thienyl
5
6
2-thienyl
Ph
–20, 4
–40, 2
82
91
1b
1b
3f: R = Ph
7
8
4-MeC6H4
r.t., 12
3g: R = 4-MeC6H4
74
84
1b
1b
4-MeOC6H4
–40, 12
3h: R = 4-MeOC6H4
3i: R = mesityl
9
mesityl
Ph
–40, 48
–40, 12
85
75
10
3f: R = Ph
1c
1c
11
4-MeOC6H4
–40, 72
3k: 4-MeOC6H4
55
12
13
1c
mesityl
Ph
r.t., 96
r.t., 39
3l: mesityl
51
40
1d
3f: R = Ph
a Isolated yields of analytically pure product.
Typical Procedure: Preparation of 2-phenylquinoline (3a).
2-Chloroquinoline (1a, 223 mg; 1.36 mmol) and anhydrous co-
balt(II) chloride (10 mg, 0.08 mmol) were charged in a dry, nitrogen
flushed 25 mL flask equipped with a rubber septum and a magnetic
stirring bar. Dry Et2O (3 mL) was added and the solution was
cooled to –40 °C. The Grignard reagent PhMgCl (1.6 mL, 1.86 M
in THF, 2.98 mmol) was added slowly and the reaction mixture was
stirred at this temperature until the cross-coupling reaction was
complete (5 h, checked by GC-analysis of reaction aliquots). The
reaction mixture was then quenched with EtOH (2 mL) and filtered
through a pad of silicagel. The silicagel was washed with 350 mL
Et2O and the solvent was concentrated in vacuo. The residue was
purified by flash column chromatography using 13:1 pentane/Et2O
as eluent affording product 3a (235 mg, 1.14 mmol, 84%) as a
colorless solid (mp = 82–84 °C).
obtained, but after a reaction time of 12 hours. A similar
behaviour is observed for 1-chloroisoquinoline (1b);
Scheme 2.
metal powder (5 mol %)
PhMgCl
Et2O, r.t., 4–12 h
N
Cl
N
Ph
3a
metal = cobalt: 88 %
metal = iron: 86 %
cobalt powder (5 mol %)
Et2O, r.t., 1 h
PhMgCl
N
N
Cl
Ph
3f: 91 %
Preparation of 2,2-dimethyl-propanoic acid 4-(2-quinoli-
nyl)phenyl ester (3d).
Scheme 2
2,2-Dimethyl-propanoic acid 4-iodophenyl ester (610 mg, 2.0 mmol)
In summary, we have reported a new cobalt(II) chloride was charged in a dry, nitrogen flushed 25 mL flask equipped with a
rubber septum and a magnetic stirring bar. Dry Et2O (4 mL) was
added and the solution was cooled to –20 °C. Then i-PrMgCl (2.4
mL, 0.95 M in THF, 2.28 mmol) was added slowly and the reac-
tion mixture was stirred at this temperature until the exchange reac-
catalyzed cross-coupling reaction of heteroaryl chlorides
with arylmagnesium reagents. Due to the low cost of co-
balt compared to palladium or even nickel, this cross-cou-
pling reaction may find practical applications. The
reaction scope as well as the mechanism of the cross-cou-
pling reaction is currently studied in our laboratories.
tion was complete (1 h, checked by GC-analysis of reaction
aliquots). 2-Chloroquinoline (1a, 135 mg, 0.83 mmol) and anhy-
drous cobalt(II) chloride (6 mg, 0.05 mmol) were added and the re-
sulting suspension was stirred at –20 °C until the cross-coupling
Synlett 2003, No. 12, 1892–1894 © Thieme Stuttgart · New York

1894
T. J. Korn et al.
LETTER
reaction was complete (2 h, checked by GC-analysis of reaction
aliquots). The reaction mixture was then quenched with EtOH (2
mL) and filtered through a pad of silicagel. The silicagel was
washed with 350 mL Et2O and the solvent was concentrated in vac-
uo. The residue was purified by flash column chromatography using
7:1 pentane/Et2O as eluent affording product 3d (187 mg, 0.61
mmol, 74%) as a colorless solid (mp = 107–109 °C).
(5) (a) Fürstner, A.; Leitner, A.; Méndez, M.; Krause, H. J. Am.
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Acknowledgment
We thank the Fonds der Chemischen Industrie for generous finan-
cial support. We thank the DFG and CNRS for supporting this rese-
arch program (financial support to T. K.). We thank BASF AG
(Ludwigshafen), Degussa AG (Hanau) and Chemetall GmbH
(Frankfurt) for the generous gift of chemicals.
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Synlett 2003, No. 12, 1892–1894 © Thieme Stuttgart · New York