2,2′-bipyridine: An efficient ligand in the cobalt-catalyzed synthesis of organozinc reagents from aryl chlorides and sulfonates

Article abstract of DOI:10.1055/s-2006-939060

The synthesis of functionalized arylzinc reagents from aromatic chlorides, triflates, or mesylates, via cobalt catalysis, is reported using 2,2′-bipyridine as a ligand in a mixture of acetonitrile and pyridine. This procedure allows the synthesis of a variety of functionalized arylzinc species in good to excellent yields. Some of these arylzinc compounds have been coupled with aromatic bromides under palladium catalysis. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-939060

LETTER
881
2,2¢-Bipyridine: An Efficient Ligand in the Cobalt-Catalyzed Synthesis of
Organozinc Reagents from Aryl Chlorides and Sulfonates
N
a
ew
A
pp
g
lication of
2
o
,2
¢
-Bipyridin
r
e
as
a
Ligand Kazmierski,a Corinne Gosmini,*a Jean-Marc Paris,b Jacques Périchona
Laboratoire d’Electrochimie, Catalyse et Synthèse Organique UMR 7582, Université Paris 12-CNRS, 2 Rue Henri Dunant,
94320 Thiais, France
b
Rhodia, Research Center of Lyon, 85 rue des Frères Perret, BP 62, 69192 Saint-Fons Cedex, France
Fax +33(1)49781148; E-mail: gosmini@glvt-cnrs.fr
Received 25 January 2006
this process can not be employed to activate less reactive
compounds such as aromatic chlorides. Electrosynthetic
methods and electroanalytical studies have established
that in situ generated low-oxidation-state cobalt(I) under-
Abstract: The synthesis of functionalized arylzinc reagents from
aromatic chlorides, triflates, or mesylates, via cobalt catalysis, is re-
ported using 2,2¢-bipyridine as a ligand in a mixture of acetonitrile
and pyridine. This procedure allows the synthesis of a variety of
functionalized arylzinc species in good to excellent yields. Some of goes fast disproportionation in acetonitrile.6,7 However,
these arylzinc compounds have been coupled with aromatic bro-
mides under palladium catalysis.
the addition of pyridine allows the stabilization of Co(I),
and thus, the activation of poorly reactive aromatic ha-
Key words: cobalt halide, catalysis, zinc, aromatic chlorides, trif-
lates
lides. The first entirely chemical application of these re-
sults was reported recently:8 the non-electrochemical
synthesis of organozinc reagents from aromatic chlorides
has been achieved by using cobalt catalysis and a mixture
Although organozinc derivatives are widely used and of acetonitrile and pyridine (Equation 1).
well-documented reagents1 their synthesis from function-
However, this method exhibits several drawbacks: the
alized aromatic chlorides has been rarely reported, and
then mainly by electrochemical syntheses.2 Their synthe-
sis from aryl sulfonates has never been described to our
knowledge. Indeed, these poorly reactive starting com-
pounds are usually activated by solvated transition metal
complexes such as Ni(0) or Pd(0) derivatives;3 magne-
sium or zinc, even when activated, insert only with diffi-
culty into an aromatic carbon–chlorine or carbon–
sulfonate bond. The price and availability of numerous
functionalized aromatic chlorides or phenols, compared to
the more reactive aromatic bromides or iodides, are strong
driving forces towards the discovery of new activation
processes.4
proportion of catalyst can reach as much as 33%, and re-
action times can be as high as 24 hours, which hardly
compares to the synthesis of organozinc reagents from ar-
omatic bromides. Moreover, this last method does not al-
low the formation of arylzinc reagents from phenol
derivatives.
Recent results in our group suggest that the replacement
of CoBr2 by CoBr2(bpy) can improve these results.9 In-
deed, addition of cobalt and 2,2¢-bipyridine in a 1:1 ratio
results in shorter reaction times in the case of aryl chlo-
rides and allows arylzinc compounds to be synthesized
from aryl triflates.
Thus we decided to add several ligands (PPh3, dppe, and
bpy) and cobalt, in both 2:1 and 1:1 ratios, to the reaction
mixtures, which proved to be unsuccessful. However,
2,2¢-bipyridine leads to faster reaction times when used in
a 1:1 ratio with cobalt, as expected, whereas 2:1 mixtures
with cobalt bromide retard the reactions.
Over the past five years our research group has developed
new cobalt-catalyzed processes for the activation of aro-
matic halides under mild conditions.2c–2f Electrochemical
methods have recently given way to convenient, entirely
chemical processes.5 Indeed, functionalized aromatic bro-
mides or iodides can be efficiently converted to the corre-
sponding organozinc reagents in a single step. The
reaction requires commercially available zinc dust and co-
balt bromide, along with acetonitrile as solvent. However,
From this point, several other parameters, including zinc
dust and catalyst proportions, solvent composition, sub-
strate concentration, and the implementation of a prelimi-
1) Allyl Cl (0.3 equiv), MeCN (6 mL), CF3CO2H, 25 °C, 3 min
CoBr2
(0.1 equiv)
Zn
(3 equiv)
+
FG
ZnCl
2) pyr (4 mL), CoBr2 (0.23 equiv), r.t.,
FG
1 equiv
Cl
Equation 1
SYNLETT 2006, No. 6, pp 0881–0884
0
4.
0
4.
2
0
0
6
Advanced online publication: 14.03.2006
DOI: 10.1055/s-2006-939060; Art ID: G02606ST
© Georg Thieme Verlag Stuttgart · New York

882
I. Kazmierski et al.
LETTER
nary step5 have been investigated in order to optimize the Organozinc reagents are identified through conversion
reaction conditions with p-methyl 4-chlorobenzoate as the into their corresponding aromatic iodide by addition of io-
test substrate (Equation 2).
dine, followed by GC analysis. The standard conditions
can be successfully applied to methyl 4-chlorobenzoate
(Table 1, entry 1). In order to lower the reaction times, we
have increased the proportion of zinc powder (Table 1,
entries 2–4). The degradation of the organozinc reagent
can additionally be achieved through increasing the
amount of pyridine (Table 1, entry 3). It is possible to
slow down the reactions by simply lowering both the
amount of zinc powder and cobalt catalyst (Table 1,
entry 5).
Zn (excess),
CF3CO2H
MeO2C
Cl
MeO2C
ZnCl
CoBr2 (bpy) cat.
ZnBr2 cat.
MeCN, py, 50 °C
Equation 2
We found that MeCN–pyridine in a 6:4 ratio proved to be
the best solvent mixture, as it leads to optimum reaction
times and stopped further degradation of the organozinc
reagent into ArAr. Carrying out the reaction at 50 °C in-
stead of room temperature allowed us to reduce the
amount of both Zn powder and cobalt catalyst to 1.5 and
0.1 equivalents, respectively. Moreover, if allyl chloride
was added in a preliminary step – similarly to methods de-
scribed in previous works5 – the amount of byproduct
(ArH) formed decreased. The addition of allyl chloride
also helped in suppressing the addition of hygroscopic
ZnBr2 as allyl chloride generates Zn2+ salts in situ during
this preliminary step.5
The synthesis of the organozinc reagent from 4-chlo-
robenzonitrile has revealed that, under the standard condi-
tions (Table 1, entry 1), low-valent cobalt insertion takes
place not only into the carbon–chlorine bond, but also into
the carbon–nitrile bond, although, surprisingly this result
had been observed before in rare cases, notably with nick-
el catalysts.10 This point has been circumvented by dis-
carding the improved, 2,2¢-bipyridine-containing catalyst,
and returning to the classic cobalt bromide. A slight in-
crease in the catalyst proportion was necessary in order to
achieve satisfying reaction times (Table 1, entry 6).
Following these principles, we also looked at the synthe-
sis of organozinc reagents starting from phenol
derivatives11,12 (Table 2). Whereas the conversion of aryl
triflates works fairly well (Table 2, entries 1–4), with few
selectivity problems except in the case of 4-acetylphenyl
trifluoromethanesulfonate (Table 2, entry 4), the less re-
active aryl mesylates (Table 2, entry 5–8) give rise to
preferential S–O bond cleavage, leading to the corre-
sponding phenol. It should also be pointed out that neither
phenyl acetate nor phenyl trifluoroacetate can be convert-
ed to the corresponding organozinc reagent under these
conditions.
The optimized conditions have been successfully applied
to other poorly reactive aromatic reagents with sensitive
functional groups (Equation 3).
1) AllylCl (0.3 equiv),
MeCN (6 mL), CF3CO2H,
25 °C, 3 min
CoBr2
+
Zn
FG
2) py (4 mL),
bpy (1 equiv/Co), 50 °C
(0.1 equiv) (1.95 equiv)
X = Cl, OTf, OMs
Equation 3
ZnX
FG
X
This is the first reported synthesis of organozinc triflates
and proves that the methodology can be adapted to a wide
range of aromatic reagents.
The preliminary results indicate that this method is very
sensitive to the substituents on the aromatic ring, as every
single reagent gives rise to unique issues. As a conse-
quence, the experimental conditions have to be adapted
slightly for each case (Table 1).
Various coupling reactions have been investigated by us-
ing arylzinc chlorides or triflates as synthesized according
to the above-described procedure. These include reactions
with allylic chlorides or acetates, and bromopyridine.
Table 1 Synthesis of Organozinc Chlorides under Optimized Conditions
Entry ArCl
Catalyst (equiv)
CoBr2(bpy) (0.1)
CoBr2(bpy) (0.1)
CoBr2(bpy) (0.1)
CoBr2(bpy) (0.1)
CoBr2(bpy) (0.05)
CoBr2 (0.2)
Zn (equiv) MeCN–py Time (h)
ArHa
4
ArCla
0
ArAra
10
ArZnCla
86
1
2
3
4
5
6
4-MeO2CPhCl
1.95
3
6:4
6:4
4:6
6:4
6:4
6:4
3
PhCl
5 (18)b
3 (24)b
5 (24)b
1 (5)b
1
3 (15)b
7 (7)b
6 (7)b
13 (20)b
3
19 (32)b
4 (2)b
4 (2)b
0 (0)b
0
15 (15)b
23 (57)b
30 (57)b
0 (6)b
8
62 (38)b
66 (33)b
60 (33)b
87 (70)b
89
4-F3CPhCl
4-F3CPhCl
4-MeCOPhCl
4-NCPhCl
3
3
1.7
1.95
a GC yield of an iodinated aliquot.
b In parentheses: GC yield under the standard conditions described in Equation 3.
Synlett 2006, No. 6, 881–884 © Thieme Stuttgart · New York

LETTER
New Application of 2,2¢-Bipyridine as a Ligand
883
Table 2 Synthesis of Organozinc Triflates and Mesylates
Entry ArX
CoBr2(bpy) Zn
Time
(h)
ArOHa
ArHa
ArXa
ArAra
ArZnXa
(equiv)
(equiv)
1
2
3
4
5
6
7
8
PhOTf
0.1
3
8
2.5
0.5
1
–
6
1
7
4
0
19
19
7
87
77
81
61
–
4-EtO2CPhOTf
4-NCPhOTf
0.1
1.95
1.95
1.95
3
–
0.1
–
0
0
4-MeCOPhOTf
PhOMs
0.1
29
–
4
0
0.1
72
21
24
8
–
100
17
0
–
4-EtO2CPhOMs
4-NCPhOMs
4-MeCOPhOMs
0.2
1.95
3
74
78
13
8
0
1
0.1
3
0
19
36
0.1
3
51
0
0
a GC yield of an iodinated aliquot.
The coupling of allyl chlorides or acetates gave a 35%
yield (GC) of the coupled product, provided the coupling
step is carried out with additional cobalt catalyst and 2
equivalents of the allylic reagent. However, the poor yield
and large amounts of ArH and ArAr byproducts arising
from ArZnCl or ArZnOTf prevented any further purifica-
tion. The use of pyridine as co-solvent in the synthesis of
the arylzinc reagents has been criticized for these poor re-
sults, but no clear evidence of its precise role has been re-
ported so far. However, these reactions are in the early
stages of development and future improvements may
prove successful
(2) (a) Sibille, S.; Ratovelomanana, V.; Périchon, J. J. Chem.
Soc., Chem. Commun. 1992, 283. (b) Sibille, S.;
Ratovelomanana, V.; Nédélec, J. Y.; Périchon, J. Synlett
1993, 425. (c) Gosmini, C.; Rollin, Y.; Périchon, J. WO
Patent WO0102626, 2000. (d) Gosmini, C.; Rollin, Y.;
Nédélec, J. Y.; Périchon, J. J. Org. Chem. 2000, 65, 6024.
(e) Le Gall, E.; Gosmini, C.; Nédélec, J. Y.; Périchon, J.
Tetrahedron 2001, 57, 1923. (f) Fillon, H.; Gosmini, C.;
Nédélec, J. Y.; Périchon, J. Tetrahedron Lett. 2001, 42,
3843.
(3) Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41,
4176.
(4) (a) Zapf, A.; Beller, M. Top. Catal. 2002, 19, 101.
(b) Tucker, C. E.; de Vries, J. G. Top. Catal. 2002, 19, 111.
(5) (a) Fillon, H.; Gosmini, C.; Périchon, J. J. Am. Chem. Soc.
2003, 125, 3867. (b) Kazmierski, I.; Gosmini, C.; Paris, J.
M.; Périchon, J. Tetrahedron Lett. 2003, 44, 6417.
(6) Buriez, O.; Nédélec, J.-Y.; Périchon, J. J. Electroanal.
Chem. 2001, 506, 162.
(7) Seka, S.; Buriez, O.; Périchon, J. Chem. Eur. J. 2003, 9,
3597.
(8) Gosmini, C.; Amatore, M.; Claudel, S.; Périchon, J. Synlett
2005, 2171.
Some organozinc reagents mentioned in Tables 1 (entries
1, 4, and 5) and 2 (entry 8) obtained from aryl chlorides or
triflates have been coupled with 2-bromopyridine (1
equiv) in the presence of a catalytic amount of
PdCl2(PPh3)2 (1%) at 50 °C. These well-known Negishi
couplings13 proceeded in good yields exclusively if anoth-
er solvent such as DMF or THF (5 mL) was added to the
solution to improve solubility. Under these conditions,
each 2-arylpyridine was isolated in 85% yield versus
ArZnX; moreover, using a cobalt catalyst for carbon–car-
bon bond formation14 was not efficient, a palladium cata-
lyst is essential.
(9) Amatore, M.; Gosmini, C.; Périchon, J. Eur. J. Org. Chem.
2005, 989.
(10) (a) Penney, J. M.; Miller, J. A. Tetrahedron Lett. 2004, 45,
4989. (b) Miller, J. A.; Dankwardt, J. W.; Penney, J. M.
Synthesis 2003, 1643. (c) Miller, J. A.; Dankwardt, J. W.
Tetrahedron Lett. 2003, 44, 1907. (d) Garcia, J. J.; Brunkan,
N. M.; Jones, W. D. J. Am. Chem. Soc. 2002, 124, 9547.
(e) Taw, F. L.; White, P. S.; Bergman, R. G.; Brookhart, M.
J. Am. Chem. Soc. 2002, 124, 4192. (f) Miller, J. A.
Tetrahedron Lett. 2001, 42, 6991. (g) Abla, M.; Yamamoto,
T. J. Organomet. Chem. 1997, 532, 267.
An efficient and convenient cobalt-catalyzed synthesis of
aromatic organozinc reagents in high yields has been de-
veloped with 2,2¢-bipyridine as a ligand. This ligand is es-
sential for the formation of arylzinc reagents from phenol
derivatives.
(11) The procedure for the synthesis of mesylates and triflates is
based on: Mowery, M. E.; DeShonh, P. J. Org. Chem. 1999,
64, 3266.
Acknowledgment
(12) Functionalized Mesylates or Triflates; Typical
Procedure
The authors gratefully acknowledge the financial support provided
by Rhodia. I. Kazmierski thanks Rhodia for a scholarship.
Phenol (5.3 g, 50 mmol) and pyridine (22 mL) were cooled
to 0 °C in a three-way reaction vessel under an argon
atmosphere. Tf2O (8.5 mL, 50 mmol) was added dropwise
over 45 min to the magnetically stirred solution, giving rise
to a strong red-orange color. Then the reaction mixture was
stirred at r.t. until the starting phenol had been consumed
References and Notes
(1) (a) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117.
(b) Knochel, P.; Almena Perea, J. J.; Jones, P. Tetrahedron
1998, 54, 8275.
Synlett 2006, No. 6, 881–884 © Thieme Stuttgart · New York

884
I. Kazmierski et al.
LETTER
(monitored by GC on hydrolyzed aliquots). H2O (40 mL)
was added to the mixture, which was then extracted with
CH2Cl2 (3 × 40 mL). The organic layer was treated with 10%
HCl (40 mL), washed with a sat. solution of NaCl (40 mL),
and dried over anhyd MgSO4. After removing the solvent
under vacuum, the product was purified by flash
chromatography on silica gel (pentane) to give phenyl
trifluoromethanesulfonate in 95% yield as a colorless oil.
The same procedure was applied to the synthesis of
mesylates, by replacing Tf2O with MsCl.
Coupling of Organozinc Chlorides or Triflates with 2-
Bromopyridine; Typical Procedure (Table 1, entry 1)
Preliminary Step: Zn powder (1.27 g, 1.95 equiv, <10 mm)
and CoBr2 (219 mg, 0.1 equiv) were placed in a reaction
vessel under an argon atmosphere. MeCN (6 mL), allyl
chloride (0.25 mL, 0.3 equiv), dodecane (0.2 mL, internal
reference for GC), and TFA (0.05 mL) were added in one
batch to the vessel. The resulting reaction mixture was
magnetically stirred under a flow of argon at r.t. for 3 min.
Synthesis of the Organozinc Reagent: Pyridine (4 mL), 2,2¢-
bipyridine (0.156 g, 0.1 equiv), and methyl 4-chlorobenzo-
ate (1.71 g, 10 mmol) were added to the reaction mixture,
and stirred at 50 °C until the reaction was complete (aliquots
were removed, monitored by GC after iodination). After 3 h,
4-carboxymethylzinc chloride was obtained in 86% yield
(GC).
Coupling Reaction: DMF or THF (5 mL), 2-bromopyridine
(1 mL, 1 equiv) and PdCl2(PPh3)2 (70 mg, 0.01 equiv) were
added to the reaction mixture obtained above, and the
resulting solution was stirred for 3 h at 50 °C until 4-car-
boxymethylzinc chloride had been completely consumed.
The solution was hydrolyzed with NH4Cl (100 mL),
extracted with Et2O, the organic layer was washed with
brine, dried, and the solvent evaporated. The residue was
isolated by flash column chromatography (silica gel;
pentane–Et2O, 85:15) to give the Negishi coupled product in
73% yield. The structure was confirmed by 1H and 13C NMR
spectroscopy and MS.
(13) Negishi, E. I. Acc. Chem. Res. 1982, 15, 340.
(14) (a) Korn, T. J.; Knochel, P. Angew. Chem. Int. Ed. 2005, 44,
2947. (b) Korn, T. J.; Cahiez, G.; Knochel, P. Synlett 2003,
1892. (c) Korn, T. J.; Schade, M. A.; Wirth, S.; Knochel, P.
Org. Lett. 2006, 8, 725. (d) Shinokubo, H.; Oshima, K. Eur.
J. Org. Chem. 2004, 2081.
Synlett 2006, No. 6, 881–884 © Thieme Stuttgart · New York