Direct cobalt-catalyzed cross-coupling between aryl and alkyl halides

Article abstract of DOI:10.1055/s-0029-1218012

An operationally simple cross-coupling reaction between aryl halides and alkyl halides with high selectivity has been developed. The underlying domino process utilizes CoCl²/Me⁴-DACH as a catalyst system. The methodology exhibits hig

Full text of DOI:10.1055/s-0029-1218012

LETTER
2931
Direct Cobalt-Catalyzed Cross-Coupling Between Aryl and Alkyl Halides
D
irec
t
Cobalt-Catalyzed
a
C
ross-Cou
l
pling demar Maximilian Czaplik, Matthias Mayer, Axel Jacobi von Wangelin*
Department of Chemistry, University of Cologne, Greinstr. 4, 50939 Cologne, Germany
Fax +49(221)4705057; E-mail: axel.jacobi@uni-koeln.de
Received 17 August 2009
R3
Abstract: An operationally simple cross-coupling reaction be-
tween aryl halides and alkyl halides with high selectivity has been
developed. The underlying domino process utilizes CoCl2/Me4-
DACH as a catalyst system. The methodology exhibits high sustain-
ability as it obviates the need for the pre-formation and handling of
stoichiometric amounts of hazardous Grignard compounds.
R3
X
R2
[CoCl2, amine]
Mg
R1
R1
+
R2
Y
1 (X = Cl, Br)
2 (Y = Cl, Br)
3
Scheme 1 Direct cobalt-catalyzed aryl–alkyl cross-coupling
Keywords: cobalt, cross-coupling, aryl halides, domino reactions
Metal salts have been known to promote the formation of
Grignard species from the reaction of magnesium and an
organohalide.10 A sequential combination with a transi-
tion-metal catalyzed cross-coupling reaction would allow
a domino process to transform two electrophilic organo-
halides into their cross-coupling product. Based on this
concept, Gosmini et al. have recently reported on direct
cross-coupling reactions between sp2-hybridized organo-
halides.11 We set out to investigate the potential of various
metal salts to act as catalysts for the direct sp2–sp3 cross-
coupling of an aryl halide (sp2) with an alkyl halide (sp3)
in the presence of stoichiometric amounts of magnesium
as the reductant. Although electronically differentiated,12
metathesis [from Alkyl-MgX (kinetic) to ArMgX (ther-
modynamic)], competitive biaryl coupling, b-hydride
elimination, or hydrodehalogenation could reduce the se-
lectivity for the cross-coupling product. Gratifyingly, we
discovered that CoCl2 displays good activity and selectiv-
ity in such domino magnesiation–cross-coupling reac-
tions (Scheme 1), complementing our recent iron-
catalyzed procedure.13
Transition-metal catalyzed cross-coupling reactions have
matured to play a commanding role as carbon–carbon
bond forming reactions in organic synthesis.1 Especially,
palladium and nickel complexes have exhibited high cat-
alytic activity for a wide range of substrates and, thus,
prompted several industrial applications in the manufac-
ture of pharmaceuticals and materials.2 However, the high
costs3 of palladium catalysts have constricted a more gen-
eral use of such protocols in large scale productions, while
nickel catalysts are highly controversial due to their aller-
genic and cancerogenic toxicity.4 Furthermore, both met-
als usually require the presence of air-sensitive phosphine
ligands of high molecular weight. The nucleophilic com-
ponent in most cross-coupling protocols is a moisture-
sensitive organometallic species (M = Mg, B, Zn, Sn) that
must be prepared from organohalides in a separate, up-
stream operation. From an economic standpoint, there is
clearly a demand for more efficient cross-coupling meth-
odologies that obviate the need for complex and toxic cat-
alyst systems as well as sensitive and hazardous
reactants.5
Table 1 shows selected optimization experiments for the
model reaction of p-tolyl bromide (1a) with cyclohexyl
bromide (2a) to give 1-cyclohexyl-4-methylbenzene
(3a).14 The reaction seemed to be highly dependent on the
structure of the amine ligand. Generally, monodentate
amines exhibited poor selectivity, while pyridine gave
moderate cross-coupling selectivity. Biaryl formation was
dominant with 1,10-phenanthroline. The employment of
TMEDA and Me4-DACH resulted in comparable reactiv-
ities, with the latter being more selective for the cross-
coupling product and giving less biaryl. The generation of
ate complexes by addition of LiI did not lead to a superior
catalyst system.7c Unlike its iron counterpart,13 the cobalt-
catalyzed reaction requires only catalytic amounts of
ligand. With catalytic FeCl3, the presence of stoichiomet-
ric amounts of TMEDA assured a slow formation of the
intermediate Grignard species. Our observation that the
initiating Grignard formation is much slower in the pres-
ence of CoCl2 thus obviates the need for stoichiometric
amine addition.14,15 The optimized set of conditions in-
Recent developments of cobalt-catalyzed cross-coupling
protocols have addressed some of these sustainability is-
sues. Oshima et al.6 and Cahiez et al.7 have reported on
highly active cobalt/amine catalyst systems that facilitate
cross-coupling between various organohalides and
Grignard reagents under mild conditions.8 However, we
especially wanted to devise a protocol that obviates the
need for the pre-formation and handling of stoichiometric
Grignard reagents. In view of industrial applications, the
employment of highly sensitive Grignard compounds still
imposes stringent and costly safety arrangements.9 Here
we report on an operationally simple one-pot protocol for
the direct cobalt-catalyzed cross-coupling of aryl halides
(1) and alkyl halides (2) to give substituted arenes (3)
(Scheme 1).
SYNLETT 2009, No. 18, pp 2931–2934
x
x
.x
x
.2
0
0
9
Advanced online publication: 02.10.2009
DOI: 10.1055/s-0029-1218012; Art ID: G26709ST
© Georg Thieme Verlag Stuttgart · New York

2932
W. M. Czaplik et al.
LETTER
Table 1 Selected Optimization Experiments of the Model Reactiona
[CoCl2]
Mg, THF
Br
Br
+
+
conditions
1a
Temp (°C)
0
2a
3a
4a
Ligand (mol%)a
CoCl2 (mol%)
5
1a/2a
Yield 3a (4a) (%)b
–
1:1
6 (15)
3 (22)
Et3N (5)
DABCO (5)
py (5)
phen (5)
TMEDA (5)
Me4-DACH (5)
23 (18)
41 (17)
3 (50)
53 (12)
57 (5)
0
(1)
1
2.5
10
1:1
1:1
5
62
55
Me4-DACH (2.5)
(10)
–10
0
10
Me4-DACH (10)
5
2
69
56
0
Me4-DACH (10)
5
1:1.5
1:1.2
1.2:1
1.5:1
45
64
73
58
0
Me4-DACH (10)
5
1:1
54c
0
TMEDA (20)
5
1.2:1
56 (14)d
a DABCO = 1,4-diazabicyclo[2.2.2]octane, py = pyridine, phen = 1,10-phenanthroline, TMEDA = N,N,N¢,N¢-tetramethylethylenediamine,
Me4-DACH = N,N,N¢,N¢-tetramethyl-1,2-diaminocyclohexane.
b GC yields.
c Mg powder (1.2 equiv).
d LiI (10 mol%) added.7c
volve reaction at 0 °C in THF solution with 5 mol% lide and collateral biaryl formation (Scheme 2).6c,8d,18 Re-
CoCl2, 10 mol% Me4-DACH and stoichiometric amounts actions with pre-formed Grignard species suggest the
of magnesium turnings. A slight excess of the aryl bro- operation of an ArMgBr–RBr coupling.18b The oxidative
mide (1.2 equiv) proved beneficial.14
addition is likely to adopt a single electron transfer (SET)
pathway via carbon-centered free radical R· and complex
II. The 17e– species III undergoes reductive elimination
of the cross-coupling product and, upon further transmet-
allation (from ArMgBr), regenerates catalyst I. The rather
slow magnesiation of ArBr at 0 °C impedes the accumu-
lation of ArMgX and hence reduces the amount of homo-
biaryl formation (Ar2). Consistently, quenching experi-
ments have documented a constantly low concentration of
ArMgX over the course of the reaction (steady-state).14
Table 2 shows a series of fifteen aryl halides and one al-
kenyl bromide that were subjected to direct cross-cou-
pling conditions in the presence of alkyl halides without
resorting to a laborious and costly pre-formation of the
sensitive Grignard compounds. Bromoarenes with alkyl,
alkoxy, amino, and fluoro substituents showed good reac-
tivity with both primary and secondary alkyl bromides. In
all cases, formation of the homocoupling products (biaryl,
bialkyl) was marginal (<15%). Isomerization of primary
alkyl bromides to the more stable secondary isomer was We also performed an asymmetric reaction in the pres-
not observed. With fluoro-substituted aryl bromides (see ence of enantiopure (R,R)-Me4-DACH as ligand
3k,l), activation of the Ar–F bond was observed in minor (Scheme 3).14 Employment of racemic 3-bromobutyl-
quantities (<10%).16 b-Bromostyrene, as a vinylic sub- benzene19 and 2-bromoanisole gave the cross-coupling
strate, exhibited moderate selectivity (3n). Low conver- product 3q with an enantiomeric excess of 20%.20
sions (<5%) were attained with ester and cyano moieties
In summary, we have developed a new protocol for the di-
in the arene or alkane component. Here, consumption of
rect cross-coupling of aryl bromides and alkyl bromides
the magnesium was largely inhibited, probably due to
under mild conditions. The reaction is highly sustainable
surficial deactivation.17 The employment of alkyl chlo-
as it obviates the pre-formation and handling of stoichio-
metric amounts of sensitive Grignard compounds. Despite
rides and aryl chlorides resulted in low conversions.
We postulate a mechanism based upon the 17e– biarylco- direct employment of two electrophilic organohalides, the
balt(0) catalyst species I that can be formed via an initial one-pot methodology leads to unexpectedly high selectiv-
reduction of the employed CoCl2 with arylmagnesium ha- ity for the cross-coupling product.
Synlett 2009, No. 18, 2931–2934 © Thieme Stuttgart · New York

LETTER
Direct Cobalt-Catalyzed Cross-Coupling
Table 2 Substrate Scope (continued)14
2933
Table 2 Substrate Scope 14
R3
R3
R1
R1
R1
R1
R3
CoCl2 (5 mol%)
Me4-DACH (10 mol%)
R3
CoCl2 (5 mol%)
Me4-DACH (10 mol%)
X
X
R2
R2
+
+
R2
Y
R2
Y
Mg, THF, 0 °C, 6 h
Mg, THF, 0 °C, 6 h
1
2
3
1
2
3
X
Y
Product
Yield of 3 (%)
X
Y
Product
Yield of 3 (%)
( )10
Br
Cl
Br
Br
Br
Cl
69
42
8
Br
Br
3m
53
3a
Br
Cl
Br
Br
79
9
( )10
3b
Br
Br
Br
Br
Br
Br
3n
39
<5
<5
( )10
Br
Br
Br
Br
3c
85
68
3o
CO2Et
3p
3d
( )10
S
LCoIICl2
4 PhMgBr
Mg
Br
Br
3e
64
PhBr
slow
Ph2
LCo0Ph2(MgBr)2
MgBr2
RBr
I
Br
Br
Br
Br
Br
Br
3f
65
76
68
PhMgBr
SET
MgBr2
MeO
LCo0Ph(MgBr)
IV
I
R⋅
LCo Ph2(MgBr)
II
3g
OMe
R
PhR
LCoIIPh2(MgBr)
3h
III
Scheme 2 Postulated mechanism
Me2N
Br
Br
Br
Br
3i
3j
52
75
Br
a
Br
+
OMe
OMe
racemic
3q (40%, 20% ee)
Scheme 3 Asymmetric cross-coupling: Reaction conditions: (a)
CoCl2 (5 mol%), (R,R)-Me4-DACH (10 mol%), Mg (1.2 equiv), THF,
3 h, 0 °C.
Br
Br
Br
Br
3k
3l
62
59
F
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
( )8
Ph
F
Synlett 2009, No. 18, 2931–2934 © Thieme Stuttgart · New York

2934
W. M. Czaplik et al.
LETTER
Coord. Chem. Rev. 2004, 248, 623. (b) For transition-metal
catalysis, see for example: Bogdanović, B.; Schwickardi, M.
Angew. Chem. Int. Ed. 2000, 39, 4610; Angew. Chem. 2000,
112, 4788.
Acknowledgment
This work was financed by the Saltigo GmbH, Leverkusen. We
thank Prof. H.-G. Schmalz (University of Cologne) for excellent
technical support. W.M.C. received a Max Buchner stipend of the
DECHEMA. M.M. is a fellow of the Deutsche Bundesstiftung Um-
welt (DBU). A.J.v.W. is an Emmy Noether fellow of the Deutsche
Forschungsgemeinschaft (DFG) and recipient of the 2009 Science
Award of the Industrieclub Düsseldorf e.V.
(11) For related direct cobalt-catalyzed sp2–sp2 cross-coupling
reactions, see: (a) Gomes, P.; Gosmini, C.; Perichon, J. Org.
Lett. 2003, 5, 1043. (b) Amatore, M.; Gosmini, C. Angew.
Chem. Int. Ed. 2008, 47, 2089; Angew. Chem. 2008, 120,
2119.
(12) (a) C(sp3)–Br and C(sp2)–Br bond strengths at 298 K: EtBr
(68 kcal mol–1); PhBr (80 kcal mol–1). Taken from: CRC
Handbook of Chemistry and Physics; Weast, R. C.; Astle,
M. J., Eds.; CRC Press: Boca Raton, 1981. (b) The single
electron transfer (SET) into the p* orbital of the ArBr is
reversible, and the p*–s* transition required for dissociation
of the C–Br bond is slow.
(13) For related iron catalysis, see: Czaplik, W. M.; Mayer, M.;
Jacobi von Wangelin, A. Angew. Chem. Int. Ed. 2009, 48,
607; Angew. Chem. 2009, 121, 616.
(14) (a) For further details, see Supporting Information.
(b) General procedure: A 10 mL flask was placed in a water
bath (r.t.), charged with Mg turnings (63 mg, 2.6 mmol),
fitted with a rubber septum, and purged with argon (1 min).
A solution of CoCl2 (13 mg, 0.1 mmol, 5 mol%) and Me4-
DACH (35 mL, 0.2 mmol, 10 mol%) in anhydrous THF (4
mL) was added via syringe. The mixture was stirred at r.t. for
15 min, then the reaction was cooled to 0 °C and aryl
bromide (2.4 mmol) and alkyl bromide (2.0 mmol) were
added. After 6 h at 0 °C, the reaction was quenched with
saturated aqueous NH4Cl (5 mL) and aqueous HCl (10%,
2 mL) and extracted with ethyl acetate (3 × 5 mL). The
combined organic phases were dried over Na2SO4,
concentrated in vacuo, and subjected to flash
chromatography (SiO2; cyclohexane–ethyl acetate).
(15) The rate of Grignard formation is not significantly
accelerated by the presence of CoCl2. The presence of
amines slows down the Grignard formation from
organohalides and Mg, probably by blocking the metal
surface.
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identical conditions gave only minimal amounts of cross-
coupling product testifying to a far less active catalyst
species being formed. See also Supporting Information.
(c) We also observed a beneficial effect on the yield of the
cross-coupling product by the employment of an excess of
ArBr. The observed formation of 5–7% of biaryl from a
5 mol% catalyst loading mirrors the stoichiometry of the
CoCl2 ® I reduction as shown in Scheme 2. A small portion
of biaryl might also result from a cobalt-catalyzed oxidative
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