Cobalt-Catalyzed Suzuki Biaryl Coupling of Aryl Halides

Article abstract of DOI:10.1002/anie.201710053

Readily accessed cobalt pre-catalysts with N-heterocyclic carbene ligands catalyze the Suzuki cross-coupling of aryl chlorides and bromides with alkyllithium-activated arylboronic pinacolate esters. Preliminary mechanistic studies indicate that the cobalt

Full text of DOI:10.1002/anie.201710053

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Accepted Article
Title: Cobalt-catalyzed Suzuki biaryl coupling of aryl halides
Authors: Robin Bedford, Soneela Asghar, Sanita Tailor, and Elorriaga
David
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10.1002/anie.201710053
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Cobalt-catalyzed Suzuki biaryl coupling of aryl halides
Soneela Asghar,[a,b] Sanita B. Tailor,[a] David Elorriaga[a] and Robin B. Bedford*[a]
Abstract: Readily accessed cobalt pre-catalysts with N-heterocyclic
well developed to date.[4,5] Iron-catalyzed Suzuki cross-coupling
can be performed between a variety of organic halides and
carbene ligands catalyze the Suzuki cross-coupling of aryl chlorides
and bromides with alkyllithium-activated arylboronic pinacolate esters. organoboron reagents,[6] but simple biaryl bond-formation
Preliminary mechanistic studies indicate that the cobalt is reduced to
Co(0) during catalysis.
remains elusive and challenging.[6a,7,8] Recently Chirik and co-
workers reported early results in the coupling of aryl triflates with
arylboron pinacol esters using
a cobalt PNP-pincer-based
catalyst.[9] We now report the cross-coupling of aryl chlorides and
bromides with activated arylboronic pinacol esters,[10,11] using
simple cobalt catalysts prepared in situ from commercial available
precursors.
The palladium-catalyzed cross-coupling of organoboronic
acids or esters with organic halides or related substrates – the
Suzuki reaction – is a powerful and very widely exploited method
for the formation of biaryl compounds (Scheme 1).[1] It is used
commercially for the production of a range of materials, including
the sartan class of angiotensin inhibitors for the treatment of
hypertension (e.g. Lorsartan) and Boscalid, a broad-spectrum
agrochemical fungicide.[2]
Table 1 summarizes selected[12] optimization studies using
4-chorotoluene and the activated phenylboronic ester 1a,[6b, c, e, 8]
catalyzed by species formed in situ from cobalt(II) chloride with a
range of different ligands and ligand precursors.
Table 1. Optimisation of ligands.
OH/R
CoCl2 (10 mol%)
O
Pd-cat
nBu
B
X
Ligand/precursor (10 mol%)
+
Cl
B
+
3
R
R
R'
base
R'
OH/R
THF, 60 oC, 48h
O
2a
1a
Li+(THF)2
commercial examples:
Ligand/
precursor
Yield
%
Ligand/
precursor
Yield
%
Entry
1
Entry
8
[a]
[a]
Cl
Bu
tBu
tBu
N
NH
N
none
0
50
N
N
O
N
N
HO
N
N
Cl
N
N
N
+
2
3
4
5
PPh3
2
6
0
8
9
24
92
71
99
Cl
H
Lorsartan
Boscalid
Cl-
N
N
+
Ph2P
PPh2
10
11
12
Scheme 1. Palladium-catalyzed Suzuki biaryl coupling and selected products.
Cl-
N
N
+
Ph2P
PPh2
Cl-
iPr
iPr
While palladium-based catalysts are ubiquitous in Suzuki
cross-coupling reactions, there is a growing impetus to replace
them with more sustainable alternatives based on Earth-abundant
metals (EAM). This is not only due to the fact that palladium, like
all platinum group metals (PGMs), is scarce and expensive, but
also because of the relatively high toxicity of PGMs; as a
consequence of this toxicity there are strict regulations in place
for the removal of PGMs to the low ppm level from active
pharmaceutical intermediates.[3] Of the EAM alternatives to
palladium for Suzuki biaryl coupling, 1st row transition metals are
particularly attractive, with nickel-based catalysts being the most
N
N
+
O
Cl-
iPr
iPr
iPr
PPh2
PPh2
iPr
6
7
0
0
13
14
99
99
N
PPh2
N
N
+
-
BF4
iPr
iPr
iPr
iPr
N
N
+
Ph2P
PPh2
PPh2
Cl-
iPr
iPr
[a] Spectroscopic yield of 2a, determined by 1H NMR
spectroscopy (1,3,5-trimethoxybenzene internal standard).
No reaction was observed in the absence of added ligand
(entry 1) and little or no product 2a was obtained when mono, bi-
or tridentate phosphine ligands were tested (entries 3 – 7).
[a]
[b]
S. Asghar, S. B. Tailor, Dr David Elorriaga, Prof. Dr R. B. Bedford
School of Chemistry
University of Bristol
Cantock’s Close, Bristol, BS8 1TS, U.K.
E-mail: r.bedford@bristol.ac.uk
S. Asghar
Department of Chemistry
Lahore University of Management Sciences
Lahore 54792, Pakistan
Modest conversion was obtained with
a bipyridyl ligand
architecture (entry 8) and some activity was also observed with
an N,N’-dialkyl N-heterocyclic carbene (NHC) precursor (entries
8 and 9 respectively). However, the star performers proved to be
N,N’-diaryl-substituted NHC precursors (entries 10 – 14) with IPr
(entries 12 and 13) and SIPr (entry 14) progenitors giving
essentially quantitative conversion to the desired product at 60
°C; reducing either the temperature or the loading of 1a proved
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201710053
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deleterious to performance.12 Importantly, a repeat of the reaction
outlined in entry 10 gave no product when the CoCl2 was omitted,
whereas repeating the reaction in entry 14 with high purity CoCl2
(99.999%) gave 2a in essentially quantitative yield. This indicates
that impurities, in either the cobalt source or one of the other
components of the reaction mixture, are not responsible for the
observed catalytic activity.[7]
Scheme 2 summarizes the effect of changing either the
halide or the boronic ester activator. Under these conditions, tBuLi
works as well as nBuLi, whereas the Grignard reagent EtMgCl
performs poorly, meanwhile no reaction is seen with lithium
isopropoxide. Interestingly, poorer activity results from the use of
4-bromotoluene as a substrate compared with the use of its
chloride congener. This is in stark contrast with palladium
catalyzed cross-coupling, where the weaker aryl bromide bonds
are cleaved more readily. This may indicate a significant deviation
in the mechanism of activation of the C-X bond between palladium
and cobalt (see below). Very poor results were obtained with 4-
iodotoluene as the electrophile.
Table 2. Reaction scope. See Chart S1 (supporting information) for
unsuccessful attempts.
CoCl2 (10 mol%)
SIPr.HCl (10mol%)
X
O
O
nBu
+
aryl
R
B
aryl
[a]
R
Li+(THF)2
X = Cl, Br
Entry[a]
Aryl halide
Product
Yield,
%
[b]
Et2OC
F3C
F
Et2OC
Cl
1
2
88
67
F3C
Br
F
Cl
3
4
93
75
H
N
H
N
Cl
Ac
Ac
O
O
5
69
Cl
Me2N
Me2N
6
Cl
92
69
79
80
82
78
O
O
1a: RM = nBuLi
b: RM = tBuLi
c: RM = EtMgCl
d: RM = iPrOLi
O
O
Et
7
RM
Et
Br
R
B
B
THF
-40 oC to 0 oC, 1h
Et
3a
8
Et
Cl
M+
9
Me2N
MeO
Br
Me2N
MeO
from 1a, X = Cl: 99%
1b, X = Cl: 99%
1c, X = Cl: 8%
1d, X = Cl: 0%
1b, X = Br: 77%
X = I: 35%
10
11
Cl
X
Br
[a]
2a
1a, X = Br: 60%
X = I: 33%
12
84
Br
Scheme 2. Varying boronic ester activator and 4-tolyl halide. [a] Conditions as
per Table 1, entry 14.
13
14
85
86
Cl
OMe
OMe
Table
2 summarizes the results obtained under the
optimized conditions in the cross-coupling of a variety of aryl
chlorides and bromides with BuLi-activated aryl pinacol boronic
Cl
n
Br
15
16
73
55
esters. A range of electron-rich and electron-poor aryl halides
were tolerated, with good to excellent isolated yields of the
desired cross-coupled products obtained. Moderate steric
hindrance in the aryl halide substrate was also well
accommodated (13 – 16, 21). Esters, tertiary amines, amides,
fluoro, trifluoromethyl and alkoxide functions were tolerated on the
aryl halide. By contrast, nitro, cyano, aldehydic and ketonic
substituents on the aryl halide groups were poorly tolerated,
giving either little or none of the desired product, or substantial
amounts of products from competitive side reactions (see chart
S1).[12] The isolated yields of the products from the heterocyclic
halides screened in entries 25 – 27 and Chart S1 were somewhat
disappointing, due largely to poor separation of the products from
biphenyl, produced by competitive homo-coupling of the
electrophile.
O
O
NEt2
NEt2
Cl
17
18
19
82
76
73
F3C
Br
Cl
Cl
OMe
F3C
Et
Et
CF3
N
O
20
21
82
78
MeO
Cl
MeO
F
OMe
OMe
Cl
The synthetic utility of the transformation was highlighted by
functionalization of the biologically relevant, heterocycle-
containing substrate Edaravone, a substance used for the
treatment of brain ischemia following a stroke.[13]
OMe
OBn
22
82
Cl
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MeO
MeO
more readily prepared and isolated using potassium graphite as
the reducing reagent, by extension of a methodology reported by
Deng and co-workers for a similar complex.[16] This synthetic
approach could also be exploited to produce the bis-norbornene
analogue, 6b. The single crystal X-ray structures of the
complexes 6a and b are shown in Figure 1.
The diene complex 6a showed no activity when trialed as a
pre-catalyst in the coupling of 4-chlorotolene with 1a. Indeed, the
diene acts as a poison for the catalytic reaction, with no 2a
produced when the reaction using CoCl2/SIPr.HCl was repeated
in its presence.[12] This lends credence to the tentative suggestion
that cobalt(0) species are formed during catalysis. By contrast,
when the bis-norbornene complex 6b was exploited as the pre-
catalyst good activity was observed, with 2a produced in 60%
spectroscopic yield. If the reaction does indeed involve a Co(0)
intermediate, then subsequent reaction with the aryl halide may
proceed via either a classical 2e-oxidative addition or, more likely,
a bimetallic, radical-centered process.[17] Certainly, the observed
preference for aryl chlorides over bromides outlined above is
atypical of simple, mononuclear oxidative addition.[18]
23
85
Cl
CF3
MeO
MeO
24
25
Br
58
37
Br
N
N
26
27
35
33
N
N
Br
Br
S
S
[a] Conditions as per Table 1. [b] Isolated yields.
Scheme 3 outlines the reaction of the commercially available
ortho-chloro-substituted analogue of Edaravone, 4a, with
activated arylBPin esters. Gratifyingly, the 2-arylated Edaravone
derivatives 5a – g could be produced in moderate to good isolated
yields. Surprisingly, the meta- and para-chloro analogues of
Edaravone, 4b and c did not undergo any coupling. This suggests
that the dihydro-3H-pyrazol-3-one moiety strongly directs to the
ortho-position; such a directing effect has previously been
exploited in palladium-catalyzed ortho-C-H functionalization of
Edaravone.[14] Indeed, in stark contrast to the reactions with
simple aryl halides, the coupling of 4a with 1a proceeded equally
well in the absence of the NHC ligand, giving 5a in 86%
spectroscopic yield, consistent with a strong ortho-directing
effect.[12]
iPr
iPr
N
N
+ 1a or KC8
Me2Si
SiMe2
THF
iPr
iPr
O
Co
O
CoCl2
+
6a
iPr
iPr
Me2Si
iPr
SiMe2
iPr
N
N
N
N
+ KC8
THF
iPr
iPr
2
iPr
iPr
SIPr
Co
6b
Scheme 4. Cobalt reduction in the presence of alkenes.
CoCl2
SIPr.HCl
N
N
O
O
N
N
O
O
nBu
R
+
B
Cl
[a]
R
Li+(THF)2
4a
N
O
N
5a: R = H; 85%
b: R = 4-Me; 73%
c: R = 4-OMe; 71%
d: R = 4-OBn; 59%
e: R = 4-CF3; 62%
f: R = 4-F; 85%
g:: R =
N
N
N
O
O
edaravone
N
No reaction
or
N
O
Cl
4b
4c
47%
Cl
Scheme 3. Suzuki coupling of an Edaravone derivative, 4a. Conditions as per
Table 1; isolated yields.
Figure 1. Single crystal X-ray structures of zero-valent cobalt complexes 6a
(left) and 6b (right). Ellipsoids set at 50% probability, H atoms omitted for clarity.
Finally, we turned our attention to preliminary mechanistic
investigations. In order to determine the lowest oxidation state
that could be accessed by Co in the presence of the reducing
organoborate, we reacted 1a with CoCl2 and free SIPr, exploiting
the diene dvtms as a trap for any low-valent, low coordinate
organocobalt intermediates obtained (Scheme 4). Following this
reaction by 1H NMR spectroscopy,[12,15] we observed the
production of the zero-valent cobalt complex 6a, which could be
In summary, we have developed the cobalt-catalyzed
Suzuki cross-coupling of aryl chlorides and bromides with
activated arylBPin esters, using simple, commercially available
ligands and cobalt salts. There remain issues to the routine
replacement of palladium with cobalt in the Suzuki coupling of aryl
halides, including the need to develop milder nucleophiles to
prevent competitive side reactions, and to reduce catalyst
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Kondo, Y. Fujiwara, H. Seike, H. Takaya, Y. Tamada, T. Ono, M.
Nakamura, J. Am. Chem. Soc. 2010, 132, 10674; c) T. Hashimoto, T.
Hatakeyama, M. Nakamura, J. Org. Chem. 2012, 77, 1168; d) T.
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Gallagher, J. N. Harvey, D. M. Murphy, E. C. Neeve, J. Nunn, D. R. Pye,
Chem. Eur. J. 2014, 20, 7935; f) R. B. Bedford, P. B. Brenner, E. Carter,
J. Clifton, P. M. Cogswell, N. J. Gower, M. F. Haddow, J. N. Harvey, J.
A. Kehl, D. M. Murphy, E. C. Neeve, M. L. Neidig, J. Nunn, B. E. R.
Snyder, J. Taylor, Organometallics 2014, 33, 5767.
loadings; these studies are ongoing within the group. Regardless,
we have unequivocally demonstrated that cobalt-catalyzed
Suzuki biaryl bond-formation using aryl halide substrates is
tractable.
Acknowledgements
We thank Commonwealth Scholarship Commission, for the
provision of split-site PhD funding (S.A.) and the EPSRC for a
studentship (S.B.T.) and post-doctoral funding (D.E.).
[7]
[8]
[9]
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Huwe, T. Hashimoto, R. A. Okopie, Tetrahedron Lett. 2009, 50, 6110.
R. B. Bedford, T. Gallagher, D. R. Pye, W. Savage, Synthesis 2015, 47,
1761.
Keywords: Suzuki coupling • cobalt • aryl halides • N-
J. M. Neely, M. J. Bezdek, P.J. Chirik, ACS Cent. Sci. 2016, 2, 935.
heterocyclic carbenes • catalysis
[10] For a review of cobat-catalyzed cross-coupling, see: G. Cahiez, A.
Moyeux, Chem. Rev. 2010, 110, 1435.
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2011, pp 213−262.
[11] For an example of a reported Co-catalyzstuff for sendinged Suzuki biaryl
cross-coupling performed under extremely high pressure, see: Y Guo, D.
J. Young, T. S. A. Hor, Tetrahedron Lett. 2008, 49, 5620.
[12] See supporting information.
[2]
[3]
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[4]
[5]
F.-S. Han, Chem. Soc. Rev. 2013, 42, 5270.
[15] Complex 6a was also produced using the borate 1b.
[16] L. Zhang, Y. Liu, L. Deng, J. Am. Chem. Soc. 2014, 136, 15525.
[17] D. Zhu, P. H. M. Budzelaar, Organometallics 2010, 29, 5759.
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Shields, E. E. Gray, A. G. Doyle, Org. Lett. 2015, 17, 2166.
[18] Furthermore,
a competition reaction between a mixture of 4-
chlorotoluene and 4-ethylbromobenzene and 1a catalyzed by CoCl2/SIPr,
quenched after 8 hours, showed an ~ 60:40 ratio of the coupled products
derived from the chloride and bromide substrates respectively. See
supporting information for details.
[6]
a) R. B.Bedford, M. A. Hall, G. R. Hodges, M. Huwe, M. C. Wilkinson,
Chem. Commun. 2009, 6430; b) T. Hatakeyama, T. Hashimoto, Y.
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Entry for the Table of Contents (Please choose one layout)
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Soneela Asghar, Sanita B. Tailor, David
Elorriaga and Robin B. Bedford*
Page No. – Page No.
Cobalt-catalyzed Suzuki biaryl
coupling of aryl halides
Co-ming of age: Simple cobalt-N-heterocyclic carbene-based catalysts allow facile
Suzuki cross-coupling of aryl chloride and bromide substrates.
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