Cobalt-Catalyzed Cross-Coupling Reactions of Arylboronic Esters and Aryl Halides

Article abstract of DOI:10.1021/acs.organomet.7b00726

An efficient cobalt catalyst system for the Suzuki-Miyaura cross-coupling reaction of arylboronic esters and aryl halides has been identified. In the presence of cobalt(II)/terpyridine catalyst and potassium methoxide, a diverse array of (hetero)biaryls have been prepared in moderate to excellent yields.

Full text of DOI:10.1021/acs.organomet.7b00726

Communication
pubs.acs.org/Organometallics
Cite This: Organometallics XXXX, XXX, XXX-XXX
Cobalt-Catalyzed Cross-Coupling Reactions of Arylboronic Esters and
Aryl Halides
Hung A. Duong,* Wenqin Wu, and Yu-Yuan Teo
Organic Chemistry, Institute of Chemical and Engineering Sciences (ICES), Agency for Science, Technology and Research
(A*STAR), 8 Biomedical Grove, Neuros #07-01, Singapore 138665, Singapore
S
* Supporting Information
ABSTRACT: An efficient cobalt catalyst system for the Suzuki−Miyaura cross-
coupling reaction of arylboronic esters and aryl halides has been identified. In the
presence of cobalt(II)/terpyridine catalyst and potassium methoxide, a diverse
array of (hetero)biaryls have been prepared in moderate to excellent yields.
Scheme 1. Iron- and Cobalt-Catalyzed Suzuki−Miyaura
Cross-Coupling Reactions
he Suzuki−Miyaura cross-coupling reaction is currently
Tone of the most frequently employed methods for
carbon−carbon bond formation in organic synthesis, including
the manufacture of complex small-molecule intermediates and
active pharmaceutical ingredients (APIs) on a commercial
scale.1 Catalysts based on palladium are predominantly used for
this purpose. Palladium, however, is a precious metal with high
price volatility and is prohibitively expensive when required in
large quantities. Thus, the search for alternative catalytic
processes employing inexpensive and highly abundant first-row
transition metals such as iron and cobalt represents an
important approach toward sustainable chemistry.
In comparison to nickel and copper,2,3 much less has been
achieved with iron and cobalt as catalyst in the Suzuki−Miyaura
reaction, presumably due to the difficulty associated with
transmetalation from boron to these earlier transition metals.4
Indeed, iron- and cobalt-catalyzed cross-coupling reactions are
generally accomplished with more reactive organometals in
Kumada- and Negishi-type reactions.5,6 To facilitate trans-
metalation, organoboron compounds can be activated by highly
reactive organolithium and organomagnesium reagents for
cross-coupling reactions under iron catalysis (Scheme 1a).7
Recently, Chirik et al. developed a bis(phosphino)pyridine
cobalt catalyst for the cross-coupling of aryl triflates and
(benzo)furanylboronic esters in the presence of an alkaline
alkoxide (Scheme 1b).8 Presumably, transmetalation was
enabled through initial coordination of the oxygen lone pair
in the heteroarylboron nucleophile to the metal center.
Concurrently, Kumar and Bhat reported an N,N′-bis-
(phosphino)-2,6-diaminopyridine pincer cobalt acetate com-
plex as catalyst for the cross-coupling of phenylboronic acid and
aryl halides (Scheme 1b).9 Notably, the scope of the
organoboron nucleophile was not described beyond phenyl-
boronic acid. We report herein a cobalt catalyst system capable
of cross-coupling a wide range of organoboronic esters with
(hetero)aryl halides, leading to a diverse array of (hetero)biaryl
products (Scheme 1b).
To probe any potential reactivity of organoboron com-
pounds under cobalt catalysis, we started out to explore the
reactions of different arylboron reagents with 2-chloropyridine
(1a), an activated substrate that had been well-studied in iron-
and cobalt-catalyzed Kumada and Negishi cross-coupling
reactions (Table 1).5a,6 After some experimentation with
different alkoxides,10 we realized that 3a could be formed in a
moderate yield in the reaction of 1a with PhB(neo) (2a) in the
presence of 12 mol % of CoCl2 and 1.5 equiv of KOMe (Table
1, entry 1). Since bis(phosphino)pyridine, pyridine diimine,
and terpyridine pincer ligands are known to support cobalt
complexes in C(sp2)−H borylation and cross-coupling
reactions,8,11 we evaluated some easily accessible or commer-
cially available ligands belonging to these families (entries 3−
5). 4′-Phenyl-2,2′:6′,2-terpyridine (TPy) was found to serve as
Received: September 26, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.7b00726
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
Table 1. Optimizations of the Co-Catalyzed Cross-Coupling
of 1a and 2a
Table 2. Scope of Arylboronic Esters in the Co-Catalyzed
Reaction
a
a
a
entry
[Co]
L
solvent
conversn (%)
yield (%)
1
2
3
4
5
6
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
none
none
bipy
tBuPNP
PDI
TPy
TPy
TPy
TPy
TPy
TPy
TPy
TPy
TPy
TPy
TPy
TPy
TPy
THF
THF
THF
THF
THF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
61
87
51
16
100
100
100
47
8
38
41
31
2
a
90
94
93
46
7
Conditions: 5 mol % of CoCl2, 5 mol % of TPy, 1.5 equiv of
ArB(neo), 1.5 equiv of KOMe, DMF, 80 °C, 16 h.
b
7
c
8
d
naphthylboronic ester proceeded under cobalt catalysis to
give 3f in an excellent yield of 95%. 2-Thienylboronic ester
underwent the coupling reaction in 75% yield, whereas the
reaction of 2-furanylboronic ester resulted in only 46% of 3h
with full consumption of 1a. We suspected that the latter could
be due to the instability of the heteroarylboron reagent.
However, an increase of 2-furanylboronic ester to 3.0 equiv (in
the presence of 1.5 or 3.0 equiv of KOMe) did not help
improve the reaction yield.
9
e
10
100
16
80
15
9
92
0
11
12
13
14
15
PdCl2
NiCl2
CuCl
12
8
0
FeCl2
CoCl2
CoCl2
0
0
f
16
85
52
75
g
17
40
A variety of 2-chloro- and 2-bromopyridines can be coupled
with 2a in moderate to excellent yields (Table 3). In
comparison to 2-chloropyridine, 2-bromopyridine gave a
slightly lower yield in the coupling with 2a to afford 3a in
86% isolated yield. 2-Halopyridines featuring electron-donating
and electron-withdrawing groups all gave the arylated products
in good yields (3j−l,n). Lower yields were obtained with the
highly activated ester 3m, and those featuring a β-substituent
(3i,o), presumably due to reduced steric accessibility. Other N-
heteroaryl chlorides, including 2-chloroquinoline (3p), 2-
chloropyrimidine (3q), and 2-chloropyrazine (3r), could be
coupled with 2a in good yields.
3-Chloropyridine was less reactive than 3-bromopyridine,
affording 3s in only 25% yield as determined by GC analysis.
Further exploration reveals that the cobalt-catalyzed reaction is
applicable to both π-electron-rich and π-electron-deficient
heteroaryl bromides featuring diverse substitution patterns.
Heterobiaryls incorporating pyrimidine, imidazole, quinoline,
thiophene, and furan units could be prepared in good yields
(3u−3aa). Reactions of 2,5-dichloropyridine and 2-chloro-5-
bromopyridine with a reduced amount of PhB(neo) (1.2 equiv)
to minimize diarylation gave the monophenylated products
3ab,ac in 94% and 74% yields, respectively. 2-Chloro-5-
phenylpyridine was also obtained in 8% yield in the latter.
Phenyl (pseudo)halides were poor substrates in the cobalt-
catalyzed reaction (Table 4). Chlorobenzene and phenyl
tosylate failed to give any trace of 3ad, while the reactions of
iodobenzene, bromobenzene, and phenyl triflate resulted in
mainly decomposition, presumably due to protodehalogena-
tion.14 Running the reactions at a higher temperature (e.g., 100
°C) did not help improve the reaction yield. This is rather
surprising, considering the reactivity displayed by π-electron-
rich 2-bromothiophene (3z) and 2-bromofuran (3aa) (Table
a
b
Determined by GC using dodecane as an internal standard. 5 mol %
CoCl2 and 5 mol % TP were used, and the reaction was run at 80 °C.
c
d
0.5 equiv of KOMe was employed. KOtBu was employed instead of
e
f
KOMe. KOEt was employed instead of KOMe. PhB(OH)2 was
employed instead of PhB(neo). PhB(pin) was employed instead of
PhB(neo).
g
an excellent ligand, as 3a was obtained in 90% yield (entry 5).
Running the reaction in DMF at 80 °C allowed the catalyst
loading to be lowered to 5 mol % without any erosion in yield
(entries 6 and 7). A reduction of KOMe to 0.5 equiv led to an
incomplete conversion of 1a (entry 8). Regarding the base
additive, the activity of KOEt was similar to that of KOMe,
whereas sterically hindered tert-butoxide performed poorly in
the reaction (entries 9 and 10).12 While the reaction with
99.998% CoCl2 exhibited a comparable level of activity, no
product was observed in the absence of a cobalt salt (entry 11).
Other metal catalysts (i.e., Pd, Ni, Cu, and Fe) resulted in poor
yields of 3a under similar conditions (entries 12−15). These
results confirmed cobalt as the active catalyst in this reaction.
Reactions employing PhB(OH)2 or PhB(pin) as the organo-
boron nucleophile were less efficient, resulting in an incomplete
conversion of 1a after heating at 80 °C for 16 h (entries 16 and
17).13
The developed conditions were amenable to the cross-
coupling of a range of boronic esters with 1a (Table 2). Both
electron-rich and electron-deficient arylboronic esters were
efficiently coupled with 1a to give 3b,c in 84% and 90% yields,
respectively. A moderate yield of 3d was obtained in the
reaction of electronically deactivated 4-cyanophenylboronic
ester. Sterically hindered 2-methylphenylboronic ester reacted
with 1a to give 3e in 78% yield. The reaction of 2-
B
DOI: 10.1021/acs.organomet.7b00726
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
Table 3. Scope of Heteroaryl Halides in the Co-Catalyzed
Reaction
Table 4. Scope of Aryl Halides in the Co-Catalyzed
a
a
Reaction
a
Conditions: 5 mol % of CoCl2, 5 mol % of TPy, 1.5 equiv of
b
ArB(neo), 1.5 equiv of KOMe, DMF, 80 °C, 16 h. Determined by
GC/GCMS analysis.
with 2a to give 3af in 60% yield, whereas less activated 4-
chlorobenzotrifluoride (3ae) and 4-chloroacetophenone (3ag)
resulted in a significant decomposition of the aryl chlorides.14
To probe whether the aryl halide is involved in catalyst
activation, we reacted 1af with CoCl2 (1 equiv), TPy (1 equiv),
and KOMe (1 equiv) (Scheme 2a). 1af was chosen because the
protodebromination product (benzonitrile), if formed, could be
monitored by GC/GCMS. However, 1af was fully recovered
after the reaction. On the other hand, a stoichiometric reaction
Scheme 2. Experiments To Probe Catalyst Activation
Pathway
a
Conditions: 5 mol % of CoCl2, 5 mol % of TPy, 1.5 equiv of
b
ArB(neo), 1.5 equiv of KOMe, DMF, 80 °C, 16 h. 2-Phenylpyridine
(3a) resulting from protodebromination of 3i was also obtained in ca.
14% yield. Determined by GC analysis. 1.2 equiv of ArB(neo) and
1.2 equiv of KOMe were used. 2-Chloro-5-phenylpyridine was also
c
d
e
obtained in 8% yield.
3). Possibly, initial coordination of the heteroatom in these
heterocycles to cobalt promotes the subsequent coupling event.
Electron-deficient aryl bromides were coupled with 2a under
cobalt catalysis to give 3ae,af in 77% and 74% yields,
respectively. 3ag incorporating a ketone functional group
could be synthesized in 52% yield. Methyl 3-bromobenzoate
was coupled with 2a to give 3ah in 65% yield, whereas 3ai was
not formed in the reaction of 1-bromo-3-nitrobenzene,
indicating the incompatibility of the cobalt catalyst with a
nitro functional group. The reaction of sterically hindered
methyl 2-bromobenzoate led to only an 11% yield of 3aj, as
determined by GC analysis of the reaction mixture. Both
electron-rich and electron-deficient arylboronic esters were
effective in the coupling reaction, as 3ak,al were formed in 73%
and 93% yields, respectively. 4-Chlorobenzonitrile was coupled
C
DOI: 10.1021/acs.organomet.7b00726
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
(3) For a review on copper-catalyzed Suzuki−Miyaura cross-coupling
reactions, see: Thapa, S.; Shrestha, B.; Gurung, S. K.; Giri, R. Org.
Biomol. Chem. 2015, 13, 4816−4827.
of PhB(neo) (2a), CoCl2 (1 equiv), and TPy (1 equiv)
(Scheme 2b) proceeded rapidly in the presence of KOMe
(entry 1). No conversion was observed in the absence of the
base additive (entry 2). These results indicate that catalyst
activation likely involves the reduction of Co(II) by an
arylborate species. Notably, Thomas et al. reported that an
alkoxide such as NaOtBu can form an “ate” species with HBpin
or silane that then serves as a reducing agent for cobalt and iron
complexes.15 Moreover, a reaction of 0.25 mmol of CoCl2/TPy
with excess PhB(neo)/KOMe resulted in only 0.117 mmol of
biphenyl even after prolonged heating (Scheme 2b, entry 3).
Since the formation of biphenyl from the organoboron is a two-
electron process, a stoichiometry close to 0.5 is in agreement
with a reduction of Co(II) to Co(I). Thus, it is possible that
Co(II) is reduced by phenylborate to a catalytically active
Co(I) species (Scheme 2c) and a Co(I)/Co(III) catalytic cycle
similar to that proposed by Chirik et al. could be in operation.8
Further studies are needed to evaluate this hypothesis and to
fully elucidate the mechanism of the cobalt-catalyzed reaction.
In conclusion, we have developed an efficient cobalt catalyst
system for the Suzuki−Miyaura cross-coupling of arylboron
reagents and aryl halides. The substrate scope encompasses a
broad array of π-electron-rich and π-electron-deficient hetero-
aryl halides and electron-deficient aryl halides. Further study is
now underway to gain more insights into the mechanism of the
cobalt-catalyzed reaction and to extend the chemistry to other
classes of substrates.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.7b00726.
(e2) Kylmala, T.; Valkonen, A.; Rissanen, K.; Xu, Y.; Franzen
́
, R.
̈
̈
Tetrahedron Lett. 2008, 49, 6679−6681. (f) Bez
́
ier, D.; Darcel, C. Adv.
Synth. Catal. 2009, 351, 1732−1736.
Experimental details and NMR spectra of the com-
pounds obtained in this paper (PDF)
(8) Neely, J. M.; Bezdek, M. J.; Chirik, P. J. ACS Cent. Sci. 2016, 2,
935−942.
(9) Kumar, L. M.; Bhat, B. R. J. Organomet. Chem. 2017, 827, 41−48.
(10) See the Supporting Information for more details on screening of
ligands, boron nucleophiles, solvents, and cobalt sources.
(11) (a) Obligacion, J. V.; Semproni, S. P.; Chirik, P. J. J. Am. Chem.
AUTHOR INFORMATION
Corresponding Author
*E-mail for H.A.D.: duong_hung@ices.a-star.edu.sg.
ORCID
Hung A. Duong: 0000-0003-0086-2463
Wenqin Wu: 0000-0002-0081-1458
Notes
■
́
Soc. 2014, 136, 4133−4136. (b) Leonard, N. G.; Bezdek, M. J.; Chirik,
P. J. Organometallics 2017, 36, 142−150.
(12) Two different KOMe batches purchased from Fluka and Sigma
Aldrich displayed a similar activity.
(13) For a comparative study of reactivity difference between
arylboron reagents in the Suzuki−Miyaura reaction, see: Zhang, N.;
Hoffman, D. J.; Gutsche, N.; Gupta, J.; Percec, V. J. Org. Chem. 2012,
77, 5956−5964 and references therein..
The authors declare no competing financial interest.
(14) The protodehalogenation products can be observed by GC-MS
in several cases, such as in the reactions to prepare 3m,af,ag,ah.
(15) Docherty, J. H.; Peng, J.; Dominey, A. P.; Thomas, A. P. Nat.
Chem. 2017, 9, 595−600.
ACKNOWLEDGMENTS
■
The financial support for this work was provided by “GSK-EDB
Singapore Partnership for Green and Sustainable Manufactur-
ing” and the Institute of Chemical and Engineering Sciences
(ICES), Agency for Science, Technology and Research
(A*STAR), Singapore.
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D
DOI: 10.1021/acs.organomet.7b00726
Organometallics XXXX, XXX, XXX−XXX