A highly practical and reliable nickel catalyst for Suzuki-Miyaura coupling of aryl halides

Article abstract of DOI:10.1002/adsc.201100101

We disclose that [1,3-bis(diphenylphosphino)methane]nickel(II) chloride [NiCl₂(dppp)] is a highly active, universally applicable, cheap, and stable catalyst for Suzuki-Miyaura cross-coupling reactions of aryl halides with a catalyst loading of lower than 1 mol%, and more notably, in the absence of extra supporting ligands. Under the optimized reaction conditions, a broad range of aryl bromides as well as the notoriously unreactive aryl chlorides, including activated, non-activated, deactivated, and heteroaromatic and sterically hindered substrates can be coupled smoothly with various boronic acids (47 examples, 48-98% yields). In addition, the transformation is tolerant of various functional groups such as ether, ester, ketone, aldehyde, cyano, and unprotected amino and hydroxy groups. Finally, the potential utilization of the methodology was further demonstrated by the gram-scale synthesis of several core structures of commercialized antihypertensive drugs and fungicides. Thus, the combination of high activity, broad applicability, cheapness, and high stability of NiCl₂(dppp) presented in this work constitutes one of the few prominent catalysts which allow for practical and reliable construction of biaryls and heterobiaryls with structural diversity from readily available aryl halides and boronic acids. Copyright

Full text of DOI:10.1002/adsc.201100101

FULL PAPERS
DOI: 10.1002/adsc.201100101
A Highly Practical and Reliable Nickel Catalyst for Suzuki–
Miyaura Coupling of Aryl Halides
Yu-Long Zhao,a,b You Li,b Shui-Ming Li,a Yi-Guo Zhou,a Feng-Yi Sun,a
Lian-Xun Gao,a and Fu-She Hana,c,*
a
Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, Jilin 130022,
Peopleꢀs Republic of China
Fax : (+86)-431-8526-2926; phone: (+86)-431-8526-2936; e-mail: fshan@ciac.jl.cn
Department of Chemistry, Northeast Normal University, Changchun, Jilin 130024, Peopleꢀs Republic of China
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, Peopleꢀs Republic of China
b
c
Received: February 10, 2011; Published online: June 16, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100101.
Abstract: We disclose that [1,3-bis(diphenylphosphi- protected amino and hydroxy groups. Finally, the po-
no)methane]nickel(II) chloride [NiCl2ACTHNUTRGNEUNG(dppp)] is a tential utilization of the methodology was further
highly active, universally applicable, cheap, and demonstrated by the gram-scale synthesis of several
stable catalyst for Suzuki–Miyaura cross-coupling re- core structures of commercialized antihypertensive
actions of aryl halides with a catalyst loading of drugs and fungicides. Thus, the combination of high
lower than 1 mol%, and more notably, in the absence activity, broad applicability, cheapness, and high sta-
of extra supporting ligands. Under the optimized re- bility of NiCl2ACTHNUTRGNEU(GN dppp) presented in this work consti-
action conditions, a broad range of aryl bromides as tutes one of the few prominent catalysts which allow
well as the notoriously unreactive aryl chlorides, in- for practical and reliable construction of biaryls and
cluding activated, non-activated, deactivated, and heterobiaryls with structural diversity from readily
heteroaromatic and sterically hindered substrates available aryl halides and boronic acids.
can be coupled smoothly with various boronic acids
(47 examples, 48–98% yields). In addition, the trans-
formation is tolerant of various functional groups Keywords: aryl bromides; aryl chlorides; biaryl for-
such as ether, ester, ketone, aldehyde, cyano, and un- mation; nickel catalysts; Suzuki coupling
Introduction
phenyl-based structures to the unstable polyfluoro-
phenyl and 2-heterocyclic analogues.
The transition metal-catalyzed cross-coupling reaction
On the other hand, since the first report on the
2
2
À
is an exceedingly powerful tool for the sp -sp C C NiCl2ACTHNUGTRNEUNG(dppf)-catalyzed Suzuki–Miyaura coupling of
bond formation. This has been well recognized with aryl sulfonates in the presence of a zinc reductant,[6]
the 2010 Nobel Prize for Chemistry awarded to Profs. numerous efforts have been devoted to the develop-
R. Heck, E. Negishi, and A. Suzuki.[1] Among the re- ment of inexpensive Ni-based catalysts, with NiCl2
ported pathways, the Suzuki–Miyaura reaction repre-
ACHTGNURETN(NUNG PCy3)2, NiACHUTNGTRENN(GU cod)2, NiCl2ACHNUTEGRTG(NNNU PPh3)2, NiCl2ACHTNUGTRNE(NUGN dppf), and
sents arguably the most important and widely used nickel/N-heterocyclic carbene (NHC) systems being
one.[2] The Pd-catalyzed couplings have been exten- frequently studied. Great success has been achieved
sively studied over the past decades,[2,3] they allow one recently for the coupling of various phenol derivatives
to conduct the reaction of various aryl halides (or such as aryl sulfonates,[7] ethers,[8] esters,[9] carba-
pseudohalides) even at room temperature,[4] and to mates,[10] carbonates,[10a] sulfamates,[10a] phosphates,[11]
handle sterically hindered substrates.[5] Also notably, a phosphoramides,[12] and phosphonium salts.[13] In addi-
very recent contribution from Buchwaldꢀs group[4d] tion, the coupling of aryl halides has also been report-
has expanded remarkably the scope of boronic acids,
ed.[7c,g,14] However, despite these great efforts, a limit-
ACHTUNGTRENNUNG
the second coupling partner, from the common ed substrate scope or a high loading of the nickel
complex (typically 3–10 mol%) paired with the extra
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Table 1. Suzuki–Miyaura coupling of 1-bromonaphthalene
(1a) with various arylboronic acids.[a]
addition of a large excess of supporting ligands (1–
5 equiv.) have restricted their general use. For in-
stance, the expense of a large excess of ligands dimin-
ished the advantages of using nickel catalysts since
many ligands are much more expensive even than the
precious metals such as palladium. In addition, the
separation of products from ligands is an important
concern. Consequently, these issues go against the
philosphy of modern synthesis referred to as efficient,
clean and atom-economic.[15]
Thus, there is great interest in developing a highly
active nickel catalyst that enables the general and
practical coupling of aryl halides, especially aryl chlor-
ides, because these substrates are commercially bulk
chemicals and have been widely used for the prepara-
tion of organic building blocks, pharmaceuticals, and
agrochemicals in industry via the transition metal-cat-
alyzed coupling protocols.[16] We have recently dem-
onstrated that a combination of NiCl2 and dppp could
be an effective precatalyst for the Suzuki–Miyaura
coupling of a broad range of phenol derivatives such
as aryl sulfonates,[7h] phosphoramides,[12] and phospho-
nium salts,[13] although several groups have shown
that dppp was inefficient in nickel-catalyzed Suzuki–
Miyaura coupling either as an external ligand or
when prior complexed with nickel.[7b,9a,14a,b] On the
basis of our recent results and our long-standing inter-
est in the development of highly active catalysts
based on the inexpensive and readily available first-
row transition metals, herein, we disclose the NiCl2
ACHTUNGTRENNUNG(dppp)-catalyzed Suzuki–Miyaura coupling of aryl
[a]
halides. Our results showed that this catalyst is a
highly active, stable, cheap, and universally applicable
catalyst, which allows for the efficient cross-coupling
of a rich variety of aryl halides, particularly, the more
challenging aryl chlorides with a catalyst loading of
lower than 1 mol% without the need of external li-
gands. Moreover, the practicality of the catalyst was
further exemplified by the efficient elaboration of
several commercial drug motifs on a gram-scale.
Reaction conditions: 1-bromonaphthalene 1a (1.0 mmol),
boronic acid
2 (1.5 mmol), NiCl2ACHTUNGTNRUEGN(dppp) (1.0 mol%),
K3PO4 (3.0 equiv.), dioxane (4 mL), 1008C, 2–12 h.
Isolated yield.
[b]
[c]
Yield was determined by 1H NMR analysis due to the
contamination of a small amount of inseparable by-prod-
uct produced from homo-coupling of boronic acids.
A mixture of dioxane and DMF (v/v=8:1) was used as
solvent.
[d]
Results and Discussion
2a proceeded smoothly to afford the desired product
in 90% isolated yield (Table 1, entry 1). In addition,
complete conversion as well as excellent yields was
also observed for various boronic acids (2b–g) whose
Cross-Coupling of Aryl Bromides
In our initial studies, we carried out the optimization structures are decorated by a strong electron-donating
of the reaction conditions using the coupling of 1-bro- OMe and NH2 (entries 1 and 2), simple Me and H
monaphthene 1a and 2a as
a model reaction (entries 3–5), and electron-withdrawing CO2Me and
(Table 1). On the basis of our previous experience in C(O)Me functional groups (entries 6 and 7). Notably,
Ni-catalyzed Suzuki–Miyaura cross-coupling of phe- the tolerance of a free NH2 group offers an opportu-
nols,[7h,12,13] we quickly established that the optimized nity for the straightforward synthesis of polyaromatic
conditions, after examining various reaction parame- amines (see also entry 11 in Table 2 and entry 2 in
ters including solvent, base, temperature, and precata- Table 3). The reaction also tolerates ortho-substituted
lyst, were NiCl2ACTHNUTRGNEUNG
(dppp)[17] (1 mol%), boronic acid boronic acids (entry 4). It should be mentioned that
(1.5 equiv.), and K3PO4 (3.0 equiv.) in dioxane at the somewhat diminished yield (48%) for unprotected
1008C. Under these conditions, the reaction of 1a and 4-hydroxyphenylboronic acid (2h) is due most proba-
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A Highly Practical and Reliable Nickel Catalyst for Suzuki–Miyaura Coupling of Aryl Halides
Table 2. Suzuki–Miyaura cross-coupling of various aryl bromides with arylbor-
onic acids.[a]
[a]
Reaction conditions: aryl bromide 1 (1.0 mmol), boronic acid 2 (1.5 mmol),
NiCl
2ACHTUNGTREN(UNNG dppp) (1.0 mol%), K3PO4 (3.0 equiv.), dioxane (4 mL), 1008C, 2–
12 h.
Isolated yield.
[b]
bly to the formation of potassium phenoxide salt that the activated aryl bromides (entries 5–9) could be
is less soluble in the dioxane solvent used (entry 8). coupled successfully with various boronic acids to
The broad applicability of this transformation was generate the desired biaryls in high yields. In addition,
further exemplified by examining the scope of aryl the reaction tolerates not only ortho-substituents on
bromides. As summarized in Table 2, the unactivated the boronic acids (Table 1, entry 4), but also the same
(entries 1 and 2), deactivated (entries 3 and 4), and steric hindrance on the aryl bromides (Table 2,
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Table 3. Suzuki–Miyaura Cross-coupling of 1-chloronaphtha-
lene (1b) with various arylboronic acids.[a]
entry 5). The examples from entries 10 to 15 demon-
strate the viability of heteroaryl bromides in this
transforamtion. For instance, bipyridines and fused
quinoline derivatives underwent smooth coupling
with various boronic acids, affording the desired poly-
heteroaromatic compounds in excellent yields. These
results are attractive since polypyridyl compounds are
ubiquitous structural scaffolds found in polymers, bio-
active compounds, coordination complexes, catalysis
and supramolecular materials.
Cross-Coupling of Aryl Chlorides
With the robust cross-coupling conditions for aryl
bromides established, we further examined the cata-
lytic efficacy of the catalyst by executing the cross-
coupling of aryl chlorides. This class of substrates is
more appealing as coupling partner in comparison
with the analogous aryl bromides and iodides due to
the lower cost and the wider availability. However,
the notoriously unreactive nature of aryl chlorides
makes their coupling reactions considerably more
challenging.[2–5,7g,14] The low reactivity is attributed to
À
the much higher bond energy of the C Cl bond than
those of the C Br and C I bonds, which results in
their reluctance to participate in oxidative addition.
[18]
À
À
Much to our delight, we found that NiCl2ACTHUNTGRENNG(U dppp) is a
prominent catalyst to couple aryl chlorides under the
similar conditions as used to couple aryl bromides,
except for a slightly increased molar equivalent of ar-
ylboronic acids and K3PO4 base. As shown in Table 3,
1-chloronaphthalene underwent smooth coupling with
a range of boronic acids whose structures are substi-
tuted by versatile functional groups such as electron-
rich OMe and the unprotected NH2, neutral Me and
H, and electron-deficient CO2Me and C(O)Me
groups (entries 1–7). Boronic acids with an unprotect-
ed amino group and an ortho-substituted boronic acid
also serve as superb coupling partners, affording the
[a]
Reaction conditions: 1-chloronaphthalene 1b (1.0 mmol),
boronic acid 2 (2.0 mmol), NiCl2ACTHNUTRGNEUNG(dppp) (1.0 mol%),
K3PO4 (4.0 equiv.), dioxane (4 mL), 1008C, 2–20 h.
Isolated yield.
[b]
[c]
[d]
Reaction was run at 1108C.
Yield was determined by 1H NMR analysis due to the
contamination of a small amount of inseparable by-prod-
uct derived from homo-coupling of boronic acids.
A mixture of dioxane and DMF (v/v=8:1) was used as
solvent.
[e]
corresponding coupled products in high yields (en- tion was also tolerant of various activated aryl chlor-
tries 2 and 4).
ides, encompassing a range of functional groups in-
Next, the catalytic efficiency of NiCl2AHCTUNGRETG(NNUN dppp) was cluding ortho- and para-substituted aldehydes (en-
further confirmed by varying the structure of the aryl tries 4 and 5), as well as cyano groups (entries 6–9),
chlorides. Thus, 2-chloronaphthalene could be trans- ketone (entry 10), and ester (entry 11). It is notewor-
formed into the desired product in 95% yield thy that the substrates with a cyano or aldehyde
(Table 4, entry 1). Most importantly the non-fused group at the ortho-position of the aryl chloride pro-
aryl chlorides, whose coupling under Suzuki–Miyaura vided the coupled biaryls in excellent yields (entries 5,
conditions often appears to be very challenging due 8 and 9). These results, together with that observed
to the less delocalized nature, are also viable sub- from the sterically hindered boronic acid (Table 3,
strates, affording the desired biaryls in good to excel- entry 4), indicate that the transformation exhibits
lent yields. For instance, reaction of the non-activated good tolerance of steric hindrance not only on aryl
phenyl chloride with 4-methoxyphenylboronic acid chlorides but also on boronic acids. As important ap-
provided the biaryl in 94% yield (entry 2). The deacti- plications for the couplings of these sterically hin-
vated 3-N,N-dimethylaminophenyl chloride under- dered substrates, they offer practical pathways for the
went smooth cross-coupling, affording the desired synthesis of several core motifs of commercialized
product in 71% yield (entry 3). In addition, the reac- drugs and bioactive compounds (vide infra). Finally,
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A Highly Practical and Reliable Nickel Catalyst for Suzuki–Miyaura Coupling of Aryl Halides
Table 4. Suzuki–Miyaura cross-coupling of various aryl chlorides with arylboronic
acids.[a]
[a]
Reaction conditions: aryl chloride 1 (1.0 mmol), boronic acid 2 (2.0 mmol), NiCl2
AHCTUNGTERGN(NNU dppp) (1.0 mol%), K3PO4 (4.0 equiv.), dioxane (4 mL), 100–1108C, 2-18 h.
Isolated yield.
[b]
the methodology also displays good compatibility to vated 3- and 4-chloropyridines (entries 12 and 13)
heteroaromatic chlorides (entries 12–14), although a were coupled slightly more efficiently than the acti-
somewhat interesting observation is that the deacti- vated 2-chloropyridine (entry 14). Such a similar
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Yu-Long Zhao et al.
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Scheme 1. Synthesis of core structure 8 of Boscalidꢂ (9).
result was also observed in the closely related Stille um salt and boronic acid 6 was also reported recent-
cross-coupling catalyzed by Pd2A
(dba)3.[19] ly.[22] Alternative pathways for the construction of 8
Now, we have clearly demonstrated that by careful included the palladium-catalyzed cross-coupling of ar-
optimization of the reaction conditions, NiCl2A
(dppp) ylgermane and aryl bromides,[23] and free radical-in-
can be a highly active catalyst to effect the cross-cou- duced cross-coupling of aryldiazonium salts.[24]
pling of a rich range of aryl halides. In contrast, out- To examine the efficiency of our methodology, we
comes from the work of Miyaura[14a] and Indolese[14b] synthesized 8 on the gram-scale starting from 2-
showed that NiCl2A(dppp) [or NiCl2A(dppe)] was less ef- chlorobenzonitrile (5). As outlined in Scheme 1, cou-
CTHUNGTRENNUNG
CTHUNGTRENNUNG
C
E
ACHTUNGTRENNUNG
ficient to couple aryl halides and boronic acids under pling of 5 with a slightly excess of 6 (1.1 equiv.) pro-
their reaction conditions either by prior reducing the ceeded smoothly in the presence of only 0.4 mol% of
nickel(II) to nickel(0) with BuLi[14a] or by employing our NiCl
2ACTHUNRTGNE(GNU dppp) catalyst to afford the coupled prod-
anisole as solvent.[14b] As a plausible explanation, it uct 7 in high yield. Hydrolysis followed by Hofmann
was suggested that NiCl2 complexes with dppp and rearrangement of 7 gave the desired key structure 8
dppe could form highly stable six- and five-membered in 82% yield over two steps (an unoptimized trial
chelates which was unfavourable for the dissociation showed that the later two-step transformation can be
of one phosphorus during the catalytic cycle. And combined into a one-pot operation without decreasing
since then, these two highly stable and readily avail- the yield). This approach offers an advantage over the
able catalysts have been less investigated over the available methods in terms of the cost of catalyst. In
past decade in the Suzuki–Miyaura coupling of aryl addition, the method is environmentally more benign
halides (and pseudohalides).
than the reported ones since the subsequent hydroly-
sis and Hofmann rearrangement of 7 were carried out
under clean conditions, avoiding the disposal of iron
waste generated from the reduction of the nitro
group.[22]
Potential Applications
To demonstrate the potential utility of our methodol-
The practicality of this transformation was further
ogy, the synthesis of 2-amino-4’-chlorobiphenyl (8) exemplified by the synthesis of biphenyl derivatives
was performed (Scheme 1). This compound is the 11 and 12 in a gram-scale operation (Scheme 2).
core motif of a new fungicide, Boscalidꢂ (9), which is These two biaryls are key intermediates for the syn-
currently one of the largest industrial applications of thesis of antihypertensive drugs such as losartan, irbe-
Suzuki–Miyaura reaction (ca. 1000 tons per year).[16,20] sartan, and valsartan,[25] or AT II antagonists,[1,16] and
Of the available approaches for accessing 8, palladi- also represent one of the most important industrial
um-catalyzed cross-couplings were exclusively used as applications of the Pd-catalyzed Suzuki–Miyaura re-
the key transformation. The industrial process in- action.[26] Here, by employing only 0.4 and 1.0 mol%
volves the palladium-catalyzed Suzuki coupling of 1- of NiCl2ACTHNUTRGNEUNG(dppp) as catalyst, ortho-substituted 2-chloro-
chloro-2-nitrobenzene with 4-chlorophenylboronic benzonitrile (5) or 2-chlorobenzaldehyde (10) could
acid (6), followed by the reduction of the nitro group be coupled efficiently with a slight excess (1.05 equiv.)
to an amino group.[21] A similar method via the palla- of 4-methylphenylboronic acid (2c) to afford 11 and
dim-catalyzed cross-coupling of 2-nitrophenyldiazoni- 12, respectively, in high yields.
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A Highly Practical and Reliable Nickel Catalyst for Suzuki–Miyaura Coupling of Aryl Halides
Scheme 2. Gram-scale synthesis of biphenyls 11 and 12.
Ltd and Alfa Aesar, respectively. The 1H NMR and
Conclusions
13C NMR spectra were recorded at 400 and 100 MHz (or
600 and 125 MHz), respectively, in CDCl3 with TMS as in-
ternal standard. All chemical shifts were given in ppm. All
coupling constants (J values) are reported in Hertz (Hz).
High resolution mass spectra were measured by using Ion-
Spec 7.0T MALDI-FT-ICRMs. Column chromatography
was performed on silica gel 100 mesh. Melting points were
obtained on a Laboratory Devices Mel-Temp II instrument
and were uncorrected.
In summary, through an extensive study, we have un-
ambiguously demonstrated that NiCl2ACTHNUTRGNE(NUG dppp) is a relia-
ble and practical catalyst for Suzuki–Miyaura cross-
couplings of aryl bromides and chlorides. The reaction
proceeds smoothly with a catalyst loading lower than
1.0 mol% and, more notably, without the need of
extra supporting ligands. Moreover, the transforma-
tion tolerates a wide variety of aryl bromide and chlo-
ride electrophiles, as well as boronic acid nucleo-
philes, including activated, non-activated, deactivated,
and heterocyclic and sterically hindered substrates.
Also, a rich range of functional groups such as ether,
ester, ketone, aldehyde, cyano and unprotected amino
and hydroxy groups are compatible. In addition, the
potential application of this methodology was further
demonstrated by the elaboration of two core motifs
of commercialized sartan-type drugs and a fungicide
in gram-scale operations. Consequently, the results
presented in this work, along with those disclosed pre-
viously by us for the coupling of aryl sulfonates,[7h]
phosphoramides,[12] and phosphonium salts[13] clearly
exemplified that an appropriate combination of NiCl2
and dppp ligand is a highly active and universally ap-
plicable catalyst for Suzuki–Miyaura coupling of both
phenol derivatives and aryl halides. These advantages
combined with the high stability and ready availability
General Procedure for the Small Scale Suzuki–
Miyaura Cross-Coupling Reactions of Aryl Halides
with Arylboronic Acids
To a 25-mL Schlenk tube equipped with a magnetic stir bar
were added NiCl2ACTHNUTRGNEUNG(dppp) (0.01 mmol, 5.4 mg), aryl halides
(1.0 mmol), arylboronic acids (1.5 mmol), and anhydrous
K3PO4 (3.0 mmol) (2.0 and 4.0 mmol of boronic acids and
K3PO4 were used, respectively, in the case of aryl chlorides).
The tube was then evacuated (3ꢄ10 min) under vacuum and
backfilled with N2. Dried dioxane (4.0 mL) was injected via
a syringe, and the reaction mixture was stirred at 100–1108C
until the aryl halides had disappeared as monitored by TLC.
The reaction mixture was poured into water (30 mL) and
then extracted with CH2Cl2 (20 mLꢄ3). The combined or-
ganic layer was dried over anhydrous Na2SO4, filtered and
concentrated to dryness. The crude material was purified by
flash chromatography on silica gel using a mixture of
hexane and CH2Cl2 (or hexane and ethyl acetate) as eluents
to give the desired cross-coupled products. See the Support-
ing Information for characterization data, and copies of
1H NMR and 13C NMR spectra of the coupled products.
render NiCl2ACHTUNGTRENNUNG(dppp) one of the few catalysts for practi-
cal and reliable Suzuki–Miyaura cross-couplings not
only in academic research, but also in industrial appli-
cations. Finally, the high activity of NiCl2ACTHNUTRGNEU(GN dppp) as
evidenced by the Suzuki–Miyaura reaction implies
that this catalyst may also be suitable for other transi-
tion metal-catalyzed reactions such as Heck and Stille
cross-couplings. Investigations on these reactions are
currently underway in our laboratory.
Acknowledgements
F.-S. Han is grateful to CAS (Hundred Talent Program) and
State Key Laboratory of Fine Chemicals (KF1008) for finan-
cial support. Y.-L. Zhao is grateful for the support of CPSF
(20090451144)
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