TBuLi-Mediated One-Pot Direct Highly Selective Cross-Coupling of Two Distinct Aryl Bromides

Article abstract of DOI:10.1002/chem.201502709

A Pd-catalyzed direct cross-coupling of two distinct aryl bromides mediated by tBuLi is described. The use of [Pd-PEPPSI-IPr] or [Pd-PEPPSI-IPent] as catalyst allows for the efficient one-pot synthesis of unsymmetrical biaryls at room temperature. The key for this selective cross-coupling is the use of an ortho-substituted bromide that undergoes lithium-halogen exchange preferentially. Bro to Bro: A palladium-catalyzed direct cross-coupling of two distinct aryl bromides mediated by tBuLi is described. The use of [Pd-PEPPSI-IPr] or [Pd-PEPPSI-IPent] as catalyst allows for the efficient one-pot synthesis of unsymmetrical biaryls at room temperature. The key for this selective cross-coupling is the use of an ortho-substituted bromide that undergoes lithium-halogen exchange preferentially.

Full text of DOI:10.1002/chem.201502709

DOI: 10.1002/chem.201502709
Communication
&
Cross-Coupling
tBuLi-Mediated One-Pot Direct Highly Selective Cross-Coupling of
Two Distinct Aryl Bromides
[a, b]
[a]
[a]
[a]
Carlos Vila,
Sara Cembellín, Valentín Hornillos, Massimo Giannerini, Martín FaÇanµs-
[a, c]
[a]
Mastral,
and Ben L. Feringa*
[
9]
[10]
[11]
[12]
plings, including Grignard, boron,
zinc,
tin
and sili-
Abstract: A Pd-catalyzed direct cross-coupling of two dis-
tinct aryl bromides mediated by tBuLi is described. The
use of [Pd-PEPPSI-IPr] or [Pd-PEPPSI-IPent] as catalyst
allows for the efficient one-pot synthesis of unsymmetrical
biaryls at room temperature. The key for this selective
cross-coupling is the use of an ortho-substituted bromide
that undergoes lithium–halogen exchange preferentially.
[13]
[14]
con
reagents. In contrast, organolithium reagents
have
found limited use in palladium-catalyzed cross-coupling reac-
[15]
tions. In 1979, following earlier stoichiometric approaches,
Murahashi pioneered the use of organolithium reagents in cat-
alytic cross-coupling reactions showing also the limitations as-
[16]
sociated with their high reactivity. Approaches based on Si-
[16f–h]
[16d,e]
transfer agents
and flow chemistry
have recently been
introduced and our group described the direct catalytic cross-
[
17]
coupling of organolithium compounds using aryl bromides,
[
18]
[19]
aryl chlorides and aryl triflates. However, these methods
all require the separate preparation of a stoichiometric organo-
Introduction
[
20,21]
metallic reagent,
being limited in some cases by the avail-
The development of synthetic methodologies for the prepara-
tion of unsymmetrical biaryls has attracted major interest over
ability and stability of the reagent itself.
The one-pot direct cross-coupling of two different aryl hal-
ides, would provide a more straightforward method for the
synthesis of unsymmetrical biaryls. There are some reports on
[1,2]
more than a century.
Biaryl compounds represent very im-
portant structures that have numerous applications in many
fields of chemistry. For example, the biaryl structural motif is
[
22]
the direct cross-coupling of distinct aryl halides involving Pd,
[3]
[23]
[24]
widely present in natural products and a very common
Ni or Co as the catalyst. These methodologies usually re-
quire additional reductive agents such as Zn, Mn, alcohols or
amines and sometimes harsh conditions, while, in the case of
nickel, electrochemical methods were employed. Normally, for
an effective synthesis of unsymmetrical biaryls, different hal-
ides with significant differences in reactivity are used, such as
[
4]
target in the pharmaceutical and agrochemical industry. Fur-
thermore, biaryls, especially chiral ones, play an important role
[5]
in privileged ligands in catalysis. Moreover, these compounds
[6]
have proven essential in material science. Transition metal-
mediated coupling reactions, among the innumerable meth-
ods for the construction of biaryls, are arguably the leading
cross-coupling of ArÀI with ArÀBr, ArÀI with ArÀCl, or ArÀBr
[
7]
[22–24]
strategies used. In this context, palladium-catalyzed cross-
coupling of arylmetal reagents and aryl (pseudo)halides to
form biaryls is one of the most effective methods, which has
fundamentally changed the chemist’s approach to biaryl com-
with ArÀCl.
Therefore, the development of alternative
strategies for the direct coupling of aryl halides for the synthe-
sis of unsymmetrical biaryls is highly warranted. We questioned
whether it would be possible to achieve the direct cross-cou-
pling of two different aryl bromides selectively, generating in
situ the organometallic reagent derived from one of these bro-
mides. One easy and fast method to generate an organometal-
lic compound in situ from an aryl bromide is the formation of
the corresponding aryllithium reagent via lithium–halogen ex-
[8]
pounds during the past 40 years. Many different aryl organo-
metallic reagents have been used in Pd-catalyzed cross-cou-
[
a] Dr. C. Vila, S. Cembellín, Dr. V. Hornillos, M. Giannerini,
Dr. M. FaÇanµs-Mastral, Prof. Dr. B. L. Feringa
Stratingh Institute for Chemistry, University of Groningen
Nijenborgh 4, 9747 AG, Groningen (The Netherlands)
Fax: (+31)50-363-4278
[
14]
change. The fundamental issue to solve is to achieve selec-
tive lithium–halogen exchange of one of the two aryl bromide
coupling partners. For this purpose, we envisioned the use of
E-mail: b.l.feringa@rug.nl
2
-bromoanisole, which undergoes faster lithium–halogen ex-
[
b] Dr. C. Vila
Present address: Departament de Química Orgànica, Facultat de Química
change than other aryl bromides lacking an ortho-directing
group (Scheme 1).
Universitat de Val›ncia, Dr. Moliner 50, 46100 Burjassot, Val›ncia (Spain)
[
c] Dr. M. FaÇanµs-Mastral
Recently, we developed a palladium-catalyzed cross-coupling
[
17]
Present address: Department of Organic Chemistry and Center for Research
in Biological Chemistry and Molecular Materials (CIQUS)
University of Santiago de Compostela, 15782 Santiago de Compostela
of aryl bromides with aryllithium reagents.
These results
prompted us to study the in situ formation of the organolithi-
um reagent via lithium–halogen exchange. In this way, we
could avoid the pre-formation of the organometallic reagent,
providing fast, versatile and more straightforward methodolo-
(
Spain)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502709.
Chem. Eur. J. 2015, 21, 15520 – 15524
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Communication
[a]
Table 1. Optimization of the direct cross-coupling.
[b]
Entry Pd source
tBuLi [equiv] Yield [%]
[
c]
1
2
3
4
5
6
7
8
9
10
[Pd(PtBu
[Pd (dba)
3
)
2
] (5 mol%)
1.1
65
52
69
80
39
88
91
89
91
93
Scheme 1. Palladium-catalyzed cross-coupling with organolithium reagents.
[d]
2
3
](2.5 mol%)+XPhos (10 mol%) 1.1
[
e]
f]
[Pd-PEPPSI-IPent] (2 mol%)
[Pd-PEPPSI-IPr] (2 mol%)
[Pd-PEPPSI-IPr] (2 mol%)
[Pd-PEPPSI-IPr] (2 mol%)
[Pd-PEPPSI-IPr] (2 mol%)
[Pd-PEPPSI-IPr] (2 mol%)
[Pd-PEPPSI-IPr] (2 mol%)
[Pd-PEPPSI-IPr] (1 mol%)
1.1
1.1
1.1
1.5
[
[
[
[
[
g]
[h]
[j]
[j]
[j]
[j]
[j]
i]
gy. We reasoned that this protocol should be based on a lithi-
um–halogen exchange being faster than the potential Pd-cata-
lyzed alkylation reaction. Therefore, tBuLi was the lithiation
k]
l]
1.5
1.25
1.25
1.3
[m]
[
25]
[17a]
[17c]
[17c]
[n]
agent of choice, as nBuLi,
sec-BuLi,
and iPrLi
can
participate in palladium-catalyzed cross-coupling with aryl bro-
mides, affording the corresponding alkylated products. Herein,
we describe the direct synthesis of unsymmetrical biaryls in
a one-pot procedure from two different aryl bromides in the
presence of tBuLi catalyzed by palladium.
[
a] Conditions, unless otherwise stated: 1a (0.3 mmol), 2a (0.3 mmol) and
Pd catalyst were dissolved in toluene (2 mL). A solution of tBuLi (x equiv
of commercially available 1.7M solution in pentane, diluted to 1 mL with
toluene) was added over 1 h; [b] isolated products; [c] 20% selectivity to
the homocoupling products by GC analysis; [d] more than 20% selectivity
to the homocoupling products by GC analysis; [e] 10% selectivity to the
homocoupling products by GC analysis; [f] less than 10% selectivity to
the homocoupling products by GC analysis; [g] Et
2
O was used as solvent;
Results and Discussion
[h] more than 30% selectivity to the homocoupling products by GC anal-
ysis; [i] 1.5 equiv of 1a were used; [j] less than 5% selectivity to the ho-
mocoupling products by GC analysis; [k] 1.5 equiv of 2a were used;
Our initial studies began with the cross-coupling reaction be-
tween 1-bromonaphthalene 1a and 2-bromoanisole 2a using
[l] 1.25 equiv of 1a were used; [m] 1.25 equiv of 2a were used;
[
26]
[
Pd(P(tBu) ) ] as catalyst (Table 1, entry 1), and a solution of
[n] 1.0 mmol of 1a and 1.2 mmol of 2a was used, and tBuLi was added
without dilution in toluene over 1.5 h.
3
2
tBuLi in toluene was added slowly over 1 h. We were pleased
to find that our hypothesis on the selective lithium–halogen
exchange was correct, and the corresponding unsymmetrical
biaryl 3a was the major product isolated in 65% yield. When
1-(2-methoxyphenyl)naphthalene 3a in 93% yield (Table 1,
[
5c]
[30]
XPhos was used in combination with [Pd (dba) ] (Table 1,
entry 10).
2
3
entry 2) the selectivity toward 3a was lower. Recently, Organ
Having established the optimized conditions and [Pd-
PEPPSI-IPr] as an efficient catalyst for the cross-coupling of 1a
and 2a, we studied the scope of the cross-coupling between
different aryl bromides and 2-bromoanisole for the synthesis of
unsymmetrical biaryls 3 (Scheme 2). For example, 9-bromophe-
nanthrene reacted smoothly, affording the biaryl 3b in 92%
yield. However, with a more hindered bromide, such as 9-bro-
moanthracene, [Pd-PEPPSI-IPent] was necessary to obtain
higher conversion to the tri-ortho-substituted biaryl 3b, al-
though full conversion was not achieved. Different substituents
and co-workers introduced highly effective [Pd-PEPPSI] pre-cat-
[
27]
alysts that are air stable and commercially available. Both
[
Pd-PEPPSI-IPr] and [Pd-PEPPSI-IPent] were effective catalysts
[28,29]
for this transformation, but with [Pd-PEPPSI-IPr],
biaryl 3a
was isolated in higher yield (80%; Table 1, entry 4). When di-
ethyl ether was used as a solvent (Table 1, entry 5), a detrimen-
tal effect on the selectivity to the desired unsymmetrical biaryl
was observed. The lack of selectivity could be attributed to the
higher reactivity of tBuLi in coordinating solvents (due to the
formation of lower order aggregates). Under these conditions,
both halides undergo a fast lithiation, independently of the
presence of the ortho-directing group. Based on these observa-
tions, we decided to use toluene as the preferred solvent.
After tuning of the ratio of the aryl bromides (Table 1, en-
tries 6–9), we found that when 2-bromoanisole was used in
small excess, the product was isolated with slightly higher
yields (Table 1, entries 7 and 9). Finally, the reaction was per-
formed with 1 mmol of 1a and 1.2 mmol of 2a, using
only 1 mol% of [Pd-PEPPSI-IPr], to afford the corresponding
in the para-position of the aromatic ring, such as Cl, NMe or
2
an acetal-protected aldehyde, were tolerated and the corre-
sponding biaryls 3d–f were obtained in good yields. Bromo-
substituted heterocycles, 3-bromobenzo[b]thiophene or 4-
bromo-1,3,5-trimethyl-1H-pyrazole, were also tested, providing
the corresponding products 3g (56%) and 3h (53%). Interest-
ingly, 2-bromofluorene reacted smoothly with 2.2 equivalents
of tBuLi, despite the acidity of the benzylic protons, and the
product 3i was obtained in good yield (69%). Furthermore,
multiple coupling of 2a took place in the twofold cross-cou-
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Scheme 2. Scope of the reaction between different aryl bromides and 2a in
the presence of tBuLi catalyzed by Pd. Conditions, unless otherwise stated:
to a solution of 1 (1 mmol), 2a (1.2 mmol) and [Pd-PEPPSI-IPr] catalyst
(
1 mol%) in toluene (6 mL), tBuLi (1.3 equiv, 0.77 mL of a commercial 1.7m
solution in pentane) was added over 1.5 h. [a] 2 mol% of [Pd-PEPPSI-IPent]
was used; [b] 2 mol% of [Pd-PEPPSI-IPr] was used; [c] the reaction was per-
formed at 358C; [d] 2.2 equiv of tBuLi; [e] the reaction was performed with
1
(
1
,4-dibromobenzene (0.5 mmol), 2a (1.3 mmol), and [Pd-PEPPSI-IPr] catalyst
2 mol%) in toluene (6 mL), and tBuLi (2.8 equiv, 0.85 mL of a commercial
.7m solution in pentane) was added over 1.5 h; [f] yields refer to isolated
products.
pling of 1,4-dibromobenzene, resulting in the terphenyl 3j, iso-
lated in 80% yield. Finally, the cross-coupling of 2-bromoani-
sole with alkenyl bromides was also feasible, illustrated by the
formation of olefins 3k and 3l.
Scheme 3. Scope for the cross-coupling of aryl bromides catalyzed by Pd in
the presence of tBuLi. Conditions, unless otherwise stated: to a solution of
1
(1 mmol), 2 (1.2 mmol) and [Pd-PEPPSI-IPr] catalyst (1 mol%) in toluene
(6 mL), tBuLi (1.3 equiv, 0.77 mL of a commercial 1.7m solution in pentane)
Having demonstrated the reaction between 2-bromoanisole
and different aryl bromides, we decided to investigate aryl
bromides with different ortho (directing) groups, such as
was added over 1.5 h. [a] 2 mol% of [Pd-PEPPSI-IPr] was used; [b] 2 mol% of
[Pd-PEPPSI-IPent] was used; [c] the reaction was performed at 408C; [d] the
reaction was performed with 4,4’-dibromo-1,1’-biphenyl (0.5 mmol), 1-
bromo-2,4-dimethoxybenzene (1.3 mmol) and [Pd-PEPPSI-IPr] catalyst
-
OMOM, -NMe , -CF , -F, or -CH OBn, as nucleophilic partners
2 3 2
(2 mol%) in toluene (6 mL), and tBuLi (2.8 equiv, 0.85 mL of a commercial
(
Scheme 3). For example, methoxymethyl ether (MOM)-protect-
1.7m solution in pentane) was added over 1.5 h; [e] 2.2 equiv of tBuLi; [f] re-
ed 2-bromophenol reacted efficiently with different aryl bro-
mides, yielding the corresponding biaryl 4a–d, including tri-
ortho-substituted biaryl 4d in 76% yield. When 2-bromo-1,3-di-
methoxybenzene was used, it was necessary to perform the re-
action at 408C to afford good conversions to the final products
action on 0.3 mmol scale; [g] yields refer to isolated products.
tained in 69% yield by the multiple coupling of 1-bromo-2,4-
dimethoxybenzene with 4,4’-dibromo-1,1’-biphenyl. Notably, al-
though pyridines do not easily undergo cross-coupling reac-
5
a and 5b in the presence of [Pd-PEPPSI-IPent] (2 mol%). The
[
31]
slightly diminished reactivity is probably due to the fact that
the corresponding 2-lithium-1,3-dimethoxybenzene reagent is
very hindered. Furthermore, more substituted 2-bromoanisole,
tions and lithiated pyridines are not stable at non-cryogenic
temperatures, 3-bromo-2-methoxypyridine was tolerated in the
reaction and the corresponding biaryls with a pyridine moiety
11 a and 11 b could be isolated.
2
-bromo-3-methoxynaphthalene and 1-bromo-2-methoxynaph-
thalene were tolerated for the reaction, and the corresponding
products 6a, 6b, 7, 8, and 10 were obtained in moderate to
good yields. Additionally, quaterphenyl 9 was successfully ob-
The methodology was also extended to the reaction of 2-
bromo-N,N-dimethylaniline with different aryl bromides (12a–
c), but in this case 2 mol% of [Pd-PEPPSI-IPent] and 2.2 equiv
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of tBuLi were used and the reaction was performed at 408C.
Fluorinated compounds are very important in the agrochemi-
cal and pharmaceutical industry, and frequently used in materi-
and the Ministry of Education Culture and Science (Gravitation
program 024.601035) are acknowledged for financial support.
C.V. was supported by an Intra-European Marie Curie Fellow-
ship (FP7-PEOPLE-2011-IEF-300826). S.C. thanks MEC for a pre-
doctoral grant.
[
32]
al science. Exploring CF and F as ortho-directing group, we
3
were grateful that 1-bromo-2-(trifluoromethyl)benzene and 1-
bromo-2-fluorobenzene could be used in cross-coupling reac-
tion to allow the synthesis of fluorinated biaryls (13a, 13b and
Keywords: biaryls · cross-coupling · lithium · N-heterocyclic
carbenes · palladium
14), without any traces of side products resulting from a nucle-
ophilic aromatic substitution or benzyne formation. However,
in the case of 1-bromo-2-fluorobenzene, the corresponding
product 14 was isolated with moderate yield. Moreover, 1-
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Conclusion
[
[
In summary, we have demonstrated the direct cross-coupling
of two different aryl bromides by palladium catalysis mediated
by tBuLi. The [Pd-PEPPSI-IPr] or [Pd-PEPPSI-IPent] complexes
were shown to be efficient catalysts for the one-pot synthesis
of unsymmetrical biaryls at room temperature. The reaction
takes advantage of an ortho-substituted bromide to effect in
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Experimental Section
Synthesis of 3a: In a dry Schlenk flask, PEPPSI-IPr (1 mol%,
0
1
.01 mmol, 6.8 mg), 1-bromonaphthalene 1a (1 mmol, 207.7 mg,
40 mL), and 2-bromoanisole (1.2 mmol, 224.4 mg, 150 mL) were
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dissolved in dry toluene (6 mL) and the mixture was stirred at
room temperature. tBuLi (1.3 mmol, 0.77 mL of commercial 1.7m
solution in pentane) was slowly added over 1.5 h by syringe pump.
When the addition was complete, the reaction was quenched with
MeOH (2 mL). The solvent was evaporated under reduced pressure
and the crude product purified by column chromatography on
silica gel (n-pentane/ether 98:2) affording product 3a as a white
solid in 93% yield.
[
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