Mild and general conditions for Negishi cross-coupling enabled by the use of palladacycle precatalysts

Article abstract of DOI:10.1002/anie.201207750

A wide range of biaryls were synthesized by palladium-catalyzed Negishi cross-couplings at ambient temperature or with low catalyst loading. This protocol features the use of a recently reported aminobiphenyl palladacycle precatalyst to generate the catalytically active XPhosPd⁰ species. Significantly, a wide range of challenging heterocyclic and polyfluorinated aromatic substrates can be employed to give products in excellent yields. Copyright

Full text of DOI:10.1002/anie.201207750

Angewandte
Chemie
DOI: 10.1002/anie.201207750
Cross-Coupling
Mild and General Conditions for Negishi Cross-Coupling Enabled by
the Use of Palladacycle Precatalysts**
Yang Yang, Nathan J. Oldenhuis, and Stephen L. Buchwald*
Biaryls, particularly those containing one or more hetero-
cyclic components, are ubiquitous among pharmaceutically
active compounds, natural products, and agrochemicals. For
their preparation, palladium-catalyzed cross-coupling reac-
tions have been extensively studied and practiced in both
academic[1] and industrial[2] settings. Although various palla-
À
dium-catalyzed cross-coupling methods to form Csp2 Csp2
bonds have been developed, the Negishi coupling is one of
the most frequently utilized. The utility of Negishi couplings is
partially due to the fact that organozinc reagents, despite their
considerable basicity, are compatible with a large number of
sensitive functional groups.[3] Equally important is that a wide
array of highly functionalized organozinc reagents can be
readily accessed.[4] Additionally, the recent development of
solid salt-stabilized organozinc reagents, which are much less
sensitive towards air and moisture,[5,6] has also rendered the
Scheme 1. Precatalysts and ligands employed for Negishi cross-cou-
pling reactions.
Negishi coupling a more practical and user-friendly technique
for synthetic organic chemists.
Numerous studies have been devoted to the development
of more general and efficient catalyst systems for Negishi
cross-coupling reactions (Scheme 1). In 2001, Fu and Dai
described the first general protocol to effect the Negishi cross-
coupling of aryl chlorides by using [Pd{P(tBu3)}2] (2 mol%) as
the precatalyst in THF/NMP at 1008C.[7] In 2004, our research
group reported a highly active catalyst based on dialkylbiar-
ylphosphine L1 (RuPhos), that permitted the efficient gen-
eration of a wide range of sterically hindered tri- and tetra-
ortho-substituted biaryls in THF at 708C with low catalyst
loadings.[8] In a series of publications, Knochel and co-workers
demonstrated the utility of biarylphosphine L2 (SPhos) as the
supporting ligand for palladium-catalyzed Negishi cou-
pling.[3,9] More recently, the group of Organ has also
developed a Pd-PEPPSI-IPent precatalyst capable of facili-
tating the reactions of a variety of extremely sterically
hindered substrates to afford tetra-ortho-substituted biaryls
under exceptionally mild reaction conditions with excellent
yields.[10,11]
Despite these advances, significant challenges still remain.
Notably, although simple aryl halides and aryl zinc reagents
are easily transformed, couplings involving heteroaryl zinc
reagents and heteroaryl halides are often less successful. This
difficulty is due partly to the different electronic properties of
heterocyclic compounds, as well as to the presence of
heteroatoms capable of binding to the transition metal
center, thus leading to catalyst deactivation and decomposi-
tion.[12] In particular, the transformation of five-membered
heterocycles bearing more than one heteroatoms, such as
pyrazoles and imidazoles, has proven to be challenging.[13,14]
Thus, the development of a catalyst system capable of
facilitating the coupling of a diverse range of heteroaryl and
functionalized substrates under mild reaction conditions is
still highly desirable. Herein, we report a general catalyst
system based on a palladacycle precatalyst ligated by
dialkylbiarylphosphine ligand L3 (XPhos) for the palla-
dium-catalyzed Negishi cross-couplings at ambient temper-
ature or with low catalyst loadings. With this system a myriad
of heteroaryl coupling partners, many of which were pre-
viously unsuccessful substrates,[8] can now be effectively
coupled. In addition, we report the success of this system
for the Negishi coupling of polyfluoroaryl zinc reagents.
We recently reported the development of a new class of
easily prepared, air- and moisture-stable aminobiphenyl-
based palladacycle precatalysts capable of rapidly and
[*] Y. Yang, N. J. Oldenhuis, Prof. Dr. S. L. Buchwald
Department of Chemistry, Room 18-490
Massachusetts Institute of Technology
Cambridge MA 02139 (USA)
E-mail: sbuchwal@mit.edu
[**] We thank the National Institutes of Health for financial support of
this work (Grant GM46059). We thank Robert Todd (Aldrich) for
a helpful discussion and a gift of the ZnCl2·THF complex. We are
grateful to Dr. Laurent Pellegatti (Massachusetts Institute of
Technology) for insightful discussions and Dr. Meredeth A. McGo-
wan (Massachusetts Institute of Technology) for help with the
preparation of this manuscript. We acknowledge Nicholas C. Bruno
(Massachusetts Institute of Technology) for providing the precata-
lyst 3 used in this study. MIT has patents on some of the ligands and
precatalysts used in this work from which S.L.B. receives royalty
payments.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201207750.
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quantitatively generating the catalytically active L1Pd0 species
under basic conditions at room temperature.[15–18] Given their
intrinsic basicity, we reasoned that organozinc reagents could
readily activate these precatalysts in situ, and furthermore
that the efficient and rapid formation of L1Pd0 facilitated by
these precatalysts would allow for Negishi cross-couplings
under mild conditions and, potentially, with low catalyst
loadings. Thus, palladacycle precatalyst 3c was compared with
other commonly used palladium sources in combination with
L3 for the Negishi cross-coupling of p-tolylzinc chloride (4)
and 2-bromoanisole (5; Figure 1). Interestingly, the protocol
Figure 2. Comparison of precatalysts with different dialkylbiarylphos-
phine ligands. Reaction conditions: p-tolylzinc chloride (0.65 mmol),
2-bromoanisole (0.5 mmol), 3 (0.1%), L=L2–5 (0.1%), THF, 758C.
catalysts based on L4 and L5. Interestingly, a catalyst derived
from L1 furnished only 55% conversion at 0.1 mol% Pd
loading, thus indicating that the catalyst based on L1 is less
effective at low palladium loadings than that generated from
L3.[22] Taken together, these studies suggest that a catalyst
system based on L3 exhibits the highest activity for Negishi
couplings.
Figure 1. Comparison of precatalyst 3c with several other palladium
sources. Reaction conditions: p-tolylzinc chloride (0.65 mmol), 2-
bromoanisole (0.5 mmol), Pd (0.1%, Pd/L=1:1), L=L3, THF, 758C,
20 min. Yields were determined by GC analysis of the crude reaction
mixture.
In light of the importance of heterocyclic compounds in
medicinal chemistry and materials chemistry,[23] we focused
on the Negishi cross-coupling of heteroaryl zinc reagents with
heterocyclic halides and pseudohalides (Scheme 2). We were
interested in the Negishi coupling of five-membered 2-
heteroaromatic zinc chlorides (i.e., 2-furyl-, 2-thienyl-, 2-
benzofuranyl-, 2-benzothiophenyl-, and 2-indolylzinc chlor-
ides) and 2-pyridylzinc chloride, because the corresponding
organoboron reagents are difficult substrates for Suzuki–
Miyaura coupling owing to the rapid protodeborona-
tion.[17,24,25] We found that by using 0.25–4 mol% of 3c,
these heteroaryl zinc reagents could be efficiently coupled at
room temperature to furnish heterobiaryls (7a–7j) in excel-
lent yield. Coupling reactions of 3-furyl-, 3-thienyl-, 3-
pyrroryl-, 3-indolyl-, and 3-pyridylzinc chlorides were equally
effective under the current protocol (7k–7o). Azole coupling
partners were also evaluated with the current catalyst system.
4-Iodo-1-tritylimidazole, and 2- and 4-bromothiazoles proved
to be more-challenging substrates, requiring higher reaction
temperatures to obtain appreciable amounts of coupled
product (7p, 7q, and 7r, respectively). Benzo-fused azole
and N-substituted pyrazole electrophiles were excellent
substrates for this method and could be converted into the
desired products (7s and 7t, respectively) in excellent yields
at room temperature.[26] Products containing azoles such as
pyrazolyl (7u, 7v, 7w, and 7z), 4-isoxazolyl (7x), 2-thiazolyl
(7y) and 2-imidazolyl (7a’) can also be synthesized from the
cross-coupling of the respective zinc chlorides by using our
protocol. Finally, different types of halides and pseudohalides
can all be effectively coupled with organozinc reagents under
our reaction conditions.
employing palladacycle precatalyst 3c facilitated the coupling
in 92% yield after just 20 min, whereas the use of other
palladium sources such as Pd(OAc)2 and [Pd2dba3] resulted in
product yields lower than 40% in the same amount of time.
These results clearly indicate that palladacycle precatalyst 3
generates the catalytically active L1Pd0 species most effi-
ciently.
We next evaluated the ligand effects using palladacycle
precatalysts of type 3.[8] Given the success of bulky mono-
phosphinobiaryl ligands L3[17,19] and L5[20] in facilitating
Suzuki–Miyaura cross-couplings with high reactivity, we
were interested in carefully evaluating their activity for
Negishi cross-couplings. Differences in reaction rates for
catalyst systems derived from ligands L1, L3, L4, and L5 were
determined by monitoring the reaction progress using calo-
rimetric analysis.[21a] As depicted by Figure 2, reaction rates
for all of the catalyst systems derived from L1, L4, and L5 are
significantly lower than that observed when L3 was used as
the supporting ligand. While catalyst systems employing L3
and L4 both facilitated full conversion of 2-bromoanisole
after approximately 30 min, the initial reaction rate for the
catalyst generated from L4 was about 50% lower than the
reaction rate for the catalyst derived from L3. This result
illustrates the influence of the size of the substituents on the
nonphosphorus-containing ring of the dialkylbiarylphosphine
ligand on catalyst activity, in accordance with our previous
findings.[21b,c] Further, the benefit of using a ligand with
cyclohexyl rather than tert-butyl substituents on the phos-
phorous atom of the monophosphinobiaryl ligand is high-
lighted by the 10-fold difference in reaction rate between
To further demonstrate the utility of our method, we
sought to extend the scope of our catalyst system to reactions
of polyfluorophenyl zinc reagents (Scheme 3). We were
particularly intrigued by the coupling of fluorinated aryl
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Scheme 3. Cross-coupling of polyfluoroaryl zinc reagents and heteroaryl
halides at room temperature. Yields are of the isolated products, and an
average of two runs. Reaction conditions: ArZnCl (1.3 mmol), ArX
(1.0 mmol), 3c (1–2 mol%), L3 (1–2 mol%), THF, RT, 12 h. [a] ArZnCl
(2.3 mmol), ArX (1.0 mmol), 3c (1–2 mol%), L3 (1–2 mol%), THF, RT,
12 h. [b] ArZnCl (1.3 mmol), ArX (1.0 mmol), 3c (1–2 mol%), L3 (1–
2 mol%), THF, 408C, 12 h.
zinc reagents because methods for the preparation of
polyfluorinated biaryls remain underdeveloped. The corre-
sponding polyfluorophenyl boronic acids constitute a chal-
lenging family of nucleophiles for Suzuki–Miyaura coupling
owing to rapid protodeboronation.[17] For example, the half-
life time of 2,3,6-trifluorophenylboronic acid under our most
recently developed reaction conditions for Suzuki–Miyaura
coupling is only 2 min,[17] thus rendering the Suzuki–Miyaura
coupling of this boronic acid a formidable task. We therefore
reasoned that Negishi coupling could serve as an important
alternative to achieve this type of transformation.[27] Subject-
ing various types of polyfluorophenyl zinc reagents to the
current protocol furnished coupling products in uniformly
good yields (8a–8j). Moreover, when the reaction temper-
ature was increased to 408C, perfluoro-4-pyridylzinc chloride
reacted well with an aryl triflate derived from estrone to give
8k.[28,29]
Encouraged by the high level of reactivity of our catalyst
system, we set out to examine the scope of this system at
extremely low levels of catalyst loading (Scheme 4). The
reaction proceeded with lower catalyst loadings of 0.025–
0.05 mol% (turnover number= 2000–4000) and a variety of
functional groups, including an acetal (9e), a tertiary amine
(9 f), an amide (9 f), and heterocycles (9c and 9d), were
tolerated. These results clearly demonstrate the ability of our
catalyst to operate at low concentrations of catalyst for
a range of functionalized substrates. However, we note that
with the current catalyst system, substrates bearing an ortho
coordinating substituent such as an ester or a ketone usually
Scheme 2. Cross-coupling of heteroaryl zinc reagents and heteroaryl
halides. Reaction conditions: ArZnCl (1.3 mmol), ArX (1.0 mmol), 3c
(0.25–2 mol%), L3 (0.25–2 mol%), THF, RT, 12 h. Yields are of the
isolated products, and an average of two runs. [a] ArZnCl (1.2 mmol)
was used. [b] ArZnCl (2.3 mmol), ArX (1.0 mmol), 3c (1 mol%), L3
(1 mol%), THF, RT, 12 h. [c] 3b and L1 instead of 3c and L3;
[d] ArZnCl (1.3 mmol), ArX (1.0 mmol), 3c (2–4 mol%), L3 (2–
4 mol%), THF, 808C, 12 h.
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Scheme 4. Cross-coupling of aryl zinc chlorides and aryl halides at low
catalyst loadings. Reaction conditions: ArZnCl (1.3 mmol), ArX
(1.0 mmol), 3c (0.025–0.05 mol%), L3 (0.025–0.05 mol%), THF,
758C, 12 h. Yields are of the isolated products, and an average of two
runs.
require catalyst loadings higher than 0.1 mol% to achieve full
conversion.
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In summary, through the use of our recently developed
palladacycle precatalysts, we have identified a highly active
catalyst system based on L3 for the Negishi cross-coupling of
heteroaryl zinc reagents and polyfluoroaryl zinc reagents
under mild reaction conditions. Our method is effective with
a broad scope of heteroaryl halides, pseudohalides and other
types of challenging substrates, thus delivering a wide range of
heterobiaryls that represent structural motifs frequently
found in biologically active compounds.
Received: September 26, 2012
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Published online: November 22, 2012
Keywords: cross-coupling · heterocycles ·
.
homogeneous catalysis · organozinc reagents ·
palladacycle precatalysts
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develop a method of enhanced operational simplicity, we
evaluated the effectiveness of commercially available ZnCl2
solutions, and the 2-MeTHF solution of ZnCl2 was identified
as the optimal choice to furnish consistent results, completely
excluding the use of a glovebox. 2-MeTHF solution of ZnCl2 was
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(Scheme 3) as well as 8k (Scheme 4).
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3-bromoimidazo[1,2-a]pyrazine,
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