Towards environmentally friendlier Suzuki-Miyaura reactions with precursors of Pd-NHC (NHC = N-heterocyclic carbene) complexes

Article abstract of DOI:10.1039/c8gc00860d

The preparation of [NHC·H][Pd(η³-R-allyl)Cl₂] complexes is disclosed and represents a facile, atom-economical, environmentally friendly and rapid synthesis. These palladates are immediate synthetic precursors to the well-known [Pd(NHC)(η³-R-allyl)Cl] complexes. Their activation leading to catalytically relevant species has been studied in the Suzuki-Miyaura reaction. The need for an activation step prior to the catalysis was examined. The reaction scope showcases its ease and breadth in terms of functional group tolerance. Electron-donating and electron-withdrawing aryl chlorides and bromides were coupled effectively as well as heteroatom-containing and sterically hindered aryl halides. The catalytic reaction was conducted in ethanol with a weak and inexpensive inorganic base.

Full text of DOI:10.1039/c8gc00860d

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Towards environmentally friendlier Suzuki–
Miyaura reactions with precursors of Pd-NHC
Cite this: DOI: 10.1039/c8gc00860d
(
NHC = N-heterocyclic carbene) complexes†‡
a
a
b
c
Caroline M. Zinser, Katie G. Warren, Rebecca E. Meadows, Fady Nahra,
*
d
d
d
Abdullah M. Al-Majid, Assem Barakat,
Mohammad S. Islam,
c,d
c
Steven P. Nolan
*
and Catherine S. J. Cazin
*
3
The preparation of [NHC·H][Pd(η -R-allyl)Cl
2
] complexes is disclosed and represents a facile, atom-econ-
omical, environmentally friendly and rapid synthesis. These palladates are immediate synthetic precursors
3
to the well-known [Pd(NHC)(η -R-allyl)Cl] complexes. Their activation leading to catalytically relevant
species has been studied in the Suzuki–Miyaura reaction. The need for an activation step prior to the cata-
lysis was examined. The reaction scope showcases its ease and breadth in terms of functional group tol-
erance. Electron-donating and electron-withdrawing aryl chlorides and bromides were coupled effec-
tively as well as heteroatom-containing and sterically hindered aryl halides. The catalytic reaction was
conducted in ethanol with a weak and inexpensive inorganic base.
Received 16th March 2018,
Accepted 26th April 2018
DOI: 10.1039/c8gc00860d
rsc.li/greenchem
complexes having a well-defined metal-to-ligand ratio (usually
Introduction
1
: 1) permitting the formation of the putative L-Pd active
8
The formation of C–C bonds is one of the most important and species. This approach has offered simpler operational proto-
1
–3
common reactions in modern synthetic chemistry. Using an cols and has greatly simplified reaction condition optimization
organopalladium complex as catalyst has revolutionized this leading to improved catalytic performance. The latest develop-
field and the area has been rewarded with the 2010 Nobel ments have focused on the nature of the throw-away ligand in
9
Prize in Chemistry. Palladium complexes are nowadays widely palladium(II) precursors. Concerning the latter, one fragment
4
used for this purpose. As the area effects the polymer, fine which has emerged as favored in cross-coupling catalysis is the
3
10
3
chemical and pharmaceutical industries, research continues to η -R-allyl ligand in complexes of the type [Pd(NHC)(η -R-
be focused on improving existing methodologies and develop- allyl)Cl] (NHC = N-heterocyclic carbene), obtained through
3
ing novel transformations using this metal-catalyzed dimer cleavage of the [Pd(η -R-allyl)(μ-Cl)]
strategy.
2
1 synthon. This
5
–7
The approach to catalyst formation has been per- methodology was first reported through a free carbene gene-
fected over the past 15 years. Initially, a palladium source and ration or isolation step prior to reaction with 1.
1
0,11
A number
a ligand (or ligand precursor) were used to generate the active of synthetic protocols using either well-defined or in situ gener-
complex in situ. This situation evolved into approaches using ated palladium catalysts have recently been disclosed using
1
2
either 1 or related allyl-substituted congeners. Others have fol-
9b,11
lowed our approach with NHCs and tertiary phosphines.
As
a
b
part of these advances, the search for novel architectures for cat-
alysis and investigations into the reaction mechanism continues
with the goal of understanding and designing ever better per-
forming systems. In this context, we have recently reported on
the isolation of a key intermediate along the synthetic pathway
School of Chemistry, University of St Andrews, St Andrews, KY16 9ST, UK
AstraZeneca, Chemical Development, Pharmaceutical Technology and Development,
Etherow T/10 Silk Road Business Park, Charter Way, Macclesfield, Cheshire, SK10
NA, UK
2
c
Department of Chemistry and Centre for Sustainable Chemistry, Ghent University,
Krijgslaan 281, S-3, 9000 Ghent, Belgium. E-mail: steven.nolan@ugent.be,
catherine.cazin@ugent.be
3
leading to [Pd(NHC)(η -R-allyl)Cl] complexes, namely an imida-
d
3
13
Department of Chemistry, College of Science, King Saud University, P. O. Box 2455,
zolium palladate [NHC·H][Pd(η -R-allyl)Cl ] 2 (Scheme 1).
2
Riyadh 11451, Saudi Arabia
These palladates can be converted into the well-defined Pd-
†
7
‡
Dedicated to Professor Carl D. Hoff, mentor and friend, on the occasion of his
NHC complexes by the action of a simple inorganic base
th
0
birthday and to the memory of Prof. Elena Rybak-Akimova.
1
3
(
K CO ) in acetone. The strong bases previously required to
2 3
Electronic supplementary information (ESI) available: Materials, methods,
t
generate the free NHC, typically KO Bu or KHMDS, proved
unnecessary, a key advance as these are expensive reagents.
optimisation data, detailed synthetic procedures and spectroscopic data and
spectra. See DOI: 10.1039/c8gc00860d
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in quantitative yields and analytically pure palladate com-
plexes. As all solvents examined led to the palladate in high
yields, we were drawn to the idea of performing the reactions
in the solid-state and observed that grinding both reagents in
a mortar with a pestle led to the formation of the palladate in
>98% yield after grinding times of only 5 minutes! In fact, the
solvent-free route became the easiest to launch and we have
2
2
used this method, akin to ball-milling, to synthesize all com-
plexes reported in the Experimental section (Scheme 2). We
have exemplified the method with a number of NHCs [IPr* =
3
Scheme 1 Synthesis of [Pd(NHC)(η -R-allyl)Cl] complexes via
palladate 2.
1
3
(
N,N′-1,3-bis[2,6-bis(diphenylmethyl)-4-methylphenyl]imida-
zol-2-ylidene, IPent = N,N′-bis(2,6-di-iso-pentylphenyl)imida-
zol-2-ylidene, SIPr = N,N′-bis(2,6-di-iso-propylphenyl)imidazo-
lin-2-ylidene and IPr = N,N′-bis-[2,6-(di-iso-propyl)phenyl]imi-
dazol-2-ylidene)] to examine the effect of substituents on the
NHC and on the allyl fragment (2-crotyl, 2-Me-allyl, cinnamyl
Our earlier synthetic work made use of solvents such as
tetrahydrofuran or dichloromethane under an inert
1
4–16
atmosphere,
and our most recent work was conducted in
acetone. All these synthetic protocols leading to well-defined
Pd-NHC complexes could benefit from the use of a more
t
23
and Bu-indenyl ). We can gladly report that variations at
these positions do not lead to significant variations in yields
and purity and that the method proves general thus far. Note
that although some of these compounds are known, we
carried out full analytical characterization, including elemen-
tal analysis to unambiguously establish the identity and purity
of the complexes obtained using the grinding synthetic route.
While the solvent-free method is the most satisfactory, the
compatibility of ethanol as a solvent in this synthesis is
especially interesting as ethanol proves a very desirable solvent
from environmental and economic aspects. As the synthesis of
the palladate is possible, and quite efficient in ethanol, we
probed the feasibility of the next step in ethanol, namely the
1
7
industrially friendly solvent. Therefore, the development of
operationally greener synthetic routes to pre-catalysts and to
catalytic systems using mild conditions remains an extremely
desirable outcome. Herein, we report on the generality of a
3
synthetic method to access complexes of the type [Pd(NHC)(η -
R-allyl)Cl], on the versatility of the synthesis of palladates in
solvent-free conditions, and on the involvement of these palla-
dates as pre-catalysts in the Suzuki–Miyaura reaction using a
weak inorganic base in a green solvent.
Results and discussion
3
synthesis of the neutral [Pd(NHC)(η -R-allyl)Cl] complexes
3
The recently synthesized [NHC·H][Pd(η -R-allyl)Cl
2
] (2) com- from the palladate. This also proves efficient and the product
3
plexes are easily accessible by simply mixing [Pd(η -R-allyl) is obtained in pure form after 5 h at 60 °C. As the palladate
3
(
(
μ-Cl)]
2
(1) and two equivalents of an NHC salt in acetone can be obtained from 1 and the neutral [Pd(IPr)(η -cin)Cl] can
1
3
Scheme 1). This protocol is reminiscent of our previous be synthesized from the palladate, both in ethanol, we
3
reports on the syntheses of gold- and copper-NHC complexes reasoned that [Pd(η -cin)(μ-Cl)] (1a) and IPr·HCl (IPr = N,N′-
2
1
8
that proceed through metallate intermediates.
In this bis-[2,6-(di-iso-propyl)phenyl]imidazol-2-ylidene) in the pres-
1
3
study, we have shown that palladates 2 are intermediates
along the synthetic pathway leading to the known
3
19
N-heterocyclic carbene complexes [Pd(NHC)(η -R-allyl)Cl]. It
3
should be stated that both palladates and [Pd(NHC)(η -R-allyl)Cl]
are air- and moisture-stable Pd(II) complexes. The recently
reported synthesis consists of solubilizing the starting
3
reagents, [Pd(η -R-allyl)(μ-Cl)]
2
(1) and NHC·HCl, in acetone
1
3
and heating to 60 °C for 1 hour [Scheme 1, (i)]. In order to
improve these conditions from an environmental perspective,
the role of the solvent was examined. Several solvents were
3
tested in the reaction involving [Pd(η -cin)(μ-Cl)] (1a) (cin =
2
2
0
cinnamyl) and IPr·HCl (IPr = N,N′-bis-[2,6-(di-iso-propyl)
phenyl]imidazol-2-ylidene) and to our surprise the polarity of
these solvents did not influence the yield or purity of the iso-
lated palladate complex (see the ESI, Table S1‡). It became
apparent that a vast number of solvents could be used efficien-
tly. Among the solvents tested, acetone, cyclopentylmethylether
(CPME), ethyl acetate, ethanol and water are noteworthy. A
number of these solvents have been identified as desirable by
2
1
industry. All experiments in this solvent screening resulted Scheme 2 Palladates synthesized using the grinding method.
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ence of K
2
CO
3
, in ethanol, might lead to the well-defined is allowed for pre-activation, poorer catalyst performance is
3
[
Pd(IPr)(η -cin)Cl] product. Gratifyingly, the reaction pro- observed.
gresses smoothly in ethanol (reaction time non-optimized) at We next turned our attention to the palladates themselves
0 °C providing 98% isolated yield of the desired product on to probe the influence of the carbene and of the leaving-ligand
6
3
the multi-gram scale (Scheme 3). This reaction illustrates the (η -R-allyl) on catalyst performance (Table 1). The ease of syn-
feasibility of the synthesis of [Pd(NHC)(η -cin)Cl] complexes in thesis of these robust complexes is noteworthy as is the fact
3
a green solvent in high yield and purity.
that the catalytic reaction can be conducted under aerobic con-
We next investigated the Suzuki–Miyaura reaction in ditions. As expected, the nature of the leaving allyl moiety is
ethanol, using the palladate 2a as a pre-catalyst. Extensive important (Table 1, entries 1–4), and the bulky cinnamyl
screening of bases and solvents was undertaken using phenyl- group leads to the best activity amongst 2a–d. Variation of the
boronic acid and 4-chloroanisole as benchmark substrates (see NHC ligand is also of great importance, and amongst the pre-
2 3
the ESI‡ for details). Unsurprisingly, K CO /EtOH led to the catalysts tested (2a, 2e–g) the IPr derivative 2a leads to the best
best results, presumably due to the ease of access to the Pd- results (Table 1, entries 1 and 5–7).
NHC active species under such conditions.
Further optimization (stoichiometry of the reagents, reac-
We then probed the influence of the nature of the boron tion time, temperature) was therefore undertaken using
3
reagent on catalytic activity. In this regard, three types of [IPr·H][Pd(η -cin)Cl
2
] 2a as the pre-catalyst (see the ESI‡ for
boron substrates were selected: boronic acid, boronic ester and details). With our set of optimized reaction conditions in
potassium trifluoroborate (Scheme 4). When no thermal pre- hand, we next examined the scope of the reaction (Scheme 6).
activation was carried out, the reaction with phenyl boronic First a range of aryl chloride derivatives was selected, and the
acid did not proceed, while the pinacol ester substrate led to
poor conversion and the trifluoroborate derivative led to a
moderate yield (40%). This is in line with the relative reactiv-
2
4
ity/stability of the boron coupling partners.
On the other hand, with a pre-activation step (60 °C, 1 h),
the cross-coupling reaction involving boronic acid reaches
completion while those involving boronic ester and the tri-
fluoroborate derivatives lead to high conversion (90 and 94%,
respectively). Hence, pre-activation of the palladate to form the
3
[
Pd(NHC)(η -cin)Cl] derivative is a crucial step, and this inde-
pendently of the boron source. Further experiments were thus
carried to determine the optimum activation time, which was
shown to be 1 hour (Scheme 5). These studies illustrate the
importance of this step, since if not enough or too much time
Scheme 5 Nature of the boron reagent in the Suzuki–Miyaura reaction.
3
Reaction conditions: [IPr·H][Pd(η -cin)Cl
2
]
2a (0.5 mol%),
0.55 mmol), EtOH (1 mL) [pre-activation 60 °C, 10–90 min], ArCl
0.5 mmol), PhB(OH) (0.55 mmol), EtOH (1 mL), 40 °C, 16 h. Yield deter-
2 3
K CO
(
(
2
mined by GC using mesitylene as the internal standard.
a
Table 1 Catalyst optimization (in air)
3
Scheme 3 One-pot large-scale synthesis of [Pd(IPr)(η -cin)Cl].
b
Entry
Palladate pre-catalyst
Yield (%)
3
1
2
3
4
5
6
7
[IPr·H][Pd(η -cin)Cl
2
] 2a
92
80
8
n.r.
30
n.r.
88
3
2
[IPr·H][Pd(η -2-Me-allyl)Cl ] 2b
3
[IPr·H][Pd(η -crotyl)Cl
2
] 2c
] 2d
] 2e
[IPent·H][Pd(η -cin)Cl ] 2f
] 2g
3
tBu
[IPr·H][Pd(η -Ind )Cl
2
3
[SIPr·H][Pd(η -cin)Cl
2
3
2
3
[IPr*·H][Pd(η -cin)Cl
2
Scheme 4 Nature of the boron reagent in the Suzuki–Miyaura reaction.
a
3
[
NHC·H][Pd(η -R-allyl)Cl
2
]
pre-catalyst
(0.5
mol%),
2 3
K CO
3
Reaction conditions: [IPr·H][Pd(η -cin)Cl
2
]
2a (0.5 mol%),
K
2
CO
3
(
0.55 mmol), EtOH (1 mL) [pre-activation 60 °C, 1 h] ArCl (0.5 mmol),
b
(
0.7 mmol), EtOH (1 mL) [pre-activation 60 °C, 1 h], ArCl (0.5 mmol),
PhB(OH)
2
(0.55 mmol) EtOH (1 mL), 40 °C for 16 h. Yield determined
PhBX
n
(0.55 mmol), EtOH (1 mL), 40 °C, 16 h. Yield determined by GC by GC, using mesitylene as the internal standard, average of at least
using mesitylene as the internal standard.
two reactions.
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Scheme 7 Large-scale Suzuki–Miyaura reaction.
great importance in particular in the pharmaceutical industry.
Functional groups of different nature are compatible with the
catalytic system (e.g. NO , C(O)Me, CN, NH ). Of note the fact
2 2
that reactions involving aryl chlorides containing a heteroatom
at the ortho-position lead to high yields of cross-coupling pro-
ducts within 4 hours, while such substrates often lead to slug-
gish reactions. Finally, the scope of the reaction was further
extended using aryl bromide derivatives. The reactions were
carried out at room temperature after a pre-activation step
(
1 h, 60 °C) using boronic acids bearing various functional
groups. Hence the palladates are highly efficient pre-catalysts
for a wide range of aryl halide and boronic substrates, and
compatible with numerous functional groups.
The scalability of the system was tested in a larger scale cata-
lytic reaction (Scheme 7) in which 4-chloroanisole was reacted
with 4-tolylboronic acid in the presence of 0.3 mol% of 2a,
leading to the isolation of 4.66 g of the cross-coupling product
within 4 h. Noteworthy, a 1 : 1 aryl chloride to boronic acid ratio
was used in the larger size reaction, establishing that an excess of
boronic acid, a common operational practice, is not required here.
Conclusions
A newly synthesized class of Pd(II) pre-catalysts was studied,
focusing on its synthesis and its catalytic activity under mild
reaction conditions while using environmentally acceptable
conditions (solvent and base). The palladates require an acti-
3
vation step to permit their conversion into [Pd(NHC)(η -cin)Cl]
complexes in situ prior to them being active for catalysis. The
palladate and neutral Pd-NHC syntheses are easy to carry out,
even in air. A wide reactivity scope was demonstrated for their
use in the Suzuki–Miyaura reaction, where various classes of
Scheme 6 Scope of the Suzuki–Miyaura reaction using 2. Reaction
3
conditions: (a) X = Cl, [IPr·H][Pd(η -cin)Cl
2
] 2a (0.3 mol%), K
2
CO
3
(
0.7 mmol), EtOH (1 mL) [pre-activation 60 °C, 1 h] ArCl (0.5 mmol),
ArB(OH)
2
(0.5 mmol), EtOH (1 mL), 40 °C for 4 h; (b) X = Br, [IPr·H][Pd
] 2a (0.5 mol%), K CO
(0.5 mmol), ArBr (0.5 mmol), r.t., 24 h. simple catalytic protocol. Furthermore, the Suzuki–Miyaura reac-
3
(
η -cin)Cl
2
2
3
(0.55 mmol), EtOH (2 mL) [pre-acti- substrates were investigated and proved compatible with this
vation 60 °C, 1 h] ArB(OH)
Isolated yields average of two reactions.
2
tion and the pre-catalyst synthesis can both be easily scaled up.
The use of ethanol affords a green alternative as a reaction
medium in both pre-catalyst synthesis (which can also be carried
out under solvent-free conditions) and as solvent to perform the
Suzuki–Miyaura reaction. The role of these simple palladates
in related transformations is presently being investigated.
3
reactions were carried out using [IPr·H][Pd(η -cin)Cl
2
] 2a
(
0.3 mol%) in EtOH with K CO at 40 °C for 4 h (with a pre-
2
3
activation of 1 h at 60 °C). Of note the fact that these reactions
are carried out in air, and that room temperature reactions are
also possible, albeit requiring a longer reaction time (see the
ESI‡). The catalytic system was found efficient for all substrates
tested. Variations of electronic and/or steric properties on the
aryl fragments from both aryl chloride or aryl boronic acid
Experimental
Synthesis of [NHC·H][Pd(η -R-allyl)Cl ] complexes
3
2
substrates such as styryl boronic acid were well tolerated General procedure: In air, the corresponding NHC·HCl and
Scheme 6, 3u and 3v), as well as heterocycles, fragments of [Pd(R-allyl)(μ-Cl)] were added to a mortar. The two solids were
(
2
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13
1
mixed and ground using a pestle for 5 min. A crystalline solid 12H, CH3(IPr)), 1.20 (d, J = 6.9 Hz, 12H, CH3(IPr)). C { H} NMR
was obtained. (100 MHz, CDCl ): δ (ppm) = 145.2 (C ), 137.0 (CHNCN), 132.2
3
Ar
3
[
IPr·H][Pd(η -cin)Cl
from IPr·HCl (49.2 mg, 0.116 mmol) and [Pd(η -cin)(μ-Cl)]
30.0 mg, 0.057 mmol), the product was obtained as a yellow (CHInd), 109.1–107.0 (CHInd), 70.7 (CHInd), 34.3 (CHInd), 29.2
2
] (2a). Following the general procedure (CHAr), 130.0 (CAr), 127.7 (CHimid), 127.4 (CHInd), 125.4
3
2
(CHInd), 125.3 (CHInd), 124.8 (CHAr), 124.1 (CHInd), 120.2–117.7
(
1
3
powder in a 99% (80 mg) yield. H NMR (400 MHz, CDCl ): (CH3(IPr)), 29.0 (CH3(Ind)), 28.8 (CH3(Ind)), 24.9 (CH3(IPr)), 24.0
δ (ppm) = 9.19 (s, 1H, NCHNImid), 8.32 (d, J = 1.6 Hz, 2H, (CH3(IPr)). Elemental Analysis: Expected C 65.08, H 7.10, N
CHImid), 7.54 (t, J = 8.1 Hz, 2H, CH ), 7.45 (dd, J = 6.1 Hz, 2H, 3.79; found: C 64.87, H 7.17, N 3.94.
Ar
3
CHAr(cin)), 7.33 (d, J = 7.9 Hz, 4H, CHAr), 7.21 (m, 3H, CHAr(cin)),
Synthesis of [SIPr·H][Pd(η -cin)Cl
2
]
(2e). Following the
3
5
6
2
1
.69–5.62 (m, 1H, CH(cin)), 4.46 (m, 1H, CH2(cin)), 3.86 (d, J = general procedure from SIPr·HCl (65 mg, 0.152 mmol), [Pd(η -
.6 Hz, 1H, CH2(cin)), 2.90 (d, J = 11.9 Hz, 1H, CH(cin)), cin)(μ-Cl)] (40.0 mg, 0.076 mmol), the product was obtained
2
1
.48–2.41 (m, 4H, CH(IPr)), 1.27 (d, J = 6.8 Hz, 12H, CH3(IPr)), as a yellow powder in a 99% yield (107 mg) yield. H NMR
.19 (d, J = 6.7 Hz, 12H, CH3(IPr)). C { H} NMR (400 MHz, (400 MHz, CDCl ): δ (ppm) = 7.71 (s, 1H, NCHNImid), 7.53–7.48
3
1
3
1
CDCl ): δ (ppm) = δ 145.1 (C ), 136.9 (CHNCN), 132.1 (CHAr), (m, 4H, CHAr(IPr+cin)), 7.31–7.26 (s, 7H, CHAr(IPr+cin)), 5.80–5.72
3
Ar
1
29.9 (CAr), 128.7 (CHcin), 127.9 (CHcin), 127.7 (CHimid), 124.7 (m, 1H, CH(cin)), 4.97 (s, 4H, CH2(Imid)), 4.55 (d, J = 11.1 Hz,
(CH), 105.2 (CHcin), 81.8 (CHcin), 58.4 (CH2(cin)), 29.0 (CH(IPr)), 1H, CH2(cin)), 3.96 (d, J = 6.7 Hz, 1H, CH2(cin)), 3.15–3.08 (m,
2
4.7 (CH3(IPr)), 23.9 (CH3(IPr)). Elemental Analysis: Expected C 4H, CH(SIPr)), 3.01 (d, J = 11.9 Hz, 1H, CH(cin)), 1.42 (d, J = 6.3
1
3
1
6
3.02, H 7.05, N 4.08; found: C 63.11, H 6.95, N 4.14.
Hz, 12H, CH3(SIPr)), 1.23 (d, J = 6.3 Hz, 12H, CH3(SIPr)). C { H}
] (2b). Following the general pro- NMR (100 MHz, CDCl ): δ (ppm) = 156.9 (CHNCN), 146.6 (CAr),
cedure using IPr·HCl (75.7 mg, 0.178 mmol) and [Pd(η -2-Me- 131.6 (CH ), 129.5 (C ), 129.1 (CHcin), 128.4 (CHcin), 128.1
3
[
IPr·H][Pd(η -2-Me-allyl)Cl
2
3
3
Ar
Ar
allyl)(μ-Cl)]
2
(35 mg, 0.089 mmol), the product was obtained as (CHcin), 125.1 (CHAr), 105.9 (CHcin), 81.3 (CHcin), 59.0 (CH
2
a yellow powder in a 99% (113 mg) yield. H NMR (400 MHz, (cin)), 56.0 (CH2(imid)), 29.1 (CH(IPr)), 25.6 (CH3(IPr)), 24.1 (CH
3
CDCl ): δ (ppm) = 9.20 (s, 1H, NCHNImid), 8.36 (s, 2H, CHImid), (IPr)). Elemental analysis: Expected: C 63.02, H 7.05, N 4.08;
3
7
3
.58 (t, J = 8.5 Hz, 2H, CHAr), 7.36 (d, J = 9.1 Hz, 4H, CHAr), found: C 63.28, H 6.96, N 4.15.
3
.72 (br. s, 2H, CH2(allyl)), 2.69 (br. s, 2H, CH2(allyl)), 2.51 (sept,
2
Synthesis of [IPent·H][Pd(η -cin)Cl ] (2f). Following the
J = 7.1 Hz, 4H, CH(IPr)), 2.03 (br. s, 3H, CH3(allyl)), 1.31 (d, J = general procedure from IPent·HCl (62.2 mg, 0.116 mmol) and
1
3
3
6
{
1
.8 Hz, 12H, CH3(IPr)), 1.23 (d, J = 7.1 Hz, 12H, CH3(IPr)).
H} NMR (100 MHz, CDCl
3
C
[Pd(η -cin)(μ-Cl)]
): δ 145.3 (CAr), 136.9 (CHNCN), obtained as a yellow powder in a 99% (92 mg) yield. H NMR
32.2 (CH ), 130.0 (C ), 127.8 (CH ), 124.8 (CH ), 60.5 (400 MHz, CDCl ): δ (ppm) = 8.43 (d, J = 1.6 Hz, 2H, CHImid),
2
(30 mg, 0.06 mmol), the product was
1
1
Ar
Ar
imid
Ar
3
(
(
CH2(allyl)), 29.2 (CH(IPr)), 24.8 (CH3(IPr)), 24.1 (CH3(IPr)), 22.8 8.37 (br. s, 1H, NCHNImid), 7.60 (t, J = 7.9 Hz, 2H, CHAr), 7.50
CH3(allyl)). Elemental Analysis: Expected C 59.86, H 7.13, N (d, J = 7.5 Hz, 2H, CHAr(cin)), 7.27 (m, 7H, CHAr), 5.75 (br. s, 1H,
4
.50; found: C 59.58, H 7.19, N 4.67.
Synthesis of [IPr·H][Pd(η -crotyl)Cl
CH(cin)), 4.60 (br. s, 1H, CH2(cin)), 3.93 (br. s, 1H, CH2(cin)), 3.00
] (2c). Following the (br. s, 1H, CH(cin)), 1.96 (sept, J = 8.1 Hz, 4H, CH(IPent)),
3
2
general procedure using IPr·HCl (75.7 mg, 0.178 mmol) and 1.75–1.60 (m, 16H, CH2(IPent)), 0.86 (t, J = 7.1 Hz, 12H, CH
3
3
13
1
[
Pd(η -crotyl)(μ-Cl)] (35.0 mg, 0.089 mmol), the product was (IPent)), 0.76 (t, J = 7.4 Hz, 12H, CH3(IPent)). C { H} NMR
2
1
obtained as a yellow powder in a 99% (113 mg) yield. H NMR (100 MHz, CDCl
(
2
4
2
1
3
): δ (ppm) = δ 142.7 (CAr), 134.9 (CHNCN),
): δ (ppm) = 9.20 (s, 1H, NCHNImid), 8.33 (s, 132.8 (CAr), 132.0 (CHAr), 129.2 (CHcin), 128.9 (CHcin), 128.3
H, CHImid), 7.56 (t, J = 10.5 Hz, 2H, CH ), 7.33 (d, J = 7.3 Hz, (Ccin), 128.1 (CHimid), 125.4 (CH ), 105.6 (CHcin), 81.2 (CHcin),
400 MHz, CDCl
3
Ar
Ar
H, CHAr), 5.08 (br. s, 1H, CH(crotyl)), 3.07 (br. s, 2H, CH2(crotyl)), 59.2 (CH2(cin)), 43.5 (CH(IPent)), 29.4 (CH2(IPent)), 28.5 (CH
2
.57 (br. s, 1H, CH(crotyl)), 2.48 (sept, J = 13.5 Hz, 4H, CH(IPr)), (IPent)), 12.6 (CH3(IPent)), 12.4 (CH3(IPent)). Elemental analysis:
.30 (s, 3H, CH3(crotyl)), 1.28 (d, J = 7.2 Hz, 12H, CH3(IPr)), 1.20 Expected: C 65.07, H 7.85, N 3.52; found: C 64.77, H 7.94, N 3.68.
1
3
1
3
(d, J = 7.2 Hz, 12H, CH3(IPr)). C { H} NMR (100 MHz, CDCl
3
):
Synthesis of [IPr*·H][Pd(η -cin)Cl
2
]
(2g). Following the
δ (ppm) = 145.2 (CAr), 137.0 (CHNCN), 132.2 (CHAr), 130.0 (CAr), general procedure from IPr*·HCl (109.9 mg, 0.115 mmol) and
3
1
5
1
27.7 (CHimid), 124.8 (CH ), 110.3 (CH(allyl)), 79.4 (CH(allyl)), [Pd(η -cin)(μ-Cl)] (30.0 mg, 0.058 mmol), the product was
Ar
2
1
7.0 (CH2(allyl)), 29.1 (CH3(IPr)), 24.8 (CH3(IPr)), 24.0 (CH3(IPr)), obtained as a yellow powder in a 99% yield (139 mg). H NMR
8.1 (CH3(allyl)). Elemental Analysis: Expected C 59.86, H 7.13, (400 MHz, CDCl ): δ (ppm) = 12.52 (s, 1H, NCHNImid),
7.31–7.23 (m, 20H, CH ), 7.19–7.06 (m, 19H, CH ), 6.77–6.75
3
N 4.50; found: C 59.70, H 6.95, N 4.69.
Ar
Ar
3
tBu
Synthesis of [IPr·H][Pd(η -Ind )Cl
2
] (2d). Following the (m, 10H, CHAr), 5.87–5.75 (br. m, 1H, CH(cin)), 5.41 (s, 4H,
general procedure using IPr·HCl (100 mg, 0.235 mmol) and CH(IPr*)), 5.33 (s, 2H, CHImid), 4.60–3.85 (br. m, 2H, CH2(cin)),
3
tBu
23a
13
1
[
Pd(η -Ind )(μ-Cl)]2
obtained as a brown/beige powder in a 99% (173 mg) yield. H (100 MHz, CDCl
NMR (400 MHz, CDCl ): δ (ppm) = δ 9.22 (s, 1H, NCHNImid), (CAr), 140.7 (CAr), 140.6 (CAr), 130.7 (CHAr), 130.2 (CHAr), 129.1
.27 (s, 2H, CHImid), 7.57 (t, J = 8.2 Hz, 2H, CH ), 7.34 (d, J = (CH ), 128.3 (CH ), 127.9 (CH ), 126.6 (CH ), 126.5 (CH ),
(74 mg, 0.118 mmol), the product was 2.97–2.58 (m, 1H, CH(cin)), 2.18 (s, 6H, CH3(IPr*)). C { H} NMR
1
3
): δ (ppm) = 142.6 (CAr), 142.5 (CHNCN), 142.1
3
8
7
Ar
Ar
Ar
Ar
Ar
Ar
.8 Hz, 4H, CHAr), 7.11–7.07 (m, 1H, CHInd), 6.80–6.57 (m, 4H, 122.8 (CHimid), 105.6 (CHcin), 82.2 (CHcin), 59.3 (CHcin), 51.0
CHInd), 5.51–5.41 (m, 1H, CHInd), 2.47 (sept, J = 7.2 Hz, 7.3 Hz, (CH3(IPr)), 21.7 (CH3(IPr)). Elemental analysis: Expected: C
H, CH(IPr)), 1.36–1.31 (m, 9H, CH3(Ind)), 1.29 (d, J = 7.2 Hz, 77.38, H 5.66, N 2.31; found: C 77.25, H 5.47, N 2.36.
4
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Suzuki–Miyaura reaction, general procedure
Conflicts of interest
(
a) With ArCl substrates: in air, a vial was charged with
3
The authors declare no conflict of interest.
[
IPr·H][Pd(η -cin)Cl
2
] (0.3 mol%, 1.7 mg), K
2 3
CO (0.7 mmol,
9
7 mg), ethanol (1 mL) and a magnetic stir bar and sealed
with a screw cap. The mixture was left stirring at 60 °C for 1 h.
The vial was removed from the heating block and the corres-
ponding aryl boronic acid (0.5 mmol) was added followed by Acknowledgements
the corresponding aryl chloride (0.5 mmol). The reaction was
The authors gratefully acknowledge support from the Royal
Society (University Research Fellowship to C. S. J. C.),
AstraZeneca (Studentship to C. M. Z) and the Distinguish
Scientist Fellowship Program (DSFP) at KSU (SPN).
left to stir for 4 h at 40 °C. Ethyl acetate (10 mL) and water
10 mL) were added to the reaction mixture. The aqueous
(
phase was extracted with ethyl acetate (3 × 10 mL). The com-
bined organic phases were dried over MgSO and filtered. The
4
solvent was removed under reduced pressure. The crude
2 2
product was dissolved in CH Cl (5 mL), filtered through silica
gel and recrystallized (CH Cl /pentane); (b) with ArBr sub-
2
2
3
strates: in a screw caped vial (5 mL) [IPr·H][Pd(η -cinnamyl) Notes and references
Cl
magnetic stir bar were charged. The mixture was stirred at
0 °C for 1 h. The mixture was allowed to cool to room temp-
2 2 3
] (0.5 mol%), K CO (0.55 mmol), ethanol (2 mL) and a
1
J. P. Corbet and G. Mignani, Chem. Rev., 2006, 106, 2651–
710.
C. C. C. Johansson Seechurn, M. O. Kitching, T. J. Colacot
2
6
2
erature. Then the corresponding boronic acid (0.5 mmol) was
added followed by the corresponding aryl bromide (0.5 mmol).
The reaction was left to stir at r.t. for 24 h. Water (20 mL) was
added to the reaction mixture and the product was extracted
with ethyl acetate (3 × 15 mL). The combined organic layers
were washed with brine (20 mL) and dried over Mg SO . The
and V. Snieckus, Angew. Chem., Int. Ed., 2012, 51, 5062–
5085.
3
T. J. Colacot, in New Trends in Cross-Coupling: Theory and
Applications, ed. T. J. Colacot, Royal Society of Chemistry,
Cambridge, 2015.
K. C. Nicolaou, P. G. Bulger and D. Sarlah, Angew. Chem.,
Int. Ed., 2005, 44, 4442–4489.
2
4
4
5
6
crude was concentrated under reduced pressure and purified
by column chromatography using ethyl acetate/n-hexane as
eluent.
J. Magano and J. R. Dunetz, Chem. Rev., 2011, 111, 2177–
2
250.
P. Ruiz-Castillo and S. L. Buchwald, Chem. Rev., 2016, 116,
2564–12649.
Larger scale Suzuki–Miyaura reaction procedure
1
In air, a 100 mL round bottom flask was charged with
7 S. Würtz and F. Glorius, Acc. Chem. Res., 2008, 41, 1523–
1533.
3
[
IPr·H][Pd(η -cin)Cl
2
] (48 mg, 0.078 mmol, 0.3 mol%), K
2
CO
3
(
4.56 g, 33.1 mmol), ethanol (50 mL) and a magnetic stir bar.
8 M. S. Viciu, R. A. Kelly III, E. D. Stevens, F. Naud, M. Studer
and S. P. Nolan, Org. Lett., 2003, 5, 1479–1482.
9 For example: (a) O. Navarro, R. A. Kelly III and S. P. Nolan,
J. Am. Chem. Soc., 2003, 125, 16194–16195; (b) C. J. O’Brien,
E. A. B. Kantchev, C. Valente, N. Hadei, G. A. Chass,
A. Lough, A. C. Hopkinson and M. G. Organ, Chem. – Eur.
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The mixture was stirred at 60 °C for 1 h. The flask was
removed from the heating block and 4-chloroacetophenone
(3.65 g, 23.6 mmol), followed by 4-tolylboronic acid (3.22 g,
2
3.6 mmol), were added as solids. The reaction was left stir-
ring for 16 h at 40 °C. After this time, the reaction was allowed
to reach room temperature and then ethyl acetate (50 mL) and
water (50 mL) were added. The solution was transferred to a 10 For earliest example, see: M. S. Viciu, R. F. Germaneau and
separating funnel (250 mL) where aqueous/organic phases S. P. Nolan, Org. Lett., 2002, 4, 4053–4055.
were separated and the aqueous phase was further extracted 11 For a historical perspective, see: C. G. Fortman and
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tions were dried over MgSO , filtered and volatiles removed 12 (a) A. Chartoire, M. Lesieur, A. M. Z. Slawin, S. P. Nolan
4
under vacuum. The resulting crude solid product was dis-
solved in CH Cl (25 mL), filtered through silica gel and recrys-
and C. S. J. Cazin, Organometallics, 2011, 30, 4432–4436;
(b) A. J. DeAngelis, P. G. Gildner, R. Chow and T. J. Colacot,
J. Org. Chem., 2015, 80, 6794–6813, and references cited.
2
2
tallized (CH
2
Cl
2
/pentane). The reaction yielded 4.66 g (94%) of
1
the desired product as a white solid. H NMR spectroscopy 13 C. M. Zinser, F. Nahra, M. Brill, R. E. Meadows,
2
5 1
confirmed the identity and purity of the product.
H NMR
D. B. Cordes, A. M. Z. Slawin, C. S. J. Cazin and S. P. Nolan,
(
400 MHz, CDCl ): δ (ppm) = δ 8.03 (d, J = 8.2 Hz, 2H), 7.69 (d,
3
Chem. Commun., 2017, 53, 7990–7993.
J = 8.6 Hz, 2H), 7.55 (d, J = 8.6 Hz, 2H), 7.29 (d, J = 8.6 Hz, 2H), 14 H. Clavier, A. Correa, L. Cavallo, E. C. Escudero-Adán,
1
3
1
2
.64 (s, 3H), 2.41 (s, 3H). C { H} NMR (100 MHz, CDCl ):
J. Benet-Buchholz, A. M. Z. Slawin and S. P. Nolan,
3
δ (ppm) = δ 197.9 (COMe), 145.9 (CAr), 138.4 (CAr), 137.1 (CAr),
Eur. J. Inorg. Chem., 2009, 1767–1773.
1
35.7 (CAr), 129.8 (CHAr), 129.1 (CHAr), 127.2 (CHAr), 127.1 15 D. Guest, M.-T. Chen, G. J. Tizzard, S. J. Coles, M. L. Turner
(
CH ), 26.8 (CH ), 21.3 (CH ).
and O. Navarro, Eur. J. Inorg. Chem., 2014, 2200–2203.
Ar
3
3
Green Chem.
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Paper
1
6 O. Diebolt, V. Jurčík, R. Correa da Costa, P. Braunstein, 20 For the first report on the synthesis of IPr, see: J. Huang
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1
1
(b) O. Santoro, A. Collado, A. M. Z. Slawin, S. P. Nolan and
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2
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Green Chem.