Water-Sculpting of a Heterogeneous Nanoparticle Precatalyst for Mizoroki-Heck Couplings under Aqueous Micellar Catalysis Conditions

Article abstract of DOI:10.1021/jacs.0c11484

Powdery, spherical nanoparticles (NPs) containing ppm levels of palladium ligated by t-Bu3P, derived from FeCl3, upon simple exposure to water undergo a remarkable alteration in their morphology leading to nanorods that catalyze Mizoroki-Heck (MH) couplings. Such NP alteration is general, shown to occur with three unrelated phosphine ligand-containing NPs. Each catalyst has been studied using X-ray photoelectron spectroscopy (XPS), energy-dispersive X-ray spectroscopy (EDX), transmission electron microscopy (TEM), and cryogenic transmission electron microscopy (cryo-TEM) analyses. Couplings that rely specifically on NPs containing t-Bu3P-ligated Pd occur under aqueous micellar catalysis conditions between room temperature and 45 °C, and show broad substrate scope. Other key features associated with this new technology include low residual Pd in the product, recycling of the aqueous reaction medium, and an associated low E Factor. Synthesis of the precursor to galipinine, a member of the Hancock family of alkaloids, is suggestive of potential industrial applications.

Full text of DOI:10.1021/jacs.0c11484

pubs.acs.org/JACS
Article
Water-Sculpting of a Heterogeneous Nanoparticle Precatalyst for
Mizoroki−Heck Couplings under Aqueous Micellar Catalysis
Conditions
Haobo Pang, Yuting Hu, Julie Yu, Fabrice Gallou, and Bruce H. Lipshutz*
Cite This: J. Am. Chem. Soc. 2021, 143, 3373−3382
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Powdery, spherical nanoparticles (NPs) containing ppm
levels of palladium ligated by t-Bu3P, derived from FeCl3, upon simple
exposure to water undergo a remarkable alteration in their morphology
leading to nanorods that catalyze Mizoroki−Heck (MH) couplings.
Such NP alteration is general, shown to occur with three unrelated
phosphine ligand-containing NPs. Each catalyst has been studied using
X-ray photoelectron spectroscopy (XPS), energy-dispersive X-ray
spectroscopy (EDX), transmission electron microscopy (TEM), and
cryogenic transmission electron microscopy (cryo-TEM) analyses.
Couplings that rely specifically on NPs containing t-Bu3P-ligated Pd
occur under aqueous micellar catalysis conditions between room
temperature and 45 °C, and show broad substrate scope. Other key
features associated with this new technology include low residual Pd in
the product, recycling of the aqueous reaction medium, and an associated low E Factor. Synthesis of the precursor to galipinine, a
member of the Hancock family of alkaloids, is suggestive of potential industrial applications.
Scheme 1. Reactions Catalyzed by Ligand-Dependent, ppm
Pd-Containing NPs
INTRODUCTION
■
Transition-metal-containing nanoparticles (NPs) offer timely
opportunities for development of new heterogeneous catalysts
and their applications to a broad range of synthetic processes.1
Given the endangered status of the platinoids, and Pd in
particular,2 reducing the common use of 1−10 mol % of Pd
catalysts3 by an order of magnitude provides one solution to
this problem. While numerous types of Pd NPs have been
described over the past two decades,4 few have found their way
into the toolbox of general reagents for effecting C−C bond
formation,5−7 with most of the interest focused on their
physical characteristics and properties. Oftentimes, Pd-
containing NPs, whether composed of pure atoms or metal
on the surface of solid supports (such as Al2O3), require
exposure to gases at elevated temperatures to arrive at the
active form(s), which can be reversible both during reactions
and once reactions are completed.8 These conditions are
associated with distinct changes in NP shape and size that can
dramatically alter, and thereby decrease, catalyst activity.
In 2015,9 we described new NPs that could be easily
fashioned upon simple treatment of inexpensive FeCl3 with
MeMgCl in THF solution containing SPhos as ligand,
performed at room temperature (Scheme 1). Catalyst loading
at the ppm level of Pd, whether found naturally as an
“impurity” in this iron salt, or as added Pd(OAc)2 (≥320 ppm)
to pure FeCl3, was sufficient en route to these NPs that
mediate Suzuki−Miyaura cross-couplings, reactions that could
Received: November 1, 2020
Published: February 25, 2021
https://dx.doi.org/10.1021/jacs.0c11484
J. Am. Chem. Soc. 2021, 143, 3373−3382
© 2021 American Chemical Society
3373

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Scheme 2. Optimization Requiring a Modified Preparation of Fe/ppm Pd NPs
a
Conditions: 1-Iodo-4-methoxybenzene (0.2 mmol), tert-butyl acrylate (0.4 mmol), Fe/ppm Pd NPs (13 mg, containing 0.50 mol % or 0.25 mol %
b
c
Pd), Et3N (0.6 mmol), NaCl (1.2 mmol), 5 wt % PTS/H2O (0.4 mL), rt, 16 h. Amount relative to FeCl3. Yield determined by GC-MS;
naphthalene as standard, NR = no reaction.
be run in aqueous micellar media under very mild conditions
(20−45 °C). NP characterization was performed using several
techniques, including their cryo-TEM analyses as used in their
aqueous reaction medium that revealed their size and raft-like
shape. Switching ligands to XPhos, as well as the Grignard
reagent to MeMgBr, resulted in NPs of similar shape and size
that are also very effective for catalyzing Sonogashira couplings
under the same aqueous conditions (Scheme 1).10 As our
interests turned toward developing related NPs that catalyze
Mizoroki−Heck (MH) couplings in water, not only was a
different ligand required, but modification in the mode of
preparation was also needed to arrive, ostensibly, at the same
type of NPs. These changes necessitated a more complete
analyses of these initially formed NPs (in THF). These new
data have led to the discovery of a remarkable room temperature
transformation that converts these initially constructed NPs
into their active state upon simple exposure to the aqueous
conditions under which they would normally be used. In this
report, we disclose this unexpected and rare water-mediated
conversion, the generality of this catalyst sculpting in water,
and the application of these new ppm Pd-containing NPs as a
new heterogeneous catalyst for MH reactions that take place in
recyclable water under environmentally responsible conditions.
Fe/ppm Pd NPs as Catalyst: Preparation. After an
extensive ligand screening indicating that t-Bu3P was, by far,
the best ligand for the intended Mizoroki−Heck reactions (see
Table S1), the corresponding Fe/ppm Pd NPs were formed
using FeCl3, Pd(t-Bu3P)2, and t-Bu3P, following our earlier
procedure.9 Using 1-iodo-4-methoxybenzene and tert-butyl
acrylate as partners for this model reaction, NPs with different
equivalents of MeMgCl were tested in 2 wt % PTS11/H2O at
room temperature, but none led to significant product
formation (Scheme 2, entries 1 to 3). Modified sequences
for reagent formation (Methods B−D) were investigated to
enhance the level of activation of the resulting NPs in this same
coupling (entries 4 to 6). From the GC results obtained,
Method D afforded the best coupling yields. Further
optimization based on equivalents of MeMgCl, both prior to
and after addition of Pd and ligand (entries 7 to 9), arrived at
the best combination: initial addition of 2.0 equiv of MeMgCl
followed by another 1.5 equiv (relative to FeCl3), together with
a Pd loading of 0.25 mol % (entry 8). Refinement of the
amount of ligand afforded a further improved yield (90%; entry
3374
https://dx.doi.org/10.1021/jacs.0c11484
J. Am. Chem. Soc. 2021, 143, 3373−3382

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
9). Other palladium salts, such as Pd(OAc)2 or [Pd(allyl)Cl]2,
or ligands (L1: Cy-cBRIDP;12 L2: dppp; L3: N-Ph-2-(t-Bu)2P-
pyrrole; see also Table S1 for ligand screening) clearly showed
that the combination of Pd(t-Bu3P)2 and t-Bu3P afforded much
better yields in the aqueous PTS medium than did other
sources of palladium or ligands (entries 10 to 14).
To arrive at finalized reaction conditions for use of these
NPs, an evaluation of the base and surfactant was undertaken
(reactions 1 and 2; Scheme 3). Switching to K3PO4 from Et3N
increase the size of nanomicelle by DLS (dynamic light
scattering).14 Under otherwise identical conditions, use of pure
THF as the reaction medium together with these same NPs
(albeit at the higher loading: 0.25 mol % Pd) led to the
expected product in only 9% yield (Table 2, entry 2). Running
this reaction in micellar media in the presence of the same
amounts of Pd(t-Bu3P)2 and t-Bu3P but without prior NP
formation gave a significant reduction in yield (19% with FeCl3;
8% in the absence of FeCl3; see Table S4), indicative of the
importance of prior nanoparticle formation.
Characterization of the NPs. We next turned our
attention to investigating the nature of the NPs that catalyze
these MH couplings. As previously pursued,9,10 a variety of
techniques were applied to establishing the makeup of the
surface of this catalyst. Most informative, however, was
determination via STEM analyses of their morphology as
made initially in THF, and then again when present within an
aqueous reaction mixture. Analyses of NPs containing either
SPhos or XPhos prior to their use under aqueous micellar
catalysis conditions had never been carried out. We were
certainly not anticipating the astonishing changes in NP
morphology that would be uncovered from these STEM
studies.
Scheme 3. Optimization of Reaction Conditions
Examination of these new NPs (prepared following Method
D, L = t-Bu3P) under typical aqueous reaction conditions (i.e.,
in 2 wt % TPGS-750-M/H2O) indicated that, as seen
previously in both cases of NPs containing SPhos-ligated Pd
used for Suzuki−Miyaura couplings9 and NPs composed of
XPhos-ligated Pd for Sonogashira couplings,10 nanorods
measuring 30 to 100 nm in length were present (Figure 1C).
Figure 1. High angle annular dark-field scanning transmission
electron microscopy (HAADF-STEM) image of (A) dry Fe/ppm
Pd nanoparticles; (B) Fe/ppm Pd nanomaterial in pure degassed
water; (C) Fe/ppm Pd nanorods in 2 wt % TPGS-750-M/H2O.
a
1-Iodo-4-methoxybenzene (0.2 mmol), tert-butyl acrylate (0.4
However, the corresponding analyses of the initially formed
NPs prepared in THF revealed a completely different
morphology: these (as a dry powder) are spherical, measuring
2−5 nm (Figure 1A). Exposure of the initial spherical NPs to
just water begins the “sculpting” process (Figure 1A to 1B).
Upon addition of an aqueous solution of TPGS-750-M the
conversion to nanorods is complete (Figure 1B to 1C). Hence,
the original NPs formed, in fact, are not the actual catalyst being
used for these couplings; rather, their exposure to the aqueous
surfactant had transformed them entirely into the active form
capable of catalyzing MH couplings at the ppm level of Pd.
As revealed by elemental mapping images of spherical NPs,
O, P, Cl, Mg, and Fe are homogeneously distributed
throughout these nanoclusters, while the presence of Pd is
too low to be detected (Figure 2). The corresponding EDX
spectrum confirmed the existence of O, P, Cl, Mg, and Fe (also
with low atomic percentage of Pd; see SI). Elemental mappings
on the derived nanorods also showed the distribution of O, Cl,
Mg, and Fe; however, by contrast, phosphorus was noticeably
absent.
mmol), Fe/ppm Pd NPs (12.5 mg, 0.25 mol % or 5 mg, 0.10 mol
% Pd), base (0.6 mmol), NaCl (1.2 mmol), surfactant/H2O (0.4 mL),
b
rt, 16 h. Yield determined by GC-MS; naphthalene as standard.
c
d
Isolated yield in parentheses. 1-Iodo-4-methoxybenzene (0.2
mmol), styrene (0.4 mmol), Fe/ppm Pd NPs (12.5 mg, 0.25 mol
% Pd), K3PO4 (0.6 mmol), NaCl (1.2 mmol), 2 wt % TPGS-750-M/
H2O (0.4 mL), and cosolvent (0.04 mL) at 45 °C, 16 h. 40 h.
e
gave similar results in aqueous micellar media derived from
designer surfactant PTS11 and, remarkably, was equally
effective when the loading of Pd was reduced from 2500 to
1000 ppm (i.e., 0.1 mol %; entry 4). Other surfactants,13 as
well as different amounts (i.e., weight percent) of surfactant, in
water as the reaction medium (entries 5 to 12) indicated that 2
wt % TPGS-750-M13b afforded the best outcome (entry 6).
Using the same educts, the potential beneficial role of a
cosolvent (reaction 2, entries 13 to 18; also see Table S3) led
to the finding that, if needed, DMF was the cosolvent of choice
(entry 18). Varying percentages of cosolvent were reported to
3375
https://dx.doi.org/10.1021/jacs.0c11484
J. Am. Chem. Soc. 2021, 143, 3373−3382

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Figure 2. HAADF-STEM elemental mapping of dry Fe/ppm Pd nanoparticles vs Fe/ppm Pd nanorods in 2 wt % TPGS-750-M/H2O.
To determine if this water-induced change in morphology of
t-Bu3P-containing NPs is independent of the associated ligand,
two additional sets of NPs were made using the same approach
(i.e., Scheme 2, Method D). In these cases, however, t-Bu3P
was replaced with SPhos, and by Cy-cBRIDP. The Fe/ppm Pd
NPs for each consisted of very similar looking dry powders,
likewise made in THF. Their analyses by STEM showed
related nanospheres (2 to 5 nm; Figures 3A and 3D), as seen
upon exposure of the NPs to water to varying extents.
Subsequent addition of aqueous TPGS-750-M (or, addition of
this aqueous solution to the spherical NPs directly) leads to
complete conversion from small spherical NPs to far larger
nanorods.
Analyses via XPS was also applied to both the initially
prepared powders and the catalytically active NPs used for
Mizoroki−Heck couplings. These full scans reveal the surface
of the prenanocatalyst (i.e., the powder form) consists of
oxygen (13.15%), carbon (55.56%), iron (0.21%), chlorine
(16.24%), phosphorus (3.23%), magnesium (11.48%), and
palladium (0.13%; see p S27 in the Supporting Information
(SI)). However, after stirring in water for the same 1 h period,
over 85% of their mass had dissolved in water, with XPS
analysis now showing the surface of the newly formed
nanorods to contain oxygen (30.58%), carbon (48.65%),
iron (5.02%), chlorine (4.60%), phosphorus (2.65%),
magnesium (7.63%), and palladium (0.88%; see p S31 in the
SI). Hence, these comparisons between precatalyst spheres and
water-sculpted nanorods indicate that the proportions of
oxygen, iron, and palladium have increased, while the levels of
phosphorus, chlorine, and magnesium have decreased, which is
consistent with observations from elemental mapping (vide
supra). The percentage changes in metal content in the NPs
before and after rinsing with water could be determined by
ICP-MS (Table 1, and p S25 in the SI). Thus, in 10 mg of dry
NP powder, there was found to be present 0.983 mg of Mg,
0.627 mg of Fe, and 0.039 mg of Pd. After stirring in pure
water for 1 h, ca. 90% of the Mg had dissolved. By contrast,
over 90% of both Fe and Pd remained associated with the
nanorods. Overall, close to 90% of the mass of the original
nanoparticles had been dispersed into the aqueous medium
(i.e., the supernatant) during this 1 h process.
Figure 3. HAADF-STEM image of (A) dry Fe/ppm Pd nanoparticles
with SPhos as ligand; (B) Fe/ppm Pd nanocatalyst with SPhos as
ligand in pure water; (C) Fe/ppm Pd nanocatalyst with SPhos as
ligand in aqueous TPGS-750-M; (D) dry Fe/ppm Pd nanoparticles
with Cy-cBRIDP as ligand; (E) Fe/ppm Pd nanocatalyst with Cy-
cBRIDP as ligand in pure water; (F) Fe/ppm Pd nanocatalyst with
Cy-cBRIDP as ligand in aqueous TPGS-750-M.
previously when made in the presence of t-Bu3P (see Figure
1A). After stirring each in pure degassed water, both formed
nanorods to varying extents (see Figure 3B and 3E). However,
upon addition of 2 wt % TPGS-750-M/H2O, which is the
usual reaction medium, further stirring for 1 h led to complete
conversion to nanorods (50 to 130 nm; Figure 3C and 3F).
Thus, a change in morphology, independent of ligand, results
3376
https://dx.doi.org/10.1021/jacs.0c11484
J. Am. Chem. Soc. 2021, 143, 3373−3382

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Cryo-TEM analyses also provided insight as to the special
role played by (10%, v/v) DMF as cosolvent, which facilitates
these MH reactions in water. Other potential solvents (DMSO,
MeOH, etc.) that could, in principle, function similarly (e.g., if
only for substrate dissolution purposes) were totally ineffective
(Figure 4). The images reveal that the size of the typically
Table 1. ICP-MS Analyses of Dry Powder, Remaining
Material, and Supernatant
Dry powder
(10 mg)
Leftover
(1.2 mg)
Supernatant
(1.7 mL)
Mg (mg)
Fe (mg)
Pd (mg)
0.983
0.627
0.039
0.089
0.587
0.033
0.894
0.051
0.0018
High resolution XPS measurements further disclosed the
oxidation states and variation of content of different elements
in the nanomaterial before and after exposure to water (see
SI). The P 2p spectrum reveals that the proportion of P(V) is
much higher than that of P(III) on the surface of the dry
powder spheres. And the Pd 3d spectrum indicated that the
oxidation state of Pd in the nanomaterial is Pd(II), rather than
Pd(0).
Figure 4. (A) Cryo-TEM analyses of NP catalyst among nanomicelles
of TPGS-750-M. (B) Cryo-TEM of NP catalyst in the same micellar
media, but after adding DMF as cosolvent.
Control experiments, the results from which are shown in
Table 2, correlated NP catalyst changes and resulting activity
with changes in reaction conditions used for MH couplings.
First, and as expected, neither nanomicelles nor nanorods were
formed (i.e., the NPs remained as spheres) when an organic
solvent such as THF (entry 2) or DMF (entry 3) was used as
the reaction medium, leading to only 9% and 41% yields,
respectively. Reaction in pure, degassed water, in which the
nanorod structure could form but in the absence of
nanomicelles (entry 4), led to a 68% yield of cinnamate
coupling product. The reaction containing both nanomicelles
and nanorod catalyst in surfactant/water, but in the absence of
the majority of ligand (t-Bu3P) upon removal of the aqueous
medium and replacement with fresh TPGS-750-M/water
(entry 5), gave only a 78% yield. However, replenishing this
newly introduced aqueous reaction mixture by addition of
fresh ligand (entry 6) resulted in the expected yield increase.
Utilizing the initially removed aqueous supernatant (entry 7)
as reaction medium and adding fresh reaction partners (along
with base and NaCl), likewise, gave a yield quite similar to
levels observed previously (entries 1 and 6) which contained
the same amount of t-Bu3P in the pot. These last two entries
provide strong evidence that all reaction components, although
most notably, the required levels of phosphine, which under
the reaction conditions are distributed between the surface of
the NPs and, mainly, best accommodated within the
nanomicelles in the water, must be present for a highly
successful reaction outcome.
spherical nanomicelle derived from TPGS-750-M (40−60 nm;
see A)13b is expanded upon addition of DMF to 100 nm (as
seen in B). Moreover, the nanorod NPs present in water alone
are distinctly separated from the nanomicelles; there is no
interaction between them (as in A). However, upon addition
of DMF, and in addition to nanomicelle swelling,14 the crucial
“nano-to-nano” effect15 is now operating, leading to substrate
(within the micelles) delivery to the NP catalyst with the
resulting reactivity enhancement manifested by much higher
levels of conversion and associated isolated yields being
obtained under mild conditions.
Application to Mizoroki−Heck (MH) Couplings. With
considerable insight as to the nature of the active NP catalyst
involved (i.e., its optimized preparation, its interactions with
nanomicelles present in the aqueous medium, and the role of
added DMF), the scope of this ppm level Pd catalysis (1000−
2500 ppm or 0.10−0.25 mol %) for MH couplings was
evaluated (Table 3). Several aryl and heteroaryl iodides,
together with various alkenyl partners, were examined. Most
reactions took place quite smoothly and afforded excellent
yields of coupled products. Numerous functional groups are
tolerated, including methoxy- (1, 3, 6), ester (1, 2, 4, 5, 7, 8),
ketone (2), chloride- (5), nitrile- (7, 9), trifluoromethyl- (10,
11, 12, 14), thio- (10), nitro- (11, 14), a Boc-protected amine
(12), fluoride- (17, 24), isolated olefins (19), aldehyde (20,
Table 2. Control Experiments
Nanorod Aquecus Excess
Entry
Conditions
structure micelles
ligand Yield
1
2
3
4
5
2 wt % TPGS-750-M/H2O as reaction medium
THF as reaction medium
DMF as reaction medium
Degassed H2O as reaction medium
Fe/ppm Pd NPs stirred in degassed H2O for 1 h; remove H2O; add starting materials, K3PO4, and NaCI; add
fresh 2 wt % TPGS-750-M/H2O as reaction medium (no phosphine)
Fe/ppm Pd NPs stirred In degassed H2O for 1 h; remove H2O; add t-Bu3P, starting materials, K3PO4, and NaCI;
add fresh 2 wt % TPGS-750-M/H2O as reaction medium
Fe/ppm Pd NPs stirred in 2 wt % TPGS-750-M/H2O for 1 h; remove aq. surfactant solution; add fresh starting
materials, K3PO4, and NaCl; add back the previously removed aq. surfactant solution as the reaction medium
99%
9%
41%
68%
78%
95%
92%
no
no
no
no
no
no
6
7
3377
https://dx.doi.org/10.1021/jacs.0c11484
J. Am. Chem. Soc. 2021, 143, 3373−3382

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
a b
,
Table 3. Substrate Scope
a
Iodide (0.2 mmol), alkene (0.4 mmol), NaCl (1.2 mmol), K3PO4 (0.6 mmol) and Fe/ppm Pd (12.5 mg, 0.25 mol % Pd), 2 wt % TPGS-750-M/
b
c
d
e
f
g
H2O (0.4 mL), DMF (0.04 mL), 45 °C, 16 h. Isolated yield. Fe/ppm Pd NPs (5 mg, 0.10 mol % Pd). No DMF. At rt. 40 h. 72 h.
25), alkyne (23), and a TIPS-protected phenol (24).
Moreover, various heterocyclic rings, such as pyridine (3,
15), pyrazole (8), pyrrole (9), piperazine (10), dihydrobenzo-
furan (11), benzodioxol (13), thiophene (14), a THP-
protected indazole (15), morpholine (16, 22), pyrimidine
(16, 21, 26), indole (17, 22), pyrrolindine (18), tetrahy-
drofuran (20, 23), and benzo[d]oxazol (26) all led to good
yields of the anticipated products. Many of these have
extensive applications to targets in the agricultural and
pharmaceutical industries.16
A direct comparison between heterogeneous catalysts
described in the literature for Mizoroki−Heck couplings, in
this case leading to tert-butyl (E)-3-(4-methoxyphenyl)-
acrylate, is illustrated in Table 4. The results suggest that
this NP technology leads to the cinnamate product in
comparable or better yields, can be accomplished using
lower catalyst loadings and temperatures, and does so in an
aqueous reaction medium that is much more environmentally
friendly than all others used in organic solvents, especially
those run in dipolar aprotic media.
As is characteristic of designer surfactant technology in
water, recycling of the aqueous reaction mixture is straightfor-
ward and routine, thereby decreasing wastewater streams
(Scheme 4).17 In order to introduce fresh NPs, the typical “in-
flask” extraction of the reaction mixture using methyl tert-butyl
ether (MTBE) was followed by its transfer to a vessel
containing premeasured Fe/ppm Pd NPs and K3PO4. The E
Factor,18 introduced by Sheldon and co-workers as a measure
3378
https://dx.doi.org/10.1021/jacs.0c11484
J. Am. Chem. Soc. 2021, 143, 3373−3382

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Table 4. Comparisons between Heterogeneous Catalysts
Entry
Catalyst
Pd (%)
Temp (°C)
Solvent
Yield (%)
ref
1
2
3
4
5
6
7
8
Fe/ppm Pd NPs
SiO2@Fe3O4-Pd
0.1
1
1
1
5
2
4
1
0.4
0.5
0.05
0.8
rt
2 wt % TPGS-750-M/H2O
DMF
DMF
EtOH/H2O (1:1)
DMF
DMF
DMSO
DMF
H2O
H2O/DMF
H2O
99
96
88
90
94
100
95
82
this work
100
140
80
100
120
120
110
90
20
21
22
23
24
25
26
5a
5b
19
1h
K-Pd-Me10CB[5]
NO2-NHC-Pd@Fe3O,
Pd-pyridinophane unit
Pd(OAc)2/DABCO
Pd/CuFe2O4
Pd-Fe3O4
a
9
tetraimine Pd(0) complex
CPS-MNPs-NNN-Pd
PEDOT-NFs@Pd
PdTSPc@KP-GO
88
b
10
11
12
90−100
rt
100
72
89
c
c
H2O
87
a
b
c
Different alkenes were used in the couplings: styrene and 1-octene. Bromobenzene and styrene were used as coupling partners.
potential for industrial application scale up using the same
educts (albeit with fewer equivalents of alkene), under
otherwise identical conditions, afforded the desired product
in 87% isolated yield (Scheme 4, middle).
Scheme 4. Recycle, E Factor, Gram-Scale Reaction, and
Residual Pd in Products from MH Reactions
Another noteworthy feature associated with ppm level Pd-
catalyzed MH couplings focuses on the amount of residual
metal found in the product after filtration or standard
extraction/purification. According to FDA-approved guide-
lines,19 residual Pd residue must be below 10 ppm per dose per
day. Exceeding these limits, which is routine when using
traditional levels of Pd catalysts (i.e., 1−10 mol %), requires
additional time and cost. Hence, two isolated products
(Scheme 4, bottom) were chosen randomly and analyzed
independently by ICP-MS. The results obtained indicated
undetectable levels of Pd in each sample. One application leading
to a precursor to galipinine (28) was prepared using these NPs,
indicative of the potential for additional applications to targets
in the pharmaceutical industry (Scheme 5).27
Scheme 5. Synthesis of a Precursor to Galipinine
The option for sequential reactions in one pot represents
one of the hallmarks of this chemistry in recyclable water, given
the variety of reactions that can now be run under aqueous
micellar conditions. By “telescoping” such consecutive
reactions, there is typically a dramatic decrease in both
newly created organic waste and the effort normally devoted to
purification associated with each step. In the first example
shown (Scheme 6), MH coupling led to product 27, that,
without isolation, was followed by nitro group reduction using
added Fe/ppm (Ni + Pd) NPs described previously.28 In this
second step, it was important to form ligandless NPs in 2 wt %
Coolade/H2O,29 since the addition of NaBH4 leads to frothing
from hydrogen generation that is eliminated using this designer
surfactant. This reagent is then transferred to the same vial
used for the initial MH reaction (run in TPGS-750-M/H2O).
a
ICP-MS data were obtained from the UC Center for Environmental
b
Implications of Nanotechnology at UCLA. Each sample was done in
triplicate with background correction. ND = not detected.
c
of greenness (on the basis of “solvents” used), is even lower
when the product of interest is a solid that precipitates out
from the reaction and is simply filtered. As a representative
example, using tert-butyl 5-iodo-1H-indole-1-carboxylate and
4-nitrostryene as starting materials, product 27 was thus
obtained in 97% isolated yield. The crude product was washed
with small amounts of DI water and then purified by filtration
through a column. The E Factor associated with this process
based on solvent usage is only 0.62, while that including water
is only 6.3. A gram-scale reaction run as a measure of the
3379
https://dx.doi.org/10.1021/jacs.0c11484
J. Am. Chem. Soc. 2021, 143, 3373−3382

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
to an active catalyst; (3) new NPs that contain a ligand that
leads to a catalyst that, in water, effects ppm level Pd catalysis
of Mizoroki−Heck reactions.
Scheme 6. Tandem Reactions in Water
The prognosis for applications to industrial targets is further
strengthened by (1) a gram-scale experiment that affords the
intended product without variation in yield, (2) an application
to a known target in folk medicine, and (3) opportunities for
tandem reactions to be carried out in a one-pot sequence in
water, thereby eliminating individual step handling, processing,
and waste generation.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c11484.
■
sı
Full experimental details and procedures for optimiza-
tions and couplings, analyses, full spectral data, recycling,
and E Factor determination (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Bruce H. Lipshutz − Department of Chemistry and
Biochemistry, University of California, Santa Barbara,
California 93106, United States; orcid.org/0000-0001-
9116-7049; Email: lipshutz@chem.ucsb.edu
The resulting aniline 29 was then treated directly with 2,4,5-
trichloropyrimidine leading to an SNAr reaction, ultimately
affording final product 30 in 86% overall isolated yield. As a
second example (Scheme 6, bottom), by taking advantage of
inherent differences in activity between an aryl iodide and
bromide, an initial MH reaction with 31 led to bromide 32,
which (without isolation) participated in a Suzuki−Miyaura
cross-coupling to give biaryl product 33 in 82% overall yield.
Authors
Haobo Pang − Department of Chemistry and Biochemistry,
University of California, Santa Barbara, California 93106,
United States
Yuting Hu − Department of Chemistry and Biochemistry,
University of California, Santa Barbara, California 93106,
United States
Julie Yu − Department of Chemistry and Biochemistry,
University of California, Santa Barbara, California 93106,
United States
Fabrice Gallou − Novartis Pharma AG, CH-4057 Basel,
Switzerland; orcid.org/0000-0001-8996-6079
SUMMARY AND CONCLUSIONS
■
In summary, new nanoparticles (NPs) derived from FeCl3
have been formulated that effectively catalyze Mizoroki−Heck
couplings with considerable generality, used under unchar-
acteristically mild and environmentally responsible conditions.
Unlike those previously prepared from similar precursors, these
NPs require both a modified protocol as well as a significant
change in ligand for optimal catalyst activity. Notwithstanding
their differences that enable heterogeneous MH couplings to
now occur in water under such mild conditions, the initially
generated ca. 5 nm spherical NPs have been found to be, in fact, a
precatalyst to those 100−200 nm rod-shaped NPs that catalyze
these couplings. Using several methods of analyses, the actual
active catalytic species results only upon exposure to (usually
surfactant-containing) water, which is responsible for their
significant alteration, or sculpting, from small, inactive
spherical NPs into much larger, reactive nanorod-shaped
materials. Documentation is provided as to the extent of
greenness in the form of E Factor determination, and well as
the facility with which an aqueous reaction mixture can be
recycled. Notably, in situations where residual levels of metal
must meet rigorously prescribed (FDA) standards, ICP-MS
analyses reveal that products resulting from these couplings
contain undetectable amounts of palladium. The advances
discussed in this contribution therefore include the following:
(1) unprecedented use of water to completely alter the
morphology of initially formed, and inactive, NPs into an
active catalyst; (2) using various techniques common to
material science to document these changes along the pathway
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c11484
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support provided by the NSF (CHE 18-56406) and
Novartis is warmly acknowledged with thanks.
■
REFERENCES
■
(1) (a) Cortes-Clerget, M.; Akporji, N.; Takale, B. S.; Wood, A.;
Landstrom, E.; Lipshutz, B. H. In Earth-Abundant and Precious Metal
Nanoparticle Catalysis; Nanoparticles in Catalysis. Topics in Organo-
metallic Chemistry; Kobayashi, S., Ed.; Springer: Cham, 2020; Vol 66,
pp 77−129. (b) Petkar, D. R.; Kadu, B. S.; Chikate, R. C. Highly
efficient and chemoselective transfer hydrogenation of nitroarenes at
room temperature over magnetically separable Fe−Ni bimetallic
nanoparticles. RSC Adv. 2014, 4, 8004. (c) Chen, H.; Zhou, L.; Wen,
M.; Wu, Q.; Wang, C. A branched-dumbbell Pt/NiFe nanostructure
and its high catalytic reduction activity for nitro-aromatic compounds.
Mater. Res. Bull. 2014, 60, 322. (d) Chu, C.; Su, Z. Facile Synthesis of
AuPt Alloy Nanoparticles in Polyelectrolyte Multilayers with
Enhanced Catalytic Activity for Reduction of 4-Nitrophenol.
Langmuir 2014, 30, 15345. (e) Alamgholiloo, H.; Rostamnia, S.;
3380
https://dx.doi.org/10.1021/jacs.0c11484
J. Am. Chem. Soc. 2021, 143, 3373−3382

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Zhang, K.; Lee, T.; Lee, T.; Varma, R. S.; Jang, H.; Shokouhimehr, M.
Boosting Aerobic Oxidation of Alcohols via Synergistic Effect between
TEMPO and a Composite Fe3O4/Cu-BDC/GO Nanocatalyst. ACS
Omega 2020, 5, 5182. (f) Nguyen, V.; Nguyen, B.; Hu, C.; Sharma,
C.; Vo, D.; Jin, Z.; Shokouhimehr, M.; Jang, H.; Kim, S.; Le, Q.
Advances in Designing Au Nanoparticles for Catalytic Epoxidation of
Propylene with H2 and O2. Catalysts 2020, 10, 442. (g) Shokouhi-
mehr, M. Magnetically Separable and Sustainable Nanostructured
Catalysts for Heterogeneous Reduction of Nitroaromatics. Catalysts
2015, 5, 534. (h) Rezaei, S. J. T. PEDOT nanofiber/Pd(0)
composite-mediated aqueous Mizoroki−Heck reactions under ultra-
sonic irradiation: an efficient and green method for the C−C cross-
coupling reactions. J. Iran. Chem. Soc. 2017, 14, 585. (i) Hezarkhani,
Z.; Shaabani, A. Palladium(II) tetrasulfophthalocyanine covalently
immobilized on keratin protein grafted graphene oxide nanosheets as
a new high-performance catalyst for C−C coupling reactions. RSC
Adv. 2016, 6, 98956.
(2) (a) Choudary, B. M.; Madhi, S.; Chowdari, N. S.; Kantam, M. L.;
Sreedhar, B. Layered Double Hydroxide Supported Nanopalladium
Catalyst for Heck-, Suzuki-, Sonogashira-, and Stille-Type Coupling
Reactions of Chloroarenes. J. Am. Chem. Soc. 2002, 124, 14127.
(b) Liu, Y.; Bai, X. Argon glow discharge plasma-reduced palladium
nanoparticles supported on activated carbon for Suzuki and Heck
coupling reactions. Appl. Organomet. Chem. 2017, 31, e3561.
(c) Reetz, M. T.; Westermann, E. Phosphane-Free Palladium-
Catalyzed Coupling Reactions: The Decisive Role of Pd Nano-
particles. Angew. Chem., Int. Ed. 2000, 39, 165. (d) Johansson
Seechurn, C. C. C.; Li, H.; Colacot, T. J. Chapter 3: Pd−Phosphine
Precatalysts for Modern Cross-Coupling Reactions. In New Trends in
Cross-Coupling: Theory and Applications; The Royal Society of
Chemistry: 2015; p 91.
(c) Park, C. M.; Kwon, M. S.; Park, J. Palladium Nanoparticle in
Polymers: Catalyst for Alkene Hydrogenation, Carbon-Carbon Cross-
Coupling Reactions, and Aerobic Alcohol Oxidation. Synthesis 2006,
4, 618. (d) Singh, A. S.; Patil, U. B.; Nagarkar, J. M. Palladium
supported on zinc ferrite: A highly active, magnetically separable
catalyst for ligand free Suzuki and Heck coupling Palladium supported
on zinc ferrite: A highly active, magnetically separable catalyst for
ligand free Suzuki and Heck coupling. Catal. Commun. 2013, 35, 11.
(e) Nasrollahzadeh, M. A.; Azarian, A.; Ehsani, A.; Khalaj, M.
Preparation, optical properties and catalytic activity of TiO2@
Pdnanoparticles as heterogeneous and reusable catalysts for ligand-
free Heck coupling reaction. J. Mol. Catal. A: Chem. 2014, 394, 205.
(f) Ghorbani-Choghamarani, A. G.; Tahmasbi, B.; Moradi, P.
Synthesis of a new Pd(0)-complex supported on boehmite nano-
particles and study of its catalytic activity for Suzuki and Heck
reactions in H2O or PEG. RSC Adv. 2016, 6, 43205. (g) Zhang, F.;
Niu, J.; Wang, H.; Yang, H.; Jin, J.; Liu, N.; Zhang, Y.; Li, R.; Ma, J.
Palladium was supported on superparamagnetic nanoparticles: A
magnetically recoverable catalyst for Heck reaction. Mater. Res. Bull.
2012, 47, 504. (h) Niembro, S.; Shafir, A.; Vallribera, A.; Alibes, R.
Palladium Nanoparticles Supported on an Organic−Inorganic
Fluorinated Hybrid Material. Application to Microwave-Based Heck
Reaction. Org. Lett. 2008, 10, 3215. (i) Badetti, E.; Caminade, A. M.;
Majoral, J. P.; Moreno-Manas, M.; Sebastian, R. M. Palladium(0)
Nanoparticles Stabilized by Phosphorus Dendrimers Containing
Coordinating 15-Membered Triolefinic Macrocycles in Periphery.
Langmuir 2008, 24, 2090.
(6) (a) Nyathi, T. M.; Fischer, N.; York, A. P. E.; Morgan, D. J.;
Hutchings, G. J.; Gibson, E. K.; Wells, P. P.; Catlow, C. R. A.; Claeys,
M. Impact of Nanoparticle−Support Interactions in Co3O4/Al2O3
Catalysts for the Preferential Oxidation of Carbon Monoxide. ACS
Catal. 2019, 9, 7166. (b) Camposeco, R.; Castillo, S.; Mejía-Centeno,
I. Performance of V2O5/NPTiO2−Al2O3-nanoparticle- and V2O5/
NTiO2−Al2O3-nanotube model catalysts in the SCR−NO with NH3.
Catal. Commun. 2015, 60, 114. (c) Lira, E.; Merte, L. R.; Behafarid,
F.; Ono, L. K.; Zhang, L.; Roldan Cuenya, B. Role and Evolution of
Nanoparticle Structure and Chemical State during the Oxidation of
NO over Size- and Shape-Controlled Pt/γ-Al2O3 Catalysts under
Operando Conditions. ACS Catal. 2014, 4, 1875.
(7) Christoffel, F.; Ward, T. R. Palladium-Catalyzed Heck Cross-
Coupling Reactions in Water: A Comprehensive Review. Catal. Lett.
2018, 148, 489.
(8) (a) Zhang, H.; Gilbert, B.; Huang, F.; Banfield, J. F. Water-
driven structure transformation in nanoparticles at room temperature.
Nature 2003, 424, 1025. (b) Wang, P.; Wang, R.-Y.; Jin, J.-Y.; Xu, L.;
Shi, Q.-F. The Morphological Change of Silver Nanoparticles in
Water. Chin. Phys. Lett. 2012, 29, 017805.
(9) Handa, S.; Wang, Y.; Gallou, F.; Lipshutz, B. H. Sustainable Fe−
ppm Pd nanoparticle catalysis of Suzuki-Miyaura cross-couplings in
water. Science 2015, 349, 1087.
(10) Handa, S.; Jin, B.; Bora, P. P.; Wang, Y.; Zhang, X.; Gallou, F.;
Reilly, J.; Lipshutz, B. H. Sonogashira Couplings Catalyzed by Fe
Nanoparticles Containing ppm Levels of Reusable Pd, under Mild
Aqueous Micellar Conditions. ACS Catal. 2019, 9, 2423.
(11) (a) Borowy-Borowski, H.; Sikorska-Walker, M.; Walker, P. R.
Water-soluble compositions of bioactive lipophilic compounds.
US6045826, Apr 2000. (b) PTS (polyoxyethanyl-R-tocopheryl
sebacate) was obtained from Sigma-Aldrich (cat. no. 698717).
(12) Suzuki, K.; Hori, Y.; Kobayashi, T. A New Hybrid Phosphine
Ligand for Palladium-Catalyzed Amination of Aryl Halides. Adv.
Synth. Catal. 2008, 350, 652.
(3) See, for example, as used in Buchwald−Hartwig aminations:
Forero-Cortés, P. A.; Haydl, A. M. The 25th Anniversary of the
Buchwald−Hartwig Amination: Development, Applications, and
Outlook. Org. Process Res. Dev. 2019, 23, 1478.
(4) (a) Hong, K.; Sajjadi, M.; Suh, J. M.; Zhang, K.; Nasrollahzadeh,
M.; Jang, H. W.; Varma, R. S.; Shokouhimehr, M. Palladium
Nanoparticles on Assorted Nanostructured Supports: Applications
for Suzuki, Heck, and Sonogashira Cross-Coupling Reactions. ACS
Appl. Nano Mater. 2020, 3, 2070. (b) Iben Ayad, A.; Belda Marín, C.;
Colaco, E.; Lefevre, C.; Méthivier, C.; Ould Driss, A.; Landoulsi, J.;
Guénin, E. Water soluble” palladium nanoparticle engineering for C−
C coupling, reduction and cyclization catalysis. Green Chem. 2019, 21,
6646. (c) Alamgholiloo, H.; Zhang, S.; Ahadi, A.; Rostamnia, S.;
Banaei, R.; Li, Z.; Liu, X.; Shokouhimehr, M. Synthesis of bimetallic
4-PySI-Pd@Cu(BDC) via open metal site Cu-MOF: Effect of metal
and support of Pd@Cu-MOFs in H2 generation from formic acid.
Molecular. Catalysis 2019, 467, 30. (d) Alamgholiloo, H.; Rostamnia,
S.; Hassankhani, A.; Liu, X.; Eftekhari, A.; Hasanzadeh, A.; Zhang, K.;
Karimi-Maleh, H.; Khaksar, S.; Varma, R. S.; Shokouhimehr, M.
Formation and stabilization of colloidal ultra-small palladium
nanoparticles on diamine-modified Cr-MIL-101: Synergic boost to
hydrogen production from formic acid. J. Colloid Interface Sci. 2020,
567, 126. (e) Shokouhimehr, M.; Hong, K.; Lee, T.; Moon, C.; Hong,
S.; Zhang, K.; Suh, J.; Choi, K.; Varma, R. S.; Jang, H. Magnetically
retrievable nanocomposite adorned with Pd nanocatalysts: efficient
reduction of nitroaromatics in aqueous media. Green Chem. 2018, 20,
3809. (f) Zhang, K.; Cha, J.; Jeon, S.; Kirlikovali, K. O.; Ostadhassan,
M.; Rasouli, V.; Farha, O. K.; Jang, H.; Varma, R. S. Pd modified
prussian blue frameworks: Multiple electron transfer pathways for
improving catalytic activity toward hydrogenation of nitroaromatics.
Molecular catalysis 2020, 492, 110967.
(13) (a) Klumphu, P.; Lipshutz, B. H. Nok”: A Phytosterol-Based
Amphiphile Enabling Transition-Metal-Catalyzed Couplings in Water
at Room Temperature. J. Org. Chem. 2014, 79, 888. (b) Lipshutz, B.
H.; Ghorai, S.; Abela, A. R.; Moser, R.; Nishikata, T.; Duplais, C.;
Krasovskiy, A.; Gaston, R. D.; Gadwood, R. C. TPGS-750-M: A
Second Generation Amphiphile for Metal-Catalyzed Cross-Couplings
in Water at Room Temperature. J. Org. Chem. 2011, 76, 4379.
(5) (a) Mandegani, Z.; Asadi, M.; Asadi, Z.; Mohajeri, A.; Iranpoor,
N.; Omidvar, A. A nano tetraimine Pd(0) complex: synthesis,
characterization, computational studies and catalytic applications in
the Heck−Mizoroki reaction in water. Green Chem. 2015, 17, 3326.
(b) Firuzabadi, F. D.; Asadi, Z.; Panahi, F. Immobilized NNN Pd-
complex on magnetic nanoparticles: efficient and reusable catalyst for
Heck and Sonogashira coupling reactions. RSC Adv. 2016, 6, 101061.
3381
https://dx.doi.org/10.1021/jacs.0c11484
J. Am. Chem. Soc. 2021, 143, 3373−3382

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
(14) Gabriel, C. M.; Lee, N. R.; Bigorne, F.; Klumphu, P.;
Parmentier, M.; Gallou, F.; Lipshutz, B. H. Effects of Co-solvents on
Reactions Run under Micellar Catalysis Conditions. Org. Lett. 2017,
19, 194.
Alcohols. Org. Lett. 2020, 22, 5496. See, for example: (b) Davies,
S. G.; Fletcher, Ai. M.; Houlsby, I. T. T.; Roberts, P. M.; Thomson, J.
E.; Zimmer, D. The Hancock Alkaloids (−)-Cuspareine, (−)-Galipi-
nine, (−)-Galipeine, and (−)-Angustureine: Asymmetric Syntheses
1
and Corrected H and 13C NMR Data. J. Nat. Prod. 2018, 81, 2731.
(15) Lipshutz, B. H. The ‘Nano-to-Nano’ Effect Applied to Organic
Synthesis in Water. Johnson Matthey Technol. Rev. 2017, 61, 196.
(16) (a) Chekal, B. P.; Guinness, S. M.; Lillie, B. M.; McLaughlin, R.
W.; Palmer, C. W.; Post, R. J.; Sieser, J. E.; Singer, R. A.; Sluggett, G.
W.; Vaidyanathan, R.; Withbroe, G. J. Development of an Efficient
Pd-Catalyzed Coupling Process for Axitinib. Org. Process Res. Dev.
2014, 18, 266. (b) King, A. O.; Corley, E. G.; Anderson, R. K.; Larsen,
R. D.; Verhoeven, T. R.; Reider, P. J.; Xiang, Y. B.; Belley, M.;
Leblanc, Y. An efficient synthesis of LTD4 antagonist L-699,392. J.
Org. Chem. 1993, 58, 3731. (c) Kumar, U. S.; Sankar, V. R.; Rao, M.
M.; Jaganathan, T. S.; Buchi Reddy, R. Investigational Study into the
Formation of Methoxy Derivative and Other Impurities during the
Optimization of Eletriptan Hydrobromide. Org. Process Res. Dev.
2012, 16, 1917. (d) Guillemont, J.; Pasquier, E.; Palandjian, P.;
Vernier, D.; Gaurrand, S.; Lewi, P. J.; Heeres, J.; de Jonge, M. R.;
Koymans, L. M. H.; Daeyaert, F. F. D.; Vinkers, M. H.; Arnold, E.;
Das, K.; Pauwels, R.; Andries, K.; de Béthune, M.-P.; Bettens, E.;
Hertogs, K.; Wigerinck, P.; Timmerman, P.; Janssen, P. A. J. Synthesis
of Novel Diarylpyrimidine Analogues and Their Antiviral Activity
against Human Immunodeficiency Virus Type 1. J. Med. Chem. 2005,
48, 2072. (e) Hazra, S.; Tiwari, V.; Verma, A.; Dolui, P.; Elias, A. J.
NaCl as Catalyst and Water as Solvent: Highly E-Selective Olefination
of Methyl Substituted N-Heteroarenes with Benzyl Amines and
Alcohols. Org. Lett. 2020, 22, 5496.
(28) Pang, H.; Gallou, F.; Sohn, H.; Camacho-Bunquin, J.; Delferro,
M.; Lipshutz, B. H. Synergistic effects in Fe nanoparticles doped with
ppm levels of (Pd + Ni). A new catalyst for sustainable nitro group
reductions. Green Chem. 2018, 20, 130.
(29) Lee, N. R.; Cortes-Clerget, M.; Wood, A. B.; Lippincott, D. J.;
Pang, H.; Moghadam, F. A.; Gallou, F.; Lipshutz, B. H. Coolade. A
Low-Foaming Surfactant for Organic Synthesis in Water. Chem-
SusChem 2019, 12, 3159.
(17) Lipshutz, B. H.; Isley, N. A.; Fennewald, J. C.; Slack, E. D. On
the Way Towards Greener Transition-Metal-Catalyzed Processes as
Quantified by E Factors. Angew. Chem., Int. Ed. 2013, 52, 10952.
(18) (a) Sheldon, R. A.; Arends, I. W. C. E.; Hanefeld, U.
Introduction: Green Chemistry and Catalysis. Green Chemistry and
Catalysis; Wiley-VCH: Weinheim, 2007; p 1. (b) Sheldon, R. A. The
E Factor: fifteen years on. Green Chem. 2007, 9, 1273.
(19) F.D.A., Q3D Elemental Impurities Guidance for Industry,
https://www.fda.gov/media/135956/download (accessed Jan 28,
2021).
(20) Li, P.; Wang, L.; Zhang, L.; Wang, G.-W. Magnetic
Nanoparticles-Supported Palladium: A Highly Efficient and Reusable
Catalyst for the Suzuki, Sonogashira, and Heck Reactions. Adv. Synth.
Catal. 2012, 354, 1307.
(21) Li, H.; Lu, J.; Lin, J.; Huang, Y.; Cao, M.; Cao, R. Crystalline
̈
Hybrid Solid Materials of Palladium and Decamethylcucurbit[5]uril
as Recoverable Precatalysts for Heck Cross-Coupling Reactions.
Chem. - Eur. J. 2013, 19, 15661.
(22) Kandathil, V.; Fahlman, B. D.; Sasidhar, B. S.; Patil, S. A.; Patil,
S. A. A convenient, efficient and reusable N-heterocyclic carbene-
palladium(ii) based catalyst supported on magnetite for Suzuki−
Miyaura and Mizoroki−Heck cross-coupling reactions. New J. Chem.
2017, 41, 9531.
(23) Morisaki, Y.; Ishida, T.; Chujo, Y. Synthesis and Character-
ization of Dithia[3.3](2,6)pyridinophane-Containing Polymers: Ap-
plication to the Palladium-Catalyzed Heck Reaction. Org. Lett. 2006,
8, 1029.
(24) Li, J.-H.; Wang, D.-P.; Xie, Y.-X. Pd(OAc)2/DABCO as a
Highly Active Catalytic System for the Heck Reaction. Synthesis 2005,
2005, 2193.
(25) Lakshminarayana, B.; Mahendar, L.; Ghosal, P.; Sreedhar, B.;
Satyanarayana, G.; Subrahmanyam, C. Fabrication of Pd/CuFe2O4
hybrid nanowires: a heterogeneous catalyst for Heck couplings. New J.
Chem. 2018, 42, 1646.
(26) Chung, J.; Kim, J.; Jang, Y.; Byun, S.; Hyeon, T.; Kim, B. M.
Heck and Sonogashira cross-coupling reactions using recyclable Pd−
Fe3O4 heterodimeric nanocrystal catalysts. Tetrahedron Lett. 2013, 54,
5192.
(27) (a) Hazra, S.; Tiwari, V.; Verma, A.; Dolui, P.; Elias, A. J. NaCl
as Catalyst and Water as Solvent: Highly E-Selective Olefination of
Methyl Substituted N-Heteroarenes with Benzyl Amines and
3382
https://dx.doi.org/10.1021/jacs.0c11484
J. Am. Chem. Soc. 2021, 143, 3373−3382