A self-assembling NHC-PD-loaded calixarene as a potent catalyst for the Suzuki-Miyaura cross-coupling reaction in water

Article abstract of DOI:10.3390/molecules25061459

Nanoformulated calix[8]arenes functionalized with N-heterocyclic carbene (NHC)palladium complexes were found to be efficient nano-reactors for Suzuki-Miyaura cross-coupling reactions of water soluble iodo- and bromoaryl compounds with cyclic triol arylborates at low temperature in water without any organic co-solvent. Combined with an improved one-step synthesis of triol arylborates from boronic acid, this remarkably efficient new tool provided a variety of 4⁰-arylated phenylalanines and tyrosines in good yields at low catalyst loading with a wide functional group tolerance.

Full text of DOI:10.3390/molecules25061459

molecules
Article
A Self-Assembling NHC-Pd-Loaded Calixarene as a
Potent Catalyst for the Suzuki-Miyaura
Cross-Coupling Reaction in Water
Arnaud Peramo 1, Ibrahim Abdellah 2 , Shannon Pecnard 1, Julie Mougin 1, Cyril Martini 2,3
,
Patrick Couvreur 1, Vincent Huc 2,* and Didier Desmaële 1,
*
1
Institut Galien Paris-Sud, CNRS UMR 8612, Universit
é
Paris-Saclay, Facult
é
de Pharmacie, 5 rue JB Cl
é
ment,
92296 Châtenay-Malabry, France; arnaud.peramo@gmail.com (A.P.); shannon.pecnard@u-psud.fr (S.P.);
julie.mougin@u-psud.fr (J.M.); patrick.couvreur@u-psud.fr (P.C.)
Institut de Chimie Moléculaire et des Matériaux d’Orsay, CNRS UMR 8182, Université Paris Saclay,
Bâtiment 420, 91405 Orsay, France; ibrahim_abdellah@hotmail.com (I.A.); cyril.martini@novecal.com (C.M.)
NOVECAL, 86 rue de Paris, 91400 Orsay, France
2
3
*
Correspondence: vincent.huc@u-psud.fr (V.H.); didier.desmaele@u-psud.fr (D.D.);
Tel.: +33-(0)-1-6915-7436 (V.H.); +33-(0)-1-4683-5753 (D.D.)
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Yves Canac
Received: 9 March 2020; Accepted: 22 March 2020; Published: 24 March 2020
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: Nanoformulated calix[8]arenes functionalized with N-heterocyclic carbene (NHC)-
palladium complexes were found to be efficient nano-reactors for Suzuki-Miyaura cross-coupling
reactions of water soluble iodo- and bromoaryl compounds with cyclic triol arylborates at low
temperature in water without any organic co-solvent. Combined with an improved one-step synthesis
of triol arylborates from boronic acid, this remarkably efficient new tool provided a variety of
40-arylated phenylalanines and tyrosines in good yields at low catalyst loading with a wide functional
group tolerance.
Keywords: NHC; nanoparticle; calixarene; palladium catalyst; Suzuki-Miyaura reaction;
amino-acids; water
1. Introduction
The Suzuki-Miyaura reaction has emerged as one of the most powerful tool for C–C bond formation
because of its compatibility with a broad range of functional groups giving rise to numerous applications
throughout organic chemistry, synthesis of pharmaceutical compounds [1–3] and materials science [4,5].
Aqueous Suzuki-Miyaura cross-coupling reactions are particularly promising due to the water tolerance
of boronic acids compared with the organometallic reagents required for other cross-coupling protocols.
As a consequence, the Suzuki-Miyaura reaction has been widely developed under homogenous or
heterogenous catalytic conditions in water media and a large array of different ligands and palladium
complexes including micellar catalysis conditions nanoparticulate formulations have been designed to
increase efficiency under aqueous conditions [
Suzuki-Miyaura reaction culminated in the cross-coupling of iodoarylated proteins under physiological
conditions opening the way to a realm of chemical-biology applications [17 20]. Reactions in water are
6–16]. The water and functional group tolerance of the
–
not restricted to those with biomolecules: due to water’s ideal proprieties (abundance, environmental
compatibility, non-toxicity and nonflammability) a wide range of catalytic and organic reactions
have been developed in water as solvent [21]. In this context, calixarene macromolecules have been
used for Suzuki-Miyaura cross-coupling reactions as supports for palladium catalyst. In particular,
calix[4]arenes bearing phosphine or N-heterocyclic carbene (NHC) ligands have demonstrated good
catalytic efficiencies in this reaction [22–26]. There are a few examples of the use of calix[4]arenes as
Molecules 2020, 25, 1459; doi:10.3390/molecules25061459
www.mdpi.com/journal/molecules

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catalyst supports in mixtures of water and dioxane [22], however, to our knowledge no reactions in
pure water have been reported using unsupported calixarene. Recently, the synthesis of a large-cavity
calix[8]arene anchoring eight NHC-palladium catalytic heads (Pd-Calix, Figure 1) was reported [27].
This catalyst demonstrated good catalytic properties and low metal leaching for Suzuki-Miyaura
cross-coupling reactions with bromoarenes in green solvent such as ethanol, but the Pd-Calix was also
tested in water/organic mixtures giving promising results. On the other hand this catalyst was found
much less efficient in pure water [27]. Assuming that nanoparticles (NPs) embedding the Pd-Calix
would show improved catalytic efficiency over the bulk material, a nanoformulation of this Pd-Calix
was realized. Herein we describe the use of Pd-Calix nanosuspension (Pd-Calix-NS) as an efficient
catalyst for the Suzuki-Miyaura reaction in aqueous solution at 37 ◦C. A variety of water-soluble cyclic
triolborates were obtained in a one-step process from boronic acids, and their reactions with different
haloarenes under Suzuki-Miyaura cross-coupling conditions using the Pd-Calix-NS are described.
Figure 1. General structure of calix [8]arenes (top) and structure of the calix[8]arene bearing eight
NHC-palladium units (Pd-Calix) (bottom). Mes = Mesityl.
2. Results and Discussion
The calix [8] arene-NHC-Pd catalyst was synthesized according to the method previously
reported [27]. Briefly, chlorobutyl appendages were first bound to the eight free phenol groups of
benzyloxycalix[8]arene and the chlorides then displaced with 3-(mesityl)-2,3-dihydro-1H-imidazole.
The palladium carbene complexes were next generated with palladium chloride in the presence of
potassium carbonate and 3-chloropyridine as extra ligand.
Formulation of Pd-Calix was first performed using the nanoprecipitation/solvent evaporation
method using THF as organic solvent [28]. Nanoparticles with a 116 nm average hydrodynamic
diameter were obtained as revealed by dynamic light scattering (DLS) (Table 1). Unfortunately, this
formulation was found quite unstable after few days. To address this problem, the emulsion-solvent
evaporation method was attempted using CH2Cl2 to solubilize the catalyst [29]. The organic phase
was poured into an aqueous solution containing sodium cholate (1.5%) as surfactant, the two phases
were emulsified by sonication and the solvent was evaporated.
Monodisperse NPs with a mean diameter of 112 nm (Z average determined by DLS) and a
polydispersity index (PdI) of 0.2 were thus obtained. The formulation was found stable upon 30-day
storage thanks to their quite negative zeta potential (Table 1). CryoTEM imaging revealed spherical
NPs in line with DLS measurements (Figure 2).

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Table 1. Size, polydispersity index (PDI) and
ζ-Potential of the Pd-Calix-NPs as measured by dynamic
light scattering according to the method of preparation.
Method of Formulation
Size (nm)
PDI
ζ-Potential (mV)
Nanoprecipitation
Emulsion evaporation
116
112
0.18
0.21
−3.14
−16.8
Figure 2.
(A): Cryo-TEM images of the nanoparticles of the Pd-Calix-NS prepared by emulsion-solvent
evaporation; (
B
): Evolution of the mean diameter of the nanoparticles of the Pd-Calix-NS upon
incubation at 25 ◦C in water over one-month.
Following our early finding that palladium stabilized PLGA-PEG NPs were an efficient catalyst
for the Suzuki-Miyaura couplings of 4-iodophenylalanine with phenylboronic acid derivatives,
we chose to evaluate the present catalyst in the same model reaction [30]. Thus, reaction of
N-Boc-4-iodo-l-phenylalanine (1a) with phenylboronic acid in the presence of 0.005 mol% of
Pd-Calix-NS (0.04 mol% of Pd per mol of substrate) in pH 8.0 phosphate buffer at 37 ◦C reached 40%
conversion into diphenylalanine 3a after 3 h (Table 2, entry 1).
Although boronic acids are the originally used organoboron derivative for Suzuki-Miyaura reaction,
they suffered from some drawbacks such as protodeboronation and oxidation. More nucleophilic
organoboron reagents were thus developed with an improved stability and reactivity profile [31].
Among them, potassium phenylfluoroborate [32] and N-methyliminodiacetic acid phenylboronates
(MIDA) [33] provided very low conversion rate or no reaction. On the other hand, cyclic triol
phenylborate [34] turned out to give a full conversion in 3 h using 0.005 mol% of catalyst (0.04 mol% of
palladium) per mol of substrate (Table 2, entry 4). Such a superior reactivity of borate salts squared
with our previous results with Pd NPs stabilized by PLGA-PEG in water [30]. The hydrolytic stability
of the cyclic triol borate derivatives in the reaction conditions (checked by NMR in D2O-PBS) must be
emphasized and clearly accounted for the efficiency of the process. Interestingly, there was no need of
added base to carry out the reaction and the control of the pH was simply achieved using PBS buffer.
This feature is of crucial interest to enlarge the process to biomolecules.
To evaluate the influence of the nanoformulation, the bulk catalyst without sodium cholate was
used at the same concentration on the same benchmark reaction (Table 2, entry 4). However, less than
5% of conversion was observed highlighting the tremendous impact of the nano-reactor design on the
catalysis efficiency. Interestingly, the amount of catalyst can be further diminished to 0.001 mol% on
small scale reactions (3–4 mg) without reducing the overall conversion rate, highlighting the remarkable
catalytic efficiency of the present nanosuspension. Although similar full conversion was achieved with
the Pd-PLGA-PEG NPs catalyst (Entry 6), this formulation suffered of long-term stability issue. On the
other hand, the water-soluble Davis catalyst (Entry 7) is very easy to handle but required much higher
amount of palladium.

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Table 2.
Influence of the organoboron derivative on the cross-coupling reaction of
N-Boc-4-iodo-l-phenylalanine.
Entry
Pd Catalyst
X
Conv (%) a
1
2
Pd-Calix-NS
Pd-Calix-NS
B(OH)2
BF3-K+
40
10
3
4
5
Pd-Calix-NS
Pd-Calix-NS
Bulk Pd-Calix
0
98
<5
97b
6
7
Pd-PLGA-PEG NPs
B(OH)2
95c
a
N-Boc-4-iodo-l-phenylalanine (1 equiv.), boronic acid derivatives (3 equiv.), Pd-Calix-NS (0.005 mol%), phosphate
buffer (20 mM, pH = 8), 37 ◦C for 3 h. Conversion determined by 1H NMR analysis of the C-3 methylene signal.
b
c
0.01% Pd, according to reference [30]. 1 mol% Pd, according to reference [18].
Having identified the best organoboron partner we turned our efforts to expand the scope of the
process to other water-soluble aryl halides. The results obtained using various halides with cyclic triol
phenylborate 2a and 0.005 mol% of Pd-Calix-NS as catalyst are summarized in Figure 3. The influence
of the halide was briefly investigated. 4-Iodo- and 4-bromophenylalanine underwent reaction with
similar high yield. By contrast the chloride derivative 1c was found completely unreactive. In addition
to amino acid derivatives, we investigated several water soluble simple aromatic halides. The presence
of carboxylic acid, phenol or amino groups on the arene ring did not affect the reaction, the main
limitation being the solubility of the starting material in water. Even 2-iodoaniline underwent the
desired coupling albeit at lower rate.
The influence of the structure of the cyclic triol borate was next explored. Synthesis of cyclic triol
borates from boronic acids usually involved initial ester formation with 1,1,1-tris (hydroxymethyl)
ethane in toluene with azeotropic removal of water followed by cyclization upon treatment with KOH
in the same conditions. We found that the requisite cyclic triol borates can more easily be obtained in a
one-step process from boronic acids by a simple stirring with the triol in the presence of 1 equiv. of
KOH in dioxane at 30 ◦C.
The desired compounds were then isolated by simple filtration. This new method was found more
convenient that the original procedure and was amenable to large laboratory scale preparation [34].
The bench-stable borate salts were thus obtained in good yields with a variety of aryl and heteroaryl
compounds (Table 3). Hindered or electron poor boronic acids required longer reaction time
(compounds 2g
corresponding metal borate salt in similar yield (compounds 2b
crystallizing tetrabutylammonium cyclic triol borate (2e) was obtained in only 20% yield.
,
2h). Replacement of KOH base by another alkaline earth metal afforded the
–
d
). On the other hand, the poorly

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Figure 3. Reactivity of cyclic phenyltriolborate with selected water-soluble aryl halides. Aryl halide
(1 equiv.), cyclic triol phenylborate (3 equiv.), Pd-Calix-NS (0.005 mol%), phosphate buffer (20 mM,
pH = 8), 37 ◦C 3 h. Isolated yield after chromatographic purification.
Table 3. Synthesis of cyclic triolborates from boronic acids.
Compound
R
M
Time (h)
Yield (%)
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
Ph
Ph
Ph
Ph
K
Li
Na
Cs
3
3
3
3
3
80
46
87
67
20
69
59a
72
67
65
n-Bu4N
p-MeOPh
o-Tol
m-NO2Ph
2-furanyl
3-thiophenyl
K
K
K
K
K
3
16
16
3
2j
3
a
The reaction was conducted at 60 ◦C.
With the small library of cyclic triol borate salts in hand, their reaction with N-Boc-4-iodo-l-
phenylalanine (1a) was next examined (Table 4). The screenings of the influence of the counter anion
clearly established that potassium and at a lesser extend sodium salts were the most effective. On the
other hand the NBu4 counter ion was found detrimental to the efficiency of the coupling. It appears
that electron withdrawing group on the aromatic ring or steric hindrance made the reaction slower.
Nevertheless both, 30-nitrodiphenylalanine (3ah) and [(20-methylphenyl) phenyl] alanine (3ag) were
isolated in good yields by prolonging the reaction time to 16 h. Moreover, when the pH was reduced
to 7 and 6 the coupling still took place with only a small reduction of yield (Entries
2 and 3). The
latter result may be useful for substrates poorly soluble at basic pH and to conduct reaction with
biomolecules at physiological pH [35]. Heterocyclic triolborates, including furan and thiophene rings
could also be used affording 3ai, 3aj in satisfactory yields. Possibility to recycle the catalyst was briefly

Molecules 2020, 25, 1459
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investigated. Unfortunately attempts to resuspend the catalyst pellet obtained by centrifugation after
the first reaction cycle failed, presumably because it was not possible to adjust the require amount of
sodium cholate.
Table 4. Reactivity of aryl and heteroaryl cyclic triolborates with N-Boc-4-iodophenylalanine.
Cyclic
borate
Entry
R
Metal
pH
Product
Yield(%) a
1
2
3
4
5
6
7
8
9
2a
2a
2a
2b
2c
2d
2e
2f
Ph
Ph
Ph
Ph
Ph
K
K
K
Li
Na
Cs
TBA
K
K
K
K
K
8.0
7.0
6.0
8.0
8.0
8.0
8.0
8.0
8.0
8.0
8.0
8.0
3a
3a
3a
3a
3a
98
67
56
30
90
47
22
98
79b
72b
87
63
Ph
Ph
3a
3a
p-MeOPh
o-Tol
m-NO2Ph
2-furanyl
3-thiophenyl
3af
3ag
3ah
3ai
3aj
2g
2h
2i
10
11
12
2j
a
The reaction was conducted at 60 ◦C.
3. Experimental
3.1. General Information
Infrared (IR) spectra were obtained using a Fourier Transform Bruker Vector 22 spectrometer.
Only significant absorptions are listed. The 1H and 13C NMR were recorded using a Bruker Advance
300 (300 and 75 MHz, respectively) spectrometer. Recognition of methyl, methylene, methine and
quaternary carbon nuclei in 13C NMR spectra rests on the J-modulated spin-echo sequence. All
chemical shifts are quoted on the
δ scale in ppm using residual solvent as the internal standard
(1H NMR: CDCl3 = 7.26; D2O = 4.79; DMSO-d6 = 2.50; D3COD = 3.33 and 13C NMR: DMSO-d6 =
39.5). Coupling constants (J) are reported in Hz with the following splitting abbreviations: s = singlet,
d = doublet, t = triplet, q = quartet, quint = quintet and m = multiplet. H and 13C NMR spectra of
1
compounds 2a, 2e-j, 3a, 3d, 3e-f, 3h-j, 3af, 3ag, 3ah, 3ai, 3aj are provided in Supplementary Materials.
Mass spectra were recorded using an LTQ-Velos Pro Thermofisher Scientific spectrometer. The sizes of
the obtained Pd nanoformulations were measured using a Malvern particle size analyzer [nano ZS
(173◦ scattering angle)]. The morphology of the different palladium nanoformulations was examined by
transmission electron microscope (TEM) using a JEOL JEM 100CXII transmission electron microscope
at an accelerating voltage of 100 kV and for high resolution image using a JEOL JEM 2010 instrument
at 200 kV. Deionized water was used for chemical reactions and Milli-Q purified water for nanoparticle
preparation. Bidistilled MilliQ water was produced using a water purification system (Millipore).
Chemicals were obtained from Carbosynth Limited (UK), Sigma Aldrich Chemical Co (France),
Fluorochem and Alfa Aesar (France) and were used without further purification. Solvents of analytical
grade were obtained from VWR. Phosphate buffer saline (PBS) pH 7.4 was obtained from Sigma
Aldrich. Anhydrous DMF and dioxane were obtained from Sigma Aldrich. Tetrahydrofuran (THF)
was distilled from sodium/benzophenone ketyl and CH2Cl2 from CaH2. The calix [8]arene-NHC-Pd

Molecules 2020, 25, 1459
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catalyst was synthesized according to the method previously reported [27]. All reactions involving
air- or water-sensitive compounds were routinely conducted in glassware, which was flame-dried
under a positive pressure of nitrogen or argon. Analytical thin-layer chromatography was performed
on Merck silica gel 60F254 glass precoated plates (0.25 mm layer). Column chromatography was
performed on Merck silica gel 60 (230–400 mesh ASTM (American Standard Test Sieve Series). Diaryl
and heteroaryl compounds were chromatographed eluting with AcOEt/cyclohexane mixture 1:4 to 1:1.
The 4-substituded phenylalanine derivatives were chromatographed eluting with CH2Cl2/MeOH 98:2
to 95:15.
3.2. Nanoformulation of the Calix [8]arene-NHC-Pd Catalyst
Pd-Calix-NS were prepared by the emulsion-evaporation technique. Practically, the calix [8]
arene-NHC-Pd catalyst (29.74 mg, 0.005 mmol) was dissolved into CH2Cl2 (5 mL). The organic phase
was emulsified into 10 mL of 1.5% sodium cholate (w/w) aqueous solution using a vortex for 1 min and
then a vibrating metallic tip at 30% amplitude for 1 min at 0 ◦C. The organic solvent was evaporated
by magnetic stirring overnight in an open flask under a laminar flow hood and readjusted to 10 mL to
provide a stock suspension of Pd-Calix-NS at 2.97 mg/mL.
3.3. Nanoparticles Characterization by DLS
Mean hydrodynamic diameters of the nanoassemblies and polydispersity index were measured at
25 ◦C by quasi-elastic light scattering with a Nano ZS (Malvern Instrument, 173 scattering angle). The
NPs surface charge was investigated by ζ
-potential measurement at 25 ◦C after dilution with 1 mM
NaCl solution, applying the Smoluchowski equation. Measurements were carried out in triplicate.
Colloidal stability in MilliQ water at 20 ◦C and 4 ◦C was investigated by measuring the Pd NPs mean
diameter over a period of 30 days.
3.4. Cryogenic Transmission Electron Microscopy (CryoTEM) of Pd-Calix-NS
Morphology of the NPs of Pd-Calix-NS was observed by CryoTEM. Few drops of the
nanosuspension (2.97 mg/mL) were deposited on EM grids covered with a holey carbon film
(Quantifoil R2/2) previously treated with a plasma glow discharge. Observations were conducted at
low temperature (
180 ◦C) on a JEOL 2010 FEG microscope operated at 200 kV. Images were recorded
−
with a Gatan camera.
3.5. General Method for the Synthesis of Potassium Aren-2,6,7-trioxa-1-borate-bicyclo[2.2.2]octane Salts
To a solution of the given boronic acid (1.64 mmol) and 1,1,1-tris(hydroxymethyl)ethane (197 mg,
1.65 mmol) in dioxane (10 mL) was added ground KOH (92 mg, 1.64 mmol). The mixture was flushed
with argon and water (29 µ
L, 1.65 mmol) was added. The resulting mixture was stirred at 30 ◦C for 3 h.
Cyclohexane (5 mL) was then added and the precipitated potassium triolborate salt was filtered on a
sintered glass funnel and washed twice with acetone. The solid was dried under vacuum to afford the
potassium borate salts as amorphous solids.
Potassium 4-methyl-1-phenyl-2,6,7-trioxa-1-borabicyclo-[2.2.2]octan-1-uide (2a), The general method using
1
phenyl boronic acid gave the title compound 14 in 87% yield. H NMR (300 MHz, DMSO-d6):
δ =
7.30 ppm (d, J = 7.2 Hz, 2H, H-2, H-6), 6.98–6.88 (m, 3H, H-3, H-4, H-5), 3.57 (s, 6H, CH2OB), 0.47
(s, 3H, CH3) ppm; 13C NMR (75 MHz, DMSO-d6):
= 132.1 (2CH, C-2, C-6), 125.5 (2CH, C-3, C-5),
δ
124.0 (CH, C-4), 73.6 (3CH2, B(OCH2)3), 34.4 (C, CCH3), 16.2 (CH3, CCH3) ppm. The C-B was not
observed; IR (neat, cm−1): 3064, 2958, 2843, 1613, 1351, 1207, 1093, 1042, 914, 878, 850, 714; MS (ESI−):
m/z (%) = 205.1 (100) [M − K]−, 204.1 (20).
Tetra-n-butylammonium 4-methyl-1-phenyl-2,6,7-trioxa-1-borabicyclo-[2.2.2]octan-1-uide (2e), The general
method using 1 equivalent of n-Bu4NOH as base provided the tetra-n-butylammonium borate salt
2e [36] in 20% yield as an off-white amorphous solid. 1H NMR (300 MHz, DMSO-d6):
δ, =; 733

Molecules 2020, 25, 1459
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(d, J = 6.6 Hz, 2H, H-2,H-6), 7.02–6.85 (m, 3H, H-3,H-4, H-5), 3.58 (s, 6H, CH2OB), 3.20–3.10 (m, 8H,
CH2N), 1.62–1.42 (m, 8H, CH2CH2N); 1.30 (hex, J = 7.3 Hz, 8H, CH2CH2CH2N), 0.93 (t, 7.3 Hz, 12H,
CH3CH2CH2CH2N), 0.48 (s, 3H, CH3) ppm; 13C NMR (75 MHz, DMSO-d6):
δ = 132.2 (2CH, C-2, C-6),
125.4 (2CH, C-3, C-5), 123.9 (CH, C-4), 73.5 (3CH2, B(OCH2)3), 57.5 (4CH2, CH3CH2CH2CH2N), 34.4
(C, CCH3), 23.0 (4CH2, CH3CH2CH2CH2N), 19.1 (4CH2, CH3CH2CH2CH2N), 16.2 (CH3, CCH3), 13.4
(4CH3, CH3CH2CH2CH2N) ppm. The C-B was not observed.
Potassium 1-(4-methoxyphenyl)-4-methyl-2,6,7-trioxa-1-borabicyclo-[2.2.2]octan-1-uide (2f), The general
method using 4-methoxyphenyl boronic acid give the title compound [34] as a white powder in 69%
yield; 1H NMR (300 MHz, DMSO-d6):
δ
= 7.22 (d, J = 8.1 Hz, 2H, H-2, H-6), 6.57 (d, J = 8.1 Hz, 2H, H-3,
H-5), 3.63 (s, 3H, OCH3), 3.57 (s, 6H, CH2OB), 0.48 (s, 3H, CH3) ppm; 13C NMR (75 MHz, DMSO-d6):
δ
= 157.2 (C, C-4), 133.5 (2CH, C-2, C-6), 111.7 (2CH, C-3, C-5), 74.0 (3CH2, B(OCH2)3), 54.9 (CH3,
OCH3), 34.9 (C, CCH3), 16.8 (CH3) ppm, the C-B was not observed; IR (neat, cm−1): 3230, 2863, 2841,
1598, 1510, 1451, 1399, 1283, 1214, 1178, 1078, 1045, 1024, 933, 854, 815,729, 697, 608; MS (ESI−): m/z (%)
= 235.1 (100) [M-K]−, 234.1 (20).
Potassium 4-methyl-1-(3-nitrophenyl)-2,6,7-trioxa-1-borabicyclo-[2.2.2] octan-1-uide (2h), The general
1
method using 3-nitrophenyl boronic acid gave the title compound [37] in 72% yield, H NMR
(300 MHz, DMSO-d6):
J = 6.9 Hz, H-6), 7.29 (t, 1H, J = 7.6 Hz, H-5), 3.62 (s, 6H, CH2OB), 0.51 (s, 3H, CH3) ppm; 13C NMR
(75 MHz, DMSO-d6): = 146.48 (C, C-3), 138.98 (CH, C-6), 126.90 (CH, C-2 or C-5), 126.30 (CH, C-2 or
δ = 8.17 (d, J = 1.5 Hz, 1H, H-2), 7.83 (dd, J = 8.1, 1.5 Hz, 1H, H-4), 7.75 (d, 1H,
δ
C-5), 119.26 (CH, C-4), 73.52 (3CH2, B(OCH2)3), 34.56 (C, CCH3), 15.97 (CH3) ppm, the C-B was not
observed; IR (neat, cm−1): 3015, 2948, 2850, 1606, 1519, 1458, 1402, 1342, 1278, 1238, 1216, 1083, 1054,
885, 863; MS (ESI−): m/z (%) = 250.0 (100) [M − K]−, 249 (20).
Potassium 4-methyl-1-(o-tolyl)-2,6,7-trioxa-1-borabicyclo-[2.2.2]octan-1-uide (2g), The general method using
o-tolylboronic acid gave the title compound [37] in 59% yield, 1H NMR (300 MHz, DMSO-d6):
δ
= 7.38
(d, J = 6.0 Hz, 1H, H-6), 6.90–6.75 (m, 3H, H-3,H-4,H-5), 3.61 (s, 6H, CH2OB), 2.37 (s, 3H, ArCH3), 0.52
(s, 3H, CH3) ppm; 13C NMR (75 MHz, DMSO-d6):
= 141.6 (C, C-2), 132.4 (CH, C-6), 128.0 (CH), 124.5
δ
(CH), 122.8 (CH), 73.0 (3CH2, B(OCH2)3), 34.5 (C, CCH3), 22.2 (CH3, ArCH3), 16.3 (CH3) ppm, the C-B
was not observed; IR (neat, cm−1): 3158, 2855, 1396, 1210, 1178, 1066, 1035, 970, 945, 928, 891, 829, 750,
689; MS (ESI−): m/z (%) = 219.1 (100) [M-K]−, 218 (20).
Potassium 1-(furan-2-yl)-4-methyl-2,6,7-trioxa-1-borabicyclo-[2.2.2]octan-1-uide (2i), The general method
using 2-furylboronic acid gave the title compound [38] in yield 67%; 1H NMR (300 MHz, DMSO-d6):
δ = 7.31 (s, 1H, H-5), 6.10 (m, 1H, H-3), 5.94 (d, J = 3.0 Hz, 1H, H-4), 3.54 (s, 6H, CH2OB), 0.48 (s, 3H,
CH3) ppm; 13C NMR (75 MHz, DMSO-d6):
δ = 140.6 (CH, C-5), 110.3 (CH, C-3 or C-4), 108.4 (CH,
C-3 or C-4), 72.9 (3CH2, B(OCH2)3), 34.4 (C, CCH3), 16.1 (CH3) ppm, the C-B was not observed; MS
(APCI−): m/z (%) = 195.1 (100) [M−], 194.1 (20).
Potassium 4-methyl-1-(thiophen-3-yl)-2,6,7-trioxa-1-borabicyclo-[2.2.2]octan-1-uide (2j), The general method
using 3-thienylboronic acid gave the title compound [39] in yield 65%; 1H NMR (300 MHz, DMSO-d6):
δ = 7.01 (dd, J = 4.5 Hz, J = 2.7 Hz, 1H, H-5), 6.93 (d, J = 4.5 Hz 1H, H-4), 6.85 (d, J = 1.8 Hz, 1H, H-2),
3.54 (s, 6H, CH2OB), 0.46 (s, 3H, CH3) ppm; 13C NMR (75 MHz, DMSO-d6):
δ = 132.9 (CH, C-4), 123.7
(CH, C-2), 120.9 (CH, C-5), 73.6 (3CH2, B(OCH2)3), 34.4 (C, CCH3), 16.2 (CH3) ppm, the C-B was not
observed; IR (neat, cm−1): 2948, 2847, 1630, 1468, 1421, 1400, 1351, 1215, 1172, 1071, 1000, 926, 869, 839,
774, 599, 622; MS (ESI−): m/z (%) = 211.2 (5) [M − H]−, 195.1 (100).
3.6. General Method for the Small-Scale Suzuki-Miyaura Coupling with Pd-Calix-NS
In an Eppendorf tube, the arylhalide (0.008 mmol, 1 equiv.) and the boronic acid/cyclic-triolborate
salt (0.024 mmol, 3 equiv.) were suspended in phosphate buffer pH 8.0–6.0 (200 mM, 50
Water (370 L). The suspension of Pd-Calix-NS was added (3.2
10−6 mmol; 0.00004 equiv.; 80
the reaction was mixed and shaken on a thermostated shaker (Biosan TS-100) at 800 rpm at 37 ◦C. After
µL) and MilliQ
µ
·
µL) and

Molecules 2020, 25, 1459
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3 h, the reaction was frozen in liquid nitrogen and the solution lyophilized. The crude product was
taken up in CD3OD and analyzed by 1H-NMR.
3.7. General Method for the Preparative Suzuki-Miyaura Coupling with Pd-Calix-NS
The arylhalide (0.25 mmol, 1 equiv.) and the boronic acid (0.75 mmol, 3 equiv.) were suspended
in phosphate buffer pH 8.0 (200 mM, 5 mL) and water (The stock solution of Pd-Calix-NS (0.025 mmol
◦
Pd, 0.01 equiv.) was added and the reaction was stirred at 37 C. After 3/16 h, the reaction was
frozen in liquid nitrogen and the solution was lyophilized. The crude product was purified by flash
chromatography on silica gels to afford the expected cross-coupling product.
4-Phenylbenzoic Acid (3e), The general method using 4-iodobenzoic acid and potassium phenyltriolborate
gave 4-phenylbenzoic acid [40] (Yield = 72%); 1H NMR (300 MHz, CDCl3): δ = 8.19 (d, J = 8.2 Hz, 2H,
H-20, H-60), 7.71 (d, J = 8.2 Hz, 2H, H-30, H-50), 7.64 (d, J = 7.8 Hz, 2H, H-2”, H-6”), 7.55–7.38 (m, 3H,
H3”, H-4”, H-5”) ppm; 13C NMR (75 MHz, DMSO-d6):
δ = 167.2 (C, CO2H), 144.3 (C), 139.1 (C), 130.0
(2CH), 129.7 (C), 129.1 (2CH), 128.3 (CH), 127.0 (2CH), 126.8 (2CH), ppm; MS (ESI−) m/z = 197.1 (100)
[M − H]−.
4-Phenylphenol (3f), The general method using 4-iodophenol and potassium phenyltriolborate gave
1
4-phenylphenol [41] (Yield = 90%); H NMR (300 MHz, CD3OD):
(
δ = 10.38 (1H, br s, OH), 8.37
d, J = 8.1 Hz, 2H, H-20, H-60), 8.28 (d, J = 8.7 Hz, 2H, H-3, H-5), 8.21 (t, J = 7.5 Hz, 2H, H-30, H-50),
8.07 (td, J = 7.2, 0.9 Hz, 1H, H-40), 7.66 (d, J = 8.4 Hz, 2H, H-2, H-6) ppm; 13C NMR (75 MHz, CD3OD):
δ = 160.6 (C, C-1), 149.7 (C, C-10), 140.5 (C, C-4), 138.3 (2CH, C-3, C-5), 137.3 (2CH, C-30, C-50), 135.9 (CH,
C-40), 135.5 (2CH, C-20, C-60), 125.3 (2CH, C-2, C-6) ppm; MS (ESI−) m/z (%) = 169.1 (100) [M − H]−.
2-Phenylbenzoic Acid (3h), The general method using 2-iodobenzoic acid and potassium phenyltriolborate
gave 2-phenylbenzoic acid [42] (Yield = 66%) 1H NMR (300 MHz, DMSO-d6):
δ
= 12.70 (s, 1H, OH),
7.72 (d, J = 7.5 Hz, 1H, H-6, 1H), 7.57 (t, J = 7.5 Hz, 1H, H-4, 1H), 7.45 (t, J = 7.3 Hz, 1H, H-5, 1H),
7.45–7.30 (m, 6H) ppm; 13C NMR (75 MHz, CDCl3): = 173.6 (C, CO2H), 143.5 (C, C-2), 141.1 (C, C-10),
δ
132.2 (CH), 131.3 (CH), 130.8 (CH), 129.4 (C, C-1), 128.6 (2CH), 128.2 (2CH), 127.5 (CH), 127.3 (CH) ppm.
4-Phenylaniline (3i), The general method using 4-iodooaniline and potassium phenyltriolborate gave
4-phenylaniline [43] (Yield = 70%) 1H NMR (300 MHz, DMSO-d6):
δ
= 7.52 (d, J = 8.2 Hz, 2H, H-2,
H-5, 2H), 7.42–7.32 (m, 4H, H-20, H-30, H-50, H-60), 7.20 (t, J = 7.3 Hz, 1H, H-40), 6.67 (d, J = 8.2 Hz,
2H, H-2, H-6), 5.19 (br s, 2H, NH2) ppm; 13C NMR (75 MHz, DMSO-d6):
(2CH), 127.5 (C), 127.1 (2CH), 125.6 (CH), 125.3 (2CH), 114.3 (2CH) ppm; MS (ESI+) m/z (%) = 170.1
(100) [M + H]+.
δ = 148.3 (C), 140.7(C), 128.7
2-Phenylaniline (3j), The general method using 2-iodooaniline and potassium phenyltriolborate gave
1
2-phenylaniline [44] (Yield = 32%) H NMR (300 MHz, CD3OD):
δ = 7.50–7.25(m, 5H), 7.09 (dt,
J = 8.1 Hz, 1.5 Hz, 1H, H-5), 7.02 (d, J = 7.8 Hz, 1H, H-3), 6.81 (d, J = 7.8 Hz, 1H, H-6), 6.75 (t, J = 7.3 Hz,
1H, H-4) ppm; 13C NMR (75 MHz, CD3OD):
δ
= 144.85 (C, C-2), 139.7 (C, C-10), 130.0 (CH), 128.7 (2CH,
C-30, C-50), 128.6 (2CH, C-20, C-60), 128.2 (CH), 126.7 (CH), 125.9 (C, C-1), 116.8 (CH, C-5), 115.3 (CH,
C-3) ppm; MS (ESI+) m/z (%) = 170.1 (100) [M + H]+.
N-boc-4-phenyl-l-phenylalanine (3a), The general method using N-Boc-4-iodo-l-phenylalanine and
potassium phenyltriolborate (2a) gave the title compound [45] in 87% yield: 1H NMR (300 MHz,
CD3OD)
(dd, J = 13.8, 5.1 Hz, 1H, H-3), 2.95 (dd, J = 13.8, 8.7 Hz, 1H, H-3), 1.40 (s, 9H, NCO2C(CH3)3) ppm;
13C NMR (75 MHz, CD3OD):
= 175.4 (C, CO2H), 157.8 (C, CO2t-Bu), 142.3 (C), 141.0 (C), 137.8 (C),
130.8 (2CH), 129.8 (2CH), 128.2 (CH), 128.0 (2CH), 127.9 (2CH), 80.5 (C, NCO2C(CH3)3)), 56.3 (CH,
δ 7.62–7.48 (m, 4H), 7.40 (t, J = 7.5 Hz, 2H), 7.35–7.27 (m, 3H), 4.46–4.30 (m, 1H, H-2), 3.20
δ
C-2), 38.4 (CH2, C-3), 28.7 (3CH3, NCO2C(CH3)3) ppm; MS (ESI-) m/z (%): 340.17 (100) [M
−
H]−, 266.2
(80) [M-t-BuOH-H]−.

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N-boc-3-phenyltyrosine (3d), The general method using N-Boc-4-iodo-l-tyrosine and potassium
1
phenyltriolborate (2a) gave the title compound [46] in 68% yield; H NMR (300 MHz, CD3OD):
δ
= 7.55 (d, J = 7.3 Hz, 2H, H-2”, H-6”), 7.36 (t, J = 7.3 Hz, 2H, H-3”, H-5”), 7.26 (t, J = 7.3 Hz, 1H, H-4”),
7.12 (s, 1H, H-20), 7.02 (d, J = 8.2 Hz, 1H, H-60), 6.82 (d, J = 8.2 Hz, 1H, H-50), 4.45–4.25 (m, 1H, H-3),
3.10 (dd, J = 13.1, 1.8 Hz, 1H, H-3), 2.89 (dd, J = 13.1, 7.7 Hz, 1H, H-3), 1.37 (s, 9H, NCO2C(CH3)3) ppm;
13C NMR (75 MHz, CD3OD): = 175.4 (C, CO2H), 157.8 (C, CO2t-Bu), 154.1 (C, C-40), 140.2 (C, C-10),
δ
132.7 (C), 130.4 (2CH), 130.2 (CH), 129.6 (C), 129.5 (C), 128.9 (2CH), 127.6 (CH), 117.0 (CH), 80.5 (C,
NCO2C(CH3)), 56.4 (CH, C-2), 37.9 (CH2, C-3), 28.7 (3CH3, NCO2C(CH3)3) ppm; MS m/z (%) (ESI−):
356.2 (100) [M − H]−, 282.2 (65) [M-t-BuOH-H]−.
N-Boc-4-(4-methoxyphenyl)-l-phenylalanine (3af), The general method using N-Boc-4-iodo-l-phenyl
alanine and potassium 4-methoxy-1-phenyl-2,6,7-trioxa-1-borabicyclo[2.2.2]octan-1-uide (2f) gave the
title compound [47] in 98% yield; 1H NMR (300 MHz, CD3OD):
δ
= 7.49 (t, J = 8.4 Hz, 4H, H-20, H-60,
H-2”, H-6”), 7.27 (d, J = 7.8 Hz, 2H, H-20, H-60), 6.97 (d, J = 8.7 Hz, 2H, H-3”, H-5”), 4.45–4.30 (m, 1H,
H-2), 3.82 (s, 3H, OMe), 3.18 (dd, J = 13.8, 4.8 Hz, 1H, H-3), 2.95 (dd, J = 13.8, 9.3 Hz, 1H, H-3), 1.38
(s, 9H, NCO2C(CH3)3) ppm; 13C NMR (75 MHz, CD3OD):
δ = 175.4 (C, CO2H), 160.7 (C-4”), 157.7
(C, CO2t-Bu), 140.6 (C, C-10), 137.0 (C), 134.7 (C), 130.8 (2CH), 128.8 (2CH), 127.5 (2CH), 115.2 (2CH,
C-3”, C-5”), 80.5 (C, NCO2C(CH3)), 56.4 (CH, C-2), 55.7 (CH3, OCH3), 38.4 (CH2, C-3), 28.7 (3CH3,
NCO2C(CH3)3) ppm.
N-boc-4-(2-methylphenyl)-l-phenylalanine (3ag), The general method using N-Boc-4-iodo-l-phenylalanine
and potassium 2-methyl-1-phenyl-2,6,7-trioxa-1-borabicyclo[2.2.2]octan-1-uide (2g) gave the title
compound [46] in 79% yield after 16 h reaction time. 1H NMR (300 MHz, CD3OD):
δ = 7.30
(d, J = 8.7 Hz, 2H), 7.28–7.10 (m, 6H), 4.45–4.30 (m, 1H, H-2), 3.21 (dd, J = 13.8, 4.5 Hz, 1H, H-3),
2.95 (dd, J = 13.8, 9.3 Hz, 1H, H-3), 2.21 (s, 3H, ArCH3), 1.39 (s, 9H, NCO2C(CH3)3) ppm; 13C NMR
(75 MHz, CD3OD): δ = 175.4 (C, CO2H), 157.8 (C, CO2t-Bu), 143.0 (C, C-10), 141.8 (C), 137.2 (C), 136.2
(C), 131.2 (CH), 130.6 (CH), 130.1 (4CH), 128.2 (CH), 126.7 (CH), 80.5 (C, NCO2C(CH3)), 56.3 (CH, C-2),
38.5 (CH2, C-3), 28.7 (3CH3, NCO2C(CH3)3), 20.6 (CH3, ArCH3) ppm; MS m/z (%) (ESI−): 354.2 (100)
[M − H]−, 280.2 (85) [M-t-BuOH-H]−.
N-boc-4-(3-nitrophenyl) phenylalanine (3ah), The general method using N-Boc-4-iodo-l-phenylalanine
and potassium 3-nitro-1-phenyl-2,6,7-trioxa-1-borabicyclo[2.2.2]octan-1-uide (2h) gave the title
compound [47] in 72% yield after 16 h reaction time; 1H NMR (300 MHz, CD3OD):
δ = 8.45 (s, 1H,
H-2”), 8.19 (d, J = 8.0 Hz, 1H, H-4”), 8.02 (d, J = 7.9 Hz, 1H, H-6”), 7.68 (t, J = 7.9 Hz, 1H, H-5”),
7.63 (d, J = 8.1 Hz, 2H, H-30, H-50), 7.39 (d, J = 8.1 Hz, 2H, H-20, H-60), 4.45–4.30 (m, 1H, H-2), 3.24
(
dd, J = 13.8, 4.8 Hz, 1H, H-3), 2.98 (dd, J = 13.8, 8.4 Hz, 1H, H-3), 1.39 (s, 9H, NCO2C(CH3)3) ppm;
13C NMR (75 MHz, CD3OD):
δ
= 175.2 (C, CO2H), 157.8 (C, CO2t-Bu), 150.2 (C, C-3”), 144.0 (C),
139.4 (C), 138.4 (C), 134.0 (CH), 131.3 (2CH), 131.2 (CH), 128.4 (2CH), 122.9 (CH), 122.4 (CH), 80.6
(C, NCO2C(CH3)), 56.2 (CH, C-2), 38.4 (CH2, C-3), 28.7 (3CH3, NCO2C(CH3)3), MS m/z (%) (ESI−):
385.2 (100) [M − H]−, 311.2 (65) [M-t-BuOH-H]−.
N-boc-4-(2-furanyl) phenylalanine (3ai), The general method using N-Boc-4-iodo-l-phenylalanine and
potassium 4-methyl-1-(furan-2-yl)-2,6,7-trioxa-1-borabicyclo[2.2.2]octan-1-uide (2i) gave the title
1
compound in 87% yield H NMR (300 MHz, CD3OD):
δ
= 7.60 (d, J = 8.0 Hz, 2H, H-30, H-50),
7.51 (s, 1H, H-4”), 7.25 (d, J = 8.0 Hz, 2H, H-20, H-60), 6.70 (d, J = 2.8 Hz, 1H, H-3”), 6.50 (br s 1H,
H-4”), 4.45–4.25 (m, 1H, H-2), 3.16 (dd, J = 13.8, 4.5, Hz, 1H, H-3), 2.92 (dd, J = 13.8, 9.3 Hz, 1H, H-3),
1.39 (s, 9H, NCO2C(CH3)3); 13C NMR (75 MHz, CD3OD):
155.2 (C, C-2”), 143.2 (CH), 137.8 (C), 130.7 (2CH, C-20, C-60), 129.8 (C), 124.7 (2CH, C-30, C-50), 112.6
(CH, C-3”), 105.7 (CH, C-4”), 80.5 (C, NCO2C(CH3)), 56.2 (CH, C-2), 38.5 (CH2, C-3), 28.6 (3CH3,
NHCO2C(CH3)3); MS m/z (%) (ESI−): 330.2 (100) [M − H]−, 256.2 (85) [M-tBuOH-H]−.
δ = 175.3 (C, CO2H), 157.7 (C, CO2t-Bu),
N-boc-4-(4-thienyl) phenylalanine (3aj), The general method using N-Boc-4-iodo-l-phenylalanine and
potassium 4-methyl-1-(thiophen-3-yl)-2,6,7-trioxa-1-borabicyclo[2.2.2]octan-1-uide (2j) gave the title

Molecules 2020, 25, 1459
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compound [48] in 63% yield 1H NMR (300 MHz, CD3OD):
δ
= 7.58–7.49 (m, 3H, H-2”, H-30, H-50),
7.45–7.38 (m, 2H, H-4”, H-5”), 7.25 (d, J = 7.8 Hz, 2H, H-20, H-60), 4.35–4.20 (m, 1H, H-2), 3.18
(
dd, J = 13.5, 4.5, Hz, 1H, H-3), 2.94 (dd, J = 13.5, 7.2 Hz, 1H, H-3), 1.38 (s, 9H, NCO2C(CH3)3); 13
NMR (75 MHz, CD3OD):
C
δ
= 175.4 (C, CO2H), 157.8 (C, CO2t-Bu), 143.3 (C, C-3”), 137.5 (C), 135.7 (C),
130.8 (2CH, C-20, C-60), 127.9 (2CH, C-30, C-50), 127.2 (CH, C-3” or C-4”), 127.1 (CH, C-3” or C-4”),
120.9 (CH, C-2”), 80.5 (C, NCO2C(CH3)), 56.3 (CH, C-2), 38.4 (CH2, C-3), 28.7 (3CH3, NHCO2C(CH3)3);
MS (ESI−): m/z (%) 346.2 (100) [M − H]−, 272.1 (50) [M-t-BuOH-H]−.
4. Conclusions
To conclude, we have shown that the nanoformulation of benzyloxycalix [8] arene supported
NHC-palladium complexes gave highly stable nanosuspension endowed with high catalytic activity for
the Suzuki–Miyaura couplings in pure water. In combination with cyclic triol boronates as nucleophilic
partner, this nanoformulation was successfully engaged in coupling reactions with water-soluble
substrates bearing a wide range of functional groups using a low catalyst loading.
The high catalytic activity of the Pd-Calix-NS can be attributed to the specific characteristics of the
nanostructure exalting the high catalytic power the NHC-Pd structure previously observed in organic
solvents [27,49]. The exact origin of the increase reactivity of the nanoparticulate formulation remain to
be addressed, nevertheless it may be hypothesis that the self-assembling of the calix molecules driven
by hydrophobic interaction would give NPs embedding the lipophilic crown of benzyl groups into
the core of the particles, while the more polar palladium NHC appendages would be disposed on
the surface. Such an arrangement would favorably influence the oxidative addition step with water
soluble aryl halides and hence increase the rate of the overall process.
Supplementary Materials: Copies of 1H NMR and 13C NMR spectra of the compound are available in the online
supplementary materials.
Author Contributions: V.H., D.D. and P.C. conceived and designed the experiments; A.P. and I.A. performed
the experiments; S.P. synthetized the arylborate salts; C.M. Design and synthesis the Pd-Calix complex; J.M.
performed the TEM imaging of the nanoparticles. All authors have read and agreed to the published version of
the manuscript.
Funding: The authors thank the Ministère de la Recherche et de la Technologie (Fellowship to A.P.) and the
Fondation pour la Recherche Médicale (FRM 2018 Fellowship to A.P.).
Conflicts of Interest: The authors declare no conflict of interest.
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