Palladium on Layered Double Hydroxide: A Heterogeneous System for the Enol Phosphate Carbon-Oxygen Bond Activation in Aqueous Media

Article abstract of DOI:10.1155/2017/8418939

In this work, a new catalytic approach for the C-O activation of enol phosphates based on a palladium supported on layered double hydroxide was developed. In this case, two different ketene aminal phosphates were used as models to study the synthesis of α

Full text of DOI:10.1155/2017/8418939

Hindawi
Journal of Chemistry
Volume 2017, Article ID 8418939, 10 pages
https://doi.org/10.1155/2017/8418939
Research Article
Palladium on Layered Double Hydroxide: A Heterogeneous
System for the Enol Phosphate Carbon-Oxygen Bond Activation
in Aqueous Media
Jaqueline D. Senra,1 Aires C. Silva,2 Raquel V. Santos,1
Luiz Fernando B. Malta,2 and Alessandro B. C. Simas3
1
´
Instituto de Quımica, Universidade do Estado do Rio de Janeiro, 20550-900 Rio de Janeiro, RJ, Brazil
2
´
Instituto de Quımica, Universidade Federal do Rio de Janeiro, 21941-903 Rio de Janeiro, RJ, Brazil
3Instituto de Pesquisas de Produtos Naturais Walter B. Mors, Universidade Federal do Rio de Janeiro,
21941-614 Rio de Janeiro, RJ, Brazil
Correspondence should be addressed to Jaqueline D. Senra; jdsenra@gmail.com and Luiz Fernando B. Malta; lfmalta@iq.ufrj.br
Received 7 September 2016; Accepted 23 October 2016; Published 3 January 2017
Academic Editor: Bartolo Gabriele
Copyright © 2017 Jaqueline D. Senra et al. is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
In this work, a new catalytic approach for the C-O activation of enol phosphates based on a palladium supported on layered
double hydroxide was developed. In this case, two different ketene aminal phosphates were used as models to study the synthesis
of ꢀ-phenyl enecarbamates N-Boc/CBz under the Suzuki-Miyaura conditions. e use of an ortho-bromoaniline as precursor
allowed the synthesis of the 2-phenyl indole through an arylation/Heck cyclization. Catalyst reusability enabled the synthesis of the
heterocycle in moderate yields for four consecutive runs.
1. Introduction
widely existing O-electrophiles such as phenols, alcohols,
ethers, and esters have more recently been considered as
promising starting platforms in large-scale processes envis-
aging the use of biomass-derived products.
Carbon-oxygen bonds have ubiquitous presence in several
major natural and synthetic products. Among some chemical
properties that contribute to their occurrence in complex sys-
tems the relative inertness of the C-O bond can be considered
crucial, since the bond dissociation energy is around 60 to
110 kcal/mol depending on the functionality [1, 2]. However,
recent progress in the development of metal catalysts contain-
ing specific active sites has drawn the attention of chemists
to the widely existing O-containing organic compounds in
virtue of their low cost as organic electrophiles. In the context
of metal-catalyzed cross-coupling reactions, the use of more
reliable coupling partners is desired for both economical and
ecological reasons compared to the traditional halides [2–
4]. Of these, some most widely exploited in synthesis are the
triflates due to their high reactivity compared to aryl/alkenyl
halides [5, 6]. Apart from this, there are several disadvantages
concerning the use of triflates, including their high cost and
some difficulties in the handling. On the other hand, the
Phosphates represent one of the most important classes
of esters since they have an essential role in nature [7, 8]. In
general, their leaving ability occurs mostly in the presence of
enzyme catalysis so their suitable activation under normal
conditions depends mainly on the nucleophile along with
the pH. Some palladium complexes have been known for
their ability to catalyze the addition of carbon and nitrogen
nucleophiles onto alkyl and allyl phosphates [9]. However,
depending on the reaction conditions, a complex end mixture
ꢀ
consisting of the SN2 and SN2 products can be obtained
instead of the metal-catalyzed alkylation/arylation. In con-
trast to other enolate derivatives, enol phosphates generally
have an improved stability, which avoids the formation of
side products and also the production of undesirable waste
material during the synthesis [10].

2
Journal of Chemistry
ere have been a number of synthetic applications
Fourier-Transform Infrared Spectroscopy. e measurements
were performed on Nicolet Magna 760 spectrophotometer
with 16 accumulations and 4 cm−1 resolution in the 4000–
400 cm−1 region. e samples were prepared in KBr pellets.
involving the use of enol phosphates and some correlates
(e.g., phosphonates and phosphonites) as starting materials
for the conversion into a variety of functional groups [2, 11–
17]. In these cases, enol phosphates have mostly been useful
substrates for some metal-catalyzed cross-coupling reac-
tions, such as Suzuki-Miyaura, Sonogashira, Stille, Negishi,
and Kumada mostly by palladium(0) and nickel(0) species.
e earlier reports involved the seminal studies by Takai
and coworkers which started exploring the alkylation of
enol phosphates with trialkylaluminium [11]. By considering
strategies involving both Csp2 coupling partners, some inter-
esting applications by the Nicolaou et al. [12] and Fuwa [16]
groups have been recently described towards the total syn-
thesis of natural products. Among some of these applications,
ketene aminal phosphates (ꢀ-phosphoryloxy enecarbamate)
were found to be specially convenient for the construction of
complex nitrogen-containing heterocycles by exploring the
palladium catalysis [18–20]. However, some limitations are
related to the use of specific and expensive ligands along with
the relatively high amounts of catalyst.
X-Ray Diffraction. e X-ray diffractograms were acquired at
ambient temperature with a Rigaku diffractometer, Ultima IV
model with high frequency X-ray generator (3 kW), Cu X-
ray tube (ꢁ = 1.5418 >), Universal eta-2 eta goniometer
with 185 mm radius, fixed slits, and Ni Kbeta filter with 40 kV
voltage and 20 mA current. Samples were analyzed on glass
supports. e measurements conditions were 5 < 2ꢂ < <0
degrees, 0.05∘ step, and a step time of 1 second.
X-Ray Fluorescence. e compounds were analyzed on a
Philips spectrophotometer, model PW 2400 with rhodium
lamp. Samples were fused with lithium tetraborate for the
formation of pellets.
Scanning Electron Microscopy and Energy-Dispersive X-Ray
Spectroscopy. e photomicrographs of scanning electron
microscopy (SEM) were acquired by a JEOL JSM 6460-
LV, operating between 10 and 20 kV equipped with energy
dispersive X-ray spectrometer to perform the chemical
microanalysis. e powders were adhered to a double-sided
tape graphite attached to the sample holder. Some samples
were metallized with gold for better viewing. e elemental
analysis via energy dispersive X-ray spectroscopy (EDS) had
the following parameters: resolution: 256 × 192; cutting time:
50 s; number of cuts: 5; acquisition time: 250 s; residence time:
712 ꢃs.
Recently, the interest in cutting-edge heterogeneous
materials exhibiting high activity for multistep synthesis
has led to the emergence of different classes of catalysts
with unique properties. Layered double hydroxides
(LDHs) are well-known two-dimensional (2D) anionic
clay materials having a brucite-like layers and formula
[MII(1−ꢁꢂ, MIIIꢁ(OH)2][Aꢃ−(ꢁꢄꢃꢂ(H O)]. Due to relatively
2
weak interlayer bonding a wide tunability to compensating
anions results in materials with compositional flexibility and
interesting applications in catalysis, especially under basic
conditions [21]. For instance, LDHs containing transition-
metals intercalated in the layers or metal nanoparticles have
been used as efficient catalysts for cross-couplings with aryl
halides. In most cases, the layered matrix was exploited as
special supports since high turnover frequencies (TOFs)
were observed under relatively mild reaction conditions.
Recently, our research group demonstrated that LDHs of
Mg/Al with different crystallinities can behave distinctly
regarding the ability for intercalation of palladium or
gold species [22, 23]. e application of the Pd catalyst
system in the Suzuki-Miyaura reaction with aryl bromides
enabled high yields for the corresponding biaryls under neat
water and room temperature [23]. As far as we know, the
exploration of oxygen-based electrophiles for carbon-carbon
bond formation under heterogeneous catalysis is scarce.
Here, we present first results concerning the enol phosphate
(ketene aminal phosphate) C-O bond activation promoted
by a LDH system containing palladium.
BET Analysis. Nitrogen adsorption/desorption isotherms
were obtained at −196∘C using the instrument Quantachrome
Novawin. e samples were pretreated in vacuum at 180∘C
for 5 hours. e specific surface area of the materials was
calculated by the BET method [24].
1H NMR Analysis. 1H NMR spectra of products 2a, 2b,
3a–3c, and 4a–4c are presented in the Supplementary
Information (see Supplementary Material available online at
https://doi.org/10.1155/2017/8418939). 1H NMR spectra were
recorded on a Varian VNMRSYS-500 spectrometer at 25∘C.
Chemical shif values are reported in ꢄ (ppm) relative to
tetramethylsilane with reference to internal residual solvent.
Coupling constants (ꢅ) are reported in hertz (Hz). Multi-
plicities of signals are designated as follows: s = singlet; d =
doublet; t = triplet; m = multiplet; br = broad.
2.1. TH-LDH Synthesis Containing Pd
2. Experimental
2.1.1. Synthesis of the Hydrothermally Treated Layered Double
Hydroxide. In a 250 mL round-bottomed flask with milli-
Q water (100 mL), Mg(NO ) ⋅6H O (0.006 mol, 1.538 g) and
All reactions were performed under air using conventional
reflux glassware. All chemicals were purchased at the highest
commercial grade and used as received. Analytical thin-layer
chromatography (TLC) was performed by using E. Merck
silica gel 60 F254 precoated glass plates (0.25 mm thickness).
Flash column chromatography was carried out by using E.
Merck silica gel BW-300 (200–400 mesh).
3 2
2
Al(NO ) ⋅9H O (0.003 mol, 1.125 g) were added with a Mg/Al
3 3
2
molar ratio of 2. Furthermore, under strong magnetic stirring
NaOH aqueous solution (1 mol L−1) was added dropwise until
a final pH around 10. Afer the coprecipitation the material
obtained was hydrothermally treated (80∘C) for 24 hours and

Journal of Chemistry
3
the material was filtered via common filtration and dried at
room temperature.
of Na PdCl in N,N-dimethylformamide (DMF) applying the
2
4
molar ratio Pd : HDL of 1 : 2 at 80∘C for 24 hours.
2.1.2. Immobilization of Pd on Layered Double Hydroxide. e
2.2. Typical Procedure for the Synthesis of Enol Phosphate 4c
immobilization was processed using 0.025 mol L−1 solution
Br
Br
(1) LDA, THF, −78∘C
O
N
N
Boc
(4c)
(2) ClOP(／０Ｂ)2, −78∘C
OP(／０Ｂ)2
Boc
(3c)
A solution of BuLi 1.04 M in hexanes (3.0 mL) was added
added dropwise and stirring proceeded for 1 h. en, 5% aq
to i-Pr NH (0.48 mL, 3.5 mmols) in dry THF (8 mL) under
NH OH was added and afer regular work-up, the obtained
2
4
Ar at 0∘C. Afer 30 min, imide 3c (0.384 g, 1.60 mmols) in
dry THF (1.5 mL) was added at −78∘C and the mixture was
stirred for 1 h under the same conditions. en, a solution of
residue was purified by flash chromatography (neutralized
silica gel, 2% TEA) to afford phosphate 4c (0.65 g, 78%).
(PhO) POCl (0.65 mL, 3.12 mmols) in dry THF (2.3 mL) was
2.3. Typical Procedure for the Synthesis of Product 8
2
Br
Br
O
P
OPh
Pd catalyst
Ph
+
P hB(／（)
+
2
N
Boc
N
Boc
Ph
OPh
N
Boc
(4c)
O
（2O/ethanol,
＋2＃／3, reflux
(7)
(8)
A mixture of enol phosphate 4c (0.116 g, 0.218 mmol),
phenylboronic acid (0.164 g, 0.437 mmol), potassium carbon-
ate (0.028 g, 0.656 mmol), and HT-DLH (0.012 g, 0.011 mmol)
in water/ethanol (2 : 1, 5.0 mL) was refluxed for 24 h. Afer
this period, the reaction mixture was cooled, filtered, and
extracted with a mixture of ethyl acetate/dichloromethane
(1 : 1, 3 × 15 mL). e combined organic layers were dried with
Na SO and afer filtration/evaporation of the solvent, the
3.1. Characterization of the Hydrothermally Synthesized LDH
Catalyst. Our first studies concerning the synthesis and
characterization of the coprecipitated LDH evidenced that
Pd(0) was formed during the ion-exchange process mediated
by N,N-dimethylformamide (DMF) [23]. For this material,
it was evidenced that Pd(0) was formed during the ion-
exchange process mediated by N,N-dimethylformamide. We
inferred that the elementary species of palladium were
inserted in the interlayer region [23]. In the following, we
report the characterization of the palladium containing LDH
whose matrix was submitted to hydrothermal treatment at
80∘C for 24 hours.
To proceed to a phase analysis in the LDH matrix
we obtained the X-rays diffraction patterns (Figure 1).
Figure 1(a) evidences that the hydrothermally treated LDH
(HT-LDH) is more crystalline than the coprecipitated one
[23], as expected. ere was no shif of the (003) reflection
(d = 7.66 angstroms) due to the incorporation of palladium
in the matrix (Figure 1(b)). e same behavior was observed
for the incorporation of Pd by the coprecipitated LDH [23].
In contrast the XRD pattern for the Pd containing HT-LDH,
Figure 1(b), presents no apparent Pd(0) peaks, which let us
conclude that mostly Pd2+ species were incorporated in the
matrix. However up to this point we cannot affirm that
2
4
residue was analyzed by NMR 1H.
3. Results and Discussion
PdCl 2− species were intercalated in the HT-LDH material.
4
In order to gain more information concerning the Pd
incorporation process, Fourier-transform infrared (FTIR)
spectra were acquired. ese spectra are shown in Figure 2
and evidence that few differences are noticed when they
are compared. Basically vibrational modes corresponding
2−
−
to ]asCO
at 1369 cm−1, ]asNO at 1384 cm−1, and ]OH
3
3
2−
relative to the interaction between interlayer H O and CO
2
3
at 3080 cm−1 [25] were kept for Pd/HT-HDL. Also the bands
in the 1000–400 cm−1 range, relative to ꢄ CO 2− (640 cm−1)
as
3
and relative to Al-O and Al-OH modes (780, 550, and
450 cm−1) [26], remained unchanged in contrast of what was
previously reported for the intercalation of noble metals by
LDH [25, 26]. With these results in mind it may be said that
most of the chemical conditions in the interlayer region seem
to be unchanged afer Pd incorporation.
Firstly data from X-rays fluorescence showed the incor-
poration of 0.5% palladium. It is worth noting that this
LDH absorbs less palladium, approximately half the quantity,
than coprecipitated LDH does (1.0%) [23]. Concerning this
we may conclude that the crystallinity of the matrix was
influenced in the incorporation of palladium, probably due
to the different kinds of species that were absorbed.
To further investigate this chemical system, we managed
to make some visualizations of scanning electron microscopy

4
Journal of Chemistry
5000
4000
3000
2000
1000
0
5000
4000
3000
2000
1000
0
(003)
(006)
(009)
(012)
(110)
(015)
(113)
0
5
10 15 20 25 30 35 40 45 50 55 60 65 70 75 80
0
5
10 15 20 25 30 35 40 45 50 55 60 65 70 75 80
2 (∘)
2 (∘)
(a)
(b)
Figure 1: XRD patterns for the hydrothermally treated layered double hydroxide (HT-LDH) before (a) and afer (b) palladium incorporation.
0.4
](C=O)
is more probable to correspond to some palladium chloride
that precipitated from the medium due to the association
0.2
1.4
with DMF. In the IR spectrum of this catalyst we zoomed
1.2
in the region of 1900–1200 cm−1 and we evidenced one band
0.0
1.0
above 1650 cm−1 that can be assigned as the DMF carbonyl
0.8
0.6
stretching mode (see the inset of Figure 2 for the comparison
0.4
of this material IR spectrum with that of LDH before
Pd incorporation). erefore although part of Pd and Cl
appeared homogeneously distributed throughout the particle
in Figure 3(a), probably intercalated, another part composed
a second phase that precipitated over LDH particles.
0.2
0.0
4000 3500 3000 2500 2000 1500 1000
500
Wave number ( ＝Ｇ−1
)
(b)
e nitrogen adsorption/desorption isotherms for the
Pd/HT-LDH are shown in Figure 4(a). In this isotherm it
is important to note how the hysteresis loop is narrow,
which is characteristic of crystalline materials. is isotherm
differs entirely from materials with low crystallinity as
the Pd immobilized in coprecipitated LDH, Pd/CP-LDH
(Figure 4(b)). In addition the surface area of the hydrother-
mally treated catalyst (65.12 m2 g−1) is also higher than that
of the coprecipitated one (7.834 m2 g−1). With a hydrothermal
treatment step, greater crystallites that have less reactive
surface are generated and consequently agglomerate less.
Smaller agglomerates correspond to smaller particles with
higher surface areas therefore reasoning why the surface area
of the hydrothermally treated LDH is higher compared to the
coprecipitated one.
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
2−
−
](＃／3
)
](．／3
)
4000 3500 3000 2500 2000 1500 1000
500
Wave number ( ＝Ｇ−1
)
(a)
Figure 2: Fourier-transform infrared spectra for the hydrother-
mally treated layered double hydroxide (HT-LDH) before (a)
and afer (b) palladium incorporation. Inset: zoom of the 1900–
1200 cm−1 region of both spectra signaling in the upper spectrum the
band relative to C=O stretching mode of N,N-dimethylformamide.
3.2. Reactions. Although several synthetic methodologies
have been developed to access ketene aminal phosphates,
the most convenient strategy consists of the deprotonation
of an enolisable ketone using a strong base, such as LDA,
followed by reaction of the subsequent metal enolate with
a phosphoryl chloride (Scheme 1). Also, the stability of the
phosphates depends on the electronic effects imposed on the
nitrogen moiety. Previously, our group reported that stable
ketene aminal phosphate (ꢀ-phosphoryloxy enecarbamate)
derived from N,N-diprotected acetamide could be prepared
by using p-methoxyphenyl (PMP) and CBz as protecting
groups at the nitrogen [20]. In this case, cross-couplings
under classical conditions, including the use of phosphine
and arsine as ligands, were carried out to access enynes and
dienes in moderate to good yields [20].
(Figure 3). From Figure 3(a), relative to a backscattered elec-
trons image, a phase contrast evidenced by the white brilliant
particles situated on the surface of the dark grey agglomerate
was noticed. is is unique since this phase contrast was not
observed for the coprecipitated LDH afer Pd incorporation.
We also obtained the elements distributions (Pd, Cl, and Mg)
throughout this agglomerate by using the energy-dispersive
X-rays spectroscopy facility coupled to the SEM microscope
(Figures 3(b)–3(d)). From the EDX element mapping it
became clear that the brilliant phase corresponded to a higher
density of the palladium and chlorine elements contrasting to
a lower density of the magnesium element: rather than being
caused by chemical inhomogeneity it was due to shielding
of the Mg characteristic X-rays promoted by the superficial
phase. is phase can be assigned as being composed of Pd
and Cl; however we do not believe that this would be the
precursor salt Na PdCl , since it is very soluble in DMF. It
To evaluate the catalytic activity of the Pd/HT-LDH, we
firstly run experiments with the PMP substituted, N-CBz-
protected ketene aminal phosphate 4a since this starting
2
4

Journal of Chemistry
5
21275
65535
Mg K
0
14
50 m
50 m
(a)
(b)
Pd L
Cl K
9
0
0
6
50 m
50 m
(c)
(d)
Figure 3: SEM-EDS visualizations for the catalyst of Pd on hydrothermally treated layered double hydroxide. (a) Backscattered electrons
image; (b)–(d) EDS mapping of the elements Mg, Cl, and Pd.
13.20
12.00
138.00
120.00
8.00
80.00
4.00
0.00
40.00
0.00
0.00
0.20
0.40
0.60
0.80
1.00
0.00
0.20
0.40
0.60
0.80
1.00
Relative pressure (P/P )
Relative pressure (P/P )
0
0
(a)
(b)
Figure 4: Nitrogen adsorption/desorption BET isotherms of the catalysts based on (a) hydrothermally treated and (b) coprecipitated layered
double hydroxide.

6
Journal of Chemistry
(1) LDA, THF, −78∘C
(2) CBzCl, −78∘C
O
R=4-O＃（3 (3a)
R
(80%)
N
O
CBz
R=2-Br (3b)
R
！＝2O
．（2
(73%)
N
H
R
％Ｎ3N, ＃（2＃Ｆ2
0∘C
＂Ｉ＝2O
DMAP, 25∘C
O
R
R=2-Br (3c)
R=4-O＃（3 (1a)
2-Br (1b)
R=4-O＃（3 (2a)
2-Br (2b)
N
(88%)
Boc
O
(1) LDA, THF, −78∘C
R
R
N
２
N
OP(／０Ｂ)2
(2) ClOP(／０Ｂ)2, −78∘C
２
R=4-O＃（3, ２=＃＂Ｔ (65%) (4a)
R=2-Br, ２=＃＂Ｔ (21%) (4b)
２=＂Ｉ＝ (77%) (4c)
Scheme 1: Synthesis of the enol phosphates.
material exhibited adequate stability and could represent a
model. Indeed, based on our previous work involving the
catalytic evaluation of LDH in Suzuki-Miyaura reactions
with aryl halides [22], we have explored the reaction with
the phenylboronic acid by using some clean conditions.
Since LDHs constitute a basic platform, the first catalytic
test occurred in the absence of base but this condition did
not afford the product (Table 1, entry 1). us, we explored
the HT-LDH containing 1.0 mol% Pd, K CO as base and
use of Na PdCl as the only catalyst precursor proved to be
2
4
ineffective for this reaction (Table 1, entry 10).
With the aim to test an alternative enol phosphate for
consecutive Suzuki/Heck reactions, we proceeded to explore
a substrate derived from an o-haloanilide (Table 1, entry
11) since it could be an elegant catalytic strategy for future
synthetic exploration. However, under these conditions no
conversion of 4b towards the expected coupling products was
detected. Instead, it was evident by the NMR 1H analysis that
the presence of some signals related to the substrate degrada-
tion suggesting a substrate lability. ese experiments show
that the o-brominated enol phosphate exhibited a behavior
that is dramatically different from that of 4a. With respect
to the possible carbon-bromine bond activation it cannot
be completely ruled out even though we could not found
NMR signals related to this product. Unlike this referred
cross-coupling we presume that the hydrodehalogenation
has occurred. en, once the carbon-metal bond has been
formed, the challenge is to suppress the hydrogenolysis which
produce the subproduct. Under the previous conditions,
transmetallation and/or reductive elimination, therefore,
must proceed more slowly than hydrogenolysis.
By virtue of the importance of the 2-substituted aryl
indole structural motif [27–31], we have further investigated
its synthetic feasibility by using this ligand-free catalytic
system. In fact, there are two fundamental requirements
for this challenging transformation: (1) the catalyst should
exhibit preferential chemoselectivity towards the phosphate
moiety to avoid the previous arylation of the halogenated
one. (2) e usually disfavored 5-endo-trig Heck cyclization
must have a higher reaction rate when compared to the
hydrodehalogenation which can be a competitive side path.
Indeed, it is necessary to take into account the subtle
electronic effects promoted by the N-substituents since it can
impose differences in the activation rate of each reaction site.
Fuwa and coworkers [18, 32] have earlier explored this elegant
strategy for the preparation of functionalized heterocycles
2
3
water/ethanol as solvent mixture under reflux (85–90∘C).
However, the result indicated only a modest yield afer 24 h
(Table 1, entry 2). As expected, the increase on the Pd loading
(2.0 mol%) led to the desired product in a slightly high
yield (Table 1, entry 3). Since the starting material solubility
could be a reason for these relatively low conversions, we
screened some different conditions. For instance, when it
was carried out in neat water or ethanol only product
traces were observed (Table 1, entries 4 and 5). However, the
mixture composed of H O/THF (1 : 1) was clearly superior,
2
producing the desired coupled product 6a in 72% without
the production of any side products (Table 1, entry 6). It
suggests that the solvent can have an additional influence in
the reaction outcome.
An investigation of the two different LDHs revealed that
the coprecipitated material has a poorer ability to catalyze
the reaction under the same conditions (Table 1, entry 7),
when compared to the hydrothermally treated one. is
reactivity trend could be related to the presence of fewer
active sites according to surface area analysis from BET
isotherms. In order to gain further information concerning
the use of a different ligand-free system, the PdNPs stabilized
by hydroxypropylated cyclodextrins, earlier described by
our group, were also tested under these conditions (Table 1,
entry 8). It was apparent that a moderate conversion of
4a required about 5.0 mol% Pd(0) even though with some
catalyst agglomeration. In this case, the use of high amounts
of CDs was needed (Table 1, entry 9). On the other hand, the

Journal of Chemistry
7
Table 1: Screening of the reaction conditions for the synthesis of the ꢀ-phenyl-enecarbamates from the N-CBz protected enol phosphates.
Entry
Ar
Catalyst
Reaction conditions
Yield (%)
B(／（)2
Pd catalyst
Ar
Ar
N
CBz
Ph
N
CBz
+
OP(O)(／０Ｂ)2
Solvent, base,
temperature
6a (Ar=4-／＃（3)
∘6b (Ar=2-Br)
5
4a (Ar=4-／＃（3)
4b (Ar=2-Br)
1
2
3
4
5
6
7
8
9
10
11
4-OCH
4-OCH
4-OCH
4-OCH
4-OCH
4-OCH
4-OCH
4-OCH
4-OCH
4-OCH
2-Br
HT-LDH/Pd (1.0 mol%)
HT-LDH/Pd (1.0 mol%)
HT-LDH/Pd (2.0 mol%)
HT-LDH/Pd (2.0 mol%)
HT-LDH/Pd (2.0 mol%)
HT-LDH/Pd (2.0 mol%)
CP-LDH/Pd (2.0 mol%)
Pd nanoparticles (2.0 mol%)
Pd nanoparticles (5.0 mol%)
Na PdCl (2.0 mol%)
H O/EtOH, 75–80 C
–
3
3
3
3
3
3
3
3
3
3
2
H O/EtOH, K CO , 75–80∘C
41%
50%
–
2
2
3
H O/EtOH, K CO , 75–80∘C
2
2
3
H O, K CO , 75–80∘C
2
2
3
EtOH, K CO , 75–80∘C
–
2
3
H O/THF, K CO , 75–80∘C
72%
39%
35%
40%
–
2
2
3
H O/THF, K CO , 75–80∘C
2
2
3
H O/THF, K CO , 75–80∘C
2
2
3
H O/THF, K CO , 75–80∘C
2
2
3
H O/THF, K CO , 75–80∘C
2
4
2
2
3
HT-LDH/Pd (2.0 mol%)
H O/THF, K CO , 75–80∘C
n.d.
2
2
3
even by using the classical conditions [Pd(PPh ) 10 mol%,
tandem cyclization with the HT-LDH took place in the
3 4
Et N, DMF, 100∘C, and sealed tube]. Starting from o-
presence of K CO at 90∘C for 24 h affording an inversion in
3
2
3
bromoanilide, the corresponding halogenated ketene aminal
phosphate was prepared for the catalytic tests. In this case,
we have used the N-Boc-protected substrate, obtained in
good yield (85%), which presented a good stability when
compared to the previous one. We presume that the absence
of a strong donating group (PMP) improved the stability of
the 7 : 8 ratio with an improved yield for the indole (Table 2,
entry 5). However, by changing the base to cesium carbonate
the efficiency of the cyclization was affected (Table 2, entry 6).
It is interesting to note that the 7 : 8 ratio can be tuned
not only by changing the solvent but also through the catalyst
system: by using the Pd nanoparticles stabilized by CDs,
the cyclization proceeded with a poor selectivity towards 8
(Table 2, entry 7). By comparison, the coprecipitated LDH
was also tested under this condition to verify the influence of
the catalyst structure on the cyclization. As shown in entry 8,
the reaction occurred with similar selectivity suggesting that
it can be improved by the LDH structural effect involving the
interlayer space.
the (CH ) C-O bond in Boc moiety [20]. e examination
3 3
of the Suzuki-Miyaura reaction between phenylboronic acid
and substrate 4c in H O : THF (1 : 1), in the presence of
2
2.0 mol% Pd/HT-LDH and K CO , revealed the formation
2
3
of the ꢀ-aryl enecarbamate 7 in 40% along with the minority
cyclic product 8 (17%) when the reaction was carried out by
24 h (Table 2, entry 1). However, running the reaction by 48 h
did not improve the cyclization towards the indole ring but
instead led to the partial degradation of 7 (Table 2, entry 2).
According to Fuwa and coworkers, the suppression of
Considering the formation of 7 and 8, we found, in
a control experiment, that the hypothetical product from
intramolecular Heck reaction (indole formation) containing
the phosphate moiety is not involved as the first intermediate
since no reaction occurred in the absence of the phenyl-
boronic acid. is data supports the idea of a mechanism
in which the C-O bond activation occurs followed by the
carbon-halogen coupling. In addition the catalyst deacti-
vation could be a hypothesis that for prolonged times the
reaction does not afford the cyclization leading to indole.
However its recycling ability was showed (see Table 3) hence
contrasting to the hypothesis of its deactivation. Any poi-
soning of the LDH by inspection of the catalyst without
washing/purification using infrared spectroscopy was not
detected.
the cyclic product can occur with the addition of H O and
2
a moderate reaction temperature [32]. To evaluate if this
finding follows a trend we performed a test in the presence
of dry THF as the sole solvent. However, when compared to
the previous condition (H O/THF) it gave an unsatisfactory
2
result due to the incomplete starting material conversion
and lack of selectivity (Table 2, entry 3). On the other hand,
by using commercial ethanol, we have observed an almost
complete consumption of the starting material as well as
the formation of the cyclic product in a moderate yield
(Table 2, entry 4). Based on this evidence, we argued that
water could have a role in the formation of active species.
us, our strategy involved the increase of the indole yield
by using this heterogeneous catalytic system in the presence
of a mixture based on water/ethanol. Under the condition
involving water/ethanol (2 : 1), the Suzuki-Miyaura reaction
To test the merit concerning the nature of the catalysis,
we performed in a separate experiment a hot filtration test as
a useful criterion for distinguishing between homogeneous
and heterogeneous catalysis [33]. In this case, the reaction

8
Journal of Chemistry
Table 2: Screening of the reaction conditions for the synthesis of the 2-phenyl indole from the N-Boc protected enol phosphate.
Yield (%)
Entry
Catalyst
Br
Reaction conditions
7
8
Br
O
P
OPh
Pd catalyst
Ph
5
+
+
N
Boc
OPh
N
Boc
O
N
Boc
Ph
Solvent, base,
temperature
4c
7
8
1
HT-LDH/Pd (2.0 mol%)
HT-LDH/Pd (2.0 mol%)
HT-LDH/Pd (2.0 mol%)
HT-LDH/Pd (2.0 mol%)
HT-LDH/Pd (2.0 mol%)
HT-LDH/Pd (2.0 mol%)
PdNPs (5.0 mol%)
H O/THF, K CO , 80∘C, 24 h
40
17
2
2
3
2
3
4
5
6
7
8
H O/THF, K CO , 80∘C, 48 h
–
2
2
3
THF, K CO , 80∘C, 24 h
21
38
27
22
31
13
35
65
48
24
32
2
3
Ethanol, K CO , 80∘C, 24 h
2
3
H O/ethanol (1 : 1), K CO , 80∘C, 24 h
2
2
3
H O/ethanol (1 : 1), Cs CO , 80∘C, 24 h
2
2
3
H O/ethanol (1 : 1), K CO , 80∘C, 24 h
2
2
3
CP-LDH/Pd (2.0 mol%)
H O/ethanol (1 : 1), K CO , 80∘C, 24 h
20
2
2
3
Table 3: Catalyst reusability1.
Entry
Run
Yield of 8 (%)
Br
Br
O
P
OPh
HT-LDH (2% Pd)
5
+
+
Ph
OPh
N
Boc
N
Boc
N
Boc
Ph
O
＋2＃／3, （2O/ethanol
reflux, 24 h
4c
7
8
1
1st
2nd
3rd
4th
65
58
56
56
2
3
4
1
The reusability tests were carried under identical conditions. Afer each run, the catalyst was filtered, washed with water, and dried at room temperature.
medium was filtered afer the end of the reaction and the
catalytic activity of the supernatant was analyzed under
the same conditions. Interestingly, there was no detected
amount of both coupling products, indicating that only a
limited number of species were leached. Examination of
the catalyst recyclability (Table 3) revealed that the material
can be used for four consecutive runs without significant
loss in activity. Based on these results, we hypothesized
that the heterogeneous catalysis could be the predominant
mechanism.
a delicate balance. From the comparison with the classical
catalytic conditions, the beneficial effect of this ligand-free
strategy is apparent. By using the hydrothermally treated
LDH containing Pd(0), the corresponding ꢀ-aryl enecarba-
mates were obtained in moderate to good yields. In the case
of the o-halo substituted substrate, the conditions were tuned
to improve the domino Suzuki-Miyaura/intramolecular Heck
which led to the 2-phenyl indole in moderate yields. Indeed,
the catalyst showed recycling potential since the activity was
similar for four consecutive runs towards the 2-phenyl indole.
Although improvement of the scope of the methodology
requires additional studies, the advantage of using a ligand-
free condition, as in challenging C-O/C-C domino reactions,
is retained. Ongoing work seeks to explore additional sub-
strates for these and related cross-coupling reactions.
4. Conclusion
In summary, we have demonstrated that a catalyst system
based on layered double hydroxide containing Pd(0) is
efficient for the C-O activation of acetamide-derived ketene
aminal phosphates. Based on anilines containing Boc or CBz
as protecting groups, we started catalytic studies for the cross-
coupling reactions with the phenylboronic acid. e Boc
substituted o-brominated enol phosphate was quite stable
under the catalytic conditions when compared to the CBz
counterpart evidencing that the combination between the
electron-donating and electron-withdrawing groups involves
5. Supplementary Information
1H NMR spectra of all products are available online in the
Supplementary Information file.
Competing Interests
e authors declare that they have no competing interests.

Journal of Chemistry
9
Acknowledgments
[14] F. Lepifre, S. Clavier, P. Bouyssou, and G. Coudert, “Palladium-
catalyzed coupling of vinyl phosphates with aryl or heteroaryl
boronic acids. Application to the synthesis of substituted nitro-
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6969–6975, 2001.
[15] J. Guo, J. D. Harling, P. G. Steel, and T. M. Woods, “Phosphinates
as new electrophilic partners for cross-coupling reactions,”
Organic and Biomolecular Chemistry, vol. 6, no. 21, pp. 4053–
4058, 2008.
[16] H. Fuwa, “Palladium-catalyzed synthesis of N- and O-
heterocycles starting from enol phosphates,” Synlett, no. 1, pp.
6–29, 2011.
[17] S. Begliomini, L. Sernissi, D. Scarpi, and E. G. Occhiato,
“A short, chemo-enzymatic synthesis of both enantiomers of
trans-3-hydroxypipecolic acid,” European Journal of Organic
Chemistry, vol. 2014, no. 25, pp. 5448–5455, 2014.
e authors are grateful to FAPERJ, CAPES, and CNPq
for financial support. ey also would like to thank Bruno
B. Lages for the graphical work in this manuscript and
Laborato´rio Multiusua´rio de Difrac¸a˜o de Raios-X at IQ/UFRJ
for the XRD patterns.
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