Unveiling the catalytic nature of palladium-N-heterocyclic carbene catalysts in the α-alkylation of ketones with primary alcohols

Article abstract of DOI:10.1039/d1dt01704g

We report herein the synthesis of four new Pd-PEPPSI complexes with backbone-modified N-heterocyclic carbene (NHC) ligands and their application as catalysts in the α-alkylation of ketones with primary alcohols using a borrowing hydrogen process and tandem Suzuki-Miyaura coupling/α-alkylation reactions. Among the synthesized Pd-PEPPSI complexes, complex2chaving 4-methoxyphenyl groups at the 4,5-positions and 4-methoxybenzyl substituents on the N-atoms of imidazole exhibited the highest catalytic activity in the α-alkylation of ketones with primary alcohols (18 examples) with yields reaching up to 95%. Additionally, complex2cwas demonstrated to be an effective catalyst for the tandem Suzuki-Miyaura-coupling/α-alkylation of ketones to give biaryl ketones with high yields. The heterogeneous nature of the present catalytic system was verified by mercury poisoning and hot filtration experiments. Moreover, the formation of NHC-stabilized Pd(0) nanoparticles during the α-alkylation reactions was identified by advanced analytical techniques.

Full text of DOI:10.1039/d1dt01704g

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Unveiling the catalytic nature of palladium-
N-heterocyclic carbene catalysts in the
Cite this: Dalton Trans., 2021, 50,
10896
α-alkylation of ketones with primary alcohols†
Mamajan Ovezova,a Zafer Eroğlu,b,c Önder Metin, *b Bekir Çetinkayaa and
a
Süleyman Gülcemal
*
We report herein the synthesis of four new Pd-PEPPSI complexes with backbone-modified
N-heterocyclic carbene (NHC) ligands and their application as catalysts in the α-alkylation of ketones with
primary alcohols using a borrowing hydrogen process and tandem Suzuki–Miyaura coupling/α-alkylation
reactions. Among the synthesized Pd-PEPPSI complexes, complex 2c having 4-methoxyphenyl groups at
the 4,5-positions and 4-methoxybenzyl substituents on the N-atoms of imidazole exhibited the highest
catalytic activity in the α-alkylation of ketones with primary alcohols (18 examples) with yields reaching up
to 95%. Additionally, complex 2c was demonstrated to be an effective catalyst for the tandem Suzuki–
Miyaura-coupling/α-alkylation of ketones to give biaryl ketones with high yields. The heterogeneous
nature of the present catalytic system was verified by mercury poisoning and hot filtration experiments.
Moreover, the formation of NHC-stabilized Pd(0) nanoparticles during the α-alkylation reactions was
identified by advanced analytical techniques.
Received 25th May 2021,
Accepted 6th July 2021
DOI: 10.1039/d1dt01704g
rsc.li/dalton
Kumada–Tamao–Corriu,4c,6
Heck,7
Sonogashira,8
C–H
Introduction
functionalization,9 amination,10 and sulfination11 reactions to
Over the last three decades, metal-N-heterocyclic carbene construct C–C, C–N, and C–S bonds for the synthesis of more
(NHC) complexes have been increasingly appreciated in homo- complicated molecules.
geneous catalysis and organometallic chemistry owing to their
On the other hand, the transition metal (TM)-catalyzed bor-
easy preparation, enhanced stability arising from strong metal- rowing hydrogen (BH) or the hydrogen autotransfer method-
NHC bonding, and high tunability of steric and electronic pro- ology has become a powerful and green strategy to construct a
perties of the NHC ligand.1 In particular, NHCs have emerged C(sp3)–C(sp3) bond for the one-step synthesis of more compli-
as excellent ancillary ligands in palladium-catalyzed cross- cated molecules.12 The main advantage of this methodology is
coupling reactions.2 Among the NHC-Pd precatalysts for cross- the utilization of readily available, sustainable, and easy-to-
coupling reactions, Organ’s Pd-PEPPSI complexes (PEPPSI = handle alcohols as greener alkylating agents over mutagenic
pyridine-enhanced catalyst preparation, stabilization, and alkyl halides. Additionally, this strategy offers an increased
initiation) can be mentioned as one of the most appealing step efficiency and atom economy over the conventional
ones due to not only their high catalytic activity in these reac- methods and generates water as the sole byproduct.12 In this
tions but also their easy preparation and high stability towards context, α-alkylation of ketones with primary alcohols based
air and moisture.3 Such precatalysts were successfully tested in on the BH strategy to prepare synthetically and biologically
a variety of cross-coupling reactions and found to display excel- important long-chain or branched ketones in the presence of
lent performances in the Suzuki–Miyaura,3,4 Negishi,4c,5 precious (Ru, Rh, Ir, and Pd)13–16 and nonprecious (Mn, Fe,
Co, and Ni)17–20 TM catalysts has been reported. Among the
reported catalytic systems, a number of heterogeneous16a–h,l
and homogeneous16i–k Pd-catalyzed protocols have been devel-
oped for the α-alkylation of ketones with primary alcohols for
the selective synthesis of α-alkylated ketones. However, the use
aDepartment of Chemistry, Ege University, 35100 Izmir, Turkey.
E-mail: suleyman.gulcemal@ege.edu.tr; Tel: +90 232 3111581
bDepartment of Chemistry, College of Sciences, Koç University, 34450 Istanbul,
Turkey. E-mail: ometin@ku.edu.tr; Tel: +90 212 3380942
cNanoscience and Nanoengineering Division, Graduate School of Natural and
Applied Sciences, Atatürk University, 25240 Erzurum, Turkey
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1dt01704g
of
a stoichiometric or excess amount of a base (1–3
equiv.),16a–d,f–h,k,l a high catalyst loading (2–10 mol%),16b–d,g,h,j,k
an excess amount of alkylating alcohol,16a–g,i,j,l or additional
phosphine-based16i–k ligands is required for most of the
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reported protocols. In this context, we have questioned obtained compounds are in accordance with previous
whether NHC-Pd-PEPPSI type precatalysts would be useful for reports.23 The PEPPSI type NHC-Pd (2a–d) complexes were syn-
the chemo-selective alkylation of ketones with primary alco- thesized by heating imidazolium salts (1a–d), PdCl2, and
hols, since these precatalysts are highly active, stable, and K2CO3 in pyridine at 80 °C (Scheme 1) and obtained in
among the easiest to synthesize in a single operationally 52–92% yields as air- and moisture-stable yellow solids.3 The
simple step from the corresponding NHC salt, PdCl2 and pyri- formation of 2a–d was confirmed by 1H, 13C NMR spectroscopy
dine ligand. In a recent study, our group explored the critical and HRMS analyses. The characteristic downfield signals for
role of the NHC ligand in NHC-Ir-catalyzed BH reactions and the NCHN+ protons of imidazolium salts 1a–d disappeared in
reported its superior catalytic activities for the synthesis of the 1H NMR spectrum. Meanwhile, characteristic signals in
α-alkylated ketones,15d β-alkylated alcohols,21a quinolines,21a the 13C NMR resonances at δ = 151.3, 151.4, 151.2, and
α,α-disubstituted ketones,21b and α-alkylated nitriles.21c As a 151.3 ppm of Pd–Ccarbene were observed for complexes 2a–d,
continuation of our interest in the application of NHC-TM respectively.
complexes in BH reactions, herein, we report the synthesis of
Initially, the alkylation of acetophenone (3a) with benzyl
four new NHC-Pd-PEPPSI complexes (2a–d) with backbone alcohol (4a) was selected as a model reaction to probe the
modifications on the NHC ligand and examine their catalytic potential of the NHC-Pd-PEPPSI complexes (2a–d) as catalysts.
1
activities in the α-alkylation of ketones with primary alcohols The progress of the reaction was monitored by H NMR ana-
and tandem Suzuki–Miyaura coupling/α-alkylation reactions lysis of the crude reaction mixtures and the yields are based on
under open air conditions. To the best of our knowledge, this 1,3,5-trimethoxybenzene as an internal standard (Table 1). The
study represents the first example of NHC-Pd catalyzed reaction of 3a (1 mmol) and 4a (1 mmol) was performed in the
α-alkylation of ketones with primary alcohols and also the presence of 2a–d (0.2 mol%) and KOH (10 mol%) in toluene
tandem Suzuki–Miyaura coupling/α-alkylation reaction cata- (2 mL) at 115 °C (oil bath temperature) open to air for 4 h
lyzed with a monometallic TM-complex. The mechanism of (Table 1, entries 1–4). In the presence of all catalysts tested,
the α-alkylation reaction is investigated by control experiments moderate to good yields (48–83%) of the desired product 5a
and kinetic studies. In addition, the catalyst material is along with a 4–7% yield of the over-reduced alcohol product 5′
studied by TEM, XRD, and XPS, and the nature of catalysis is a were obtained (Table 1, entries 1–4). Among all catalysts
examined by mercury poisoning and hot filtration tested, the highest yield of 5a was obtained with catalyst 2c
experiments.
(Table 1, entry 3). The differences in the catalytic abilities of
complexes 2a–d could be attributed to the different stabilities
of the palladium precatalysts. Considering 2a–d complexes
bearing the same wingtip substituents on the N-atoms of NHC
ligands, the differences in the stabilities could be attributed to
Results and discussion
Scheme 1 outlines the route used for the synthesis of NHC-Pd- the different electron densities at the palladium centers result-
PEPPSI (2a–d) complexes. NHC precursors 1a–d were syn- ing from the backbone substituents of the NHC ligands. We
thesized according to the previously developed procedure22 recently evaluated the Tolman electronic parameters of the
and the physical properties and spectroscopic data of the [IrCl(CO)2(NHC)] complexes derived from NHC precursors 1a–
Scheme 1 The route used for the synthesis of NHC-Pd-PEPPSI (2a–d) complexes.
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Table 1 Optimization of the reaction conditions for the α-alkylation of acetophenone with benzyl alcohola
Entry
Cat. (mol%)
Base
Time (h)
5a Yield (%)
5′a Yield (%)
1
2
3
4
2a (0.2)
2b (0.2)
2c (0.2)
2d (0.2)
PdCl2(py)2 (0.2)
2c (0.1)
2c (0.1)
2c (0.1)
2c (0.1)
2c (0.1)
2c (0.1)
—
KOH
KOH
KOH
KOH
KOH
KOH
KOH
NaOH
KOtBu
NaOtBu
—
4
4
4
4
4
6
6
6
6
6
6
6
8
48
74
83
75
4
6
7
6
7
7
8
7
8
4
—
5
10
5
31
6
85 (82)b
81
7c
8
55
82
37
—
9
10
11
12
13d
KOH
KOH
24
2c (0.1)
76 (71)b
a Reaction conditions: 3a (1.0 mmol), 4a (1.0 mmol), Cat. (0.1–0.2 mol%), base (10 mol%), toluene (2 mL), 115 °C (oil bath temperature), open to
air. Yields were determined by the 1H NMR analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene as an internal standard.
b Isolated yield. c Reaction was performed under an argon atmosphere. d Reaction was performed on a 20 mmol scale.
c and the results revealed that the NHC bearing 4-methoxyphe- good to excellent isolated yields (80–95%). Furthermore, the
nyl groups at the 4,5-positions of imidazole appeared as the reaction of acetophenone with ferrocenemethanol and 2-meth-
strongest electron-donating ligand among them.21c However, oxybenzyl alcohol afforded the desired products 5h and 5i in
in the presence of PdCl2(py)2 as the catalyst, only 31% conver- 92% and 63% isolated yields, respectively. In the case of
sion to the desired product was observed, which indicates the 1-naphthalenemethanol and 1-octanol, the amount of catalyst
critical role of the NHC ligand (Table 1, entry 5). was increased to 0.2 mol% and 0.5 mol%, respectively, to
Consequently, we choose complex 2c as the catalyst for further obtain related products 5j and 5k in moderate yields. Next, the
studies. Decreasing the catalyst loading to 0.1 mol% resulted scope of the reaction was examined with respect to ketones.
in a 85% NMR yield within 6 h where 5a was isolated in 82% The reaction of benzyl alcohol with aryl methyl ketones having
yield (Table 1, entry 6). It should be noted that using an inert 4-OMe, 4-Me, or 4-CF3 substitution on the aryl ring, and also
atmosphere seemed to be unnecessary (Table 1, entry 7). The with 1-acetylnaphthalene and acetylferrocene all resulted in
influence of the base was then evaluated. Replacing KOH with high yields (69–95%) to give a series of α-alkylated ketones (5l–
NaOH, KOtBu, or NaOtBu did not improve the yields (Table 1, n, 5p, and 5q). Finally, the reaction of α-tetralone, a cyclic
entries 8–10), but no product formation was observed in the ketone, with benzyl alcohol afforded product 5r in 55% yield
absence of a base (Table 1, entry 11). On the other hand, the in the presence of 0.5 mol% catalyst.
reaction resulted in only a 24% yield in the absence of a palla-
However, some limitations of the present catalytic system
dium catalyst (Table 1, entry 12). As a result, the optimized arise when substrates with –Cl or –Br substitution on the aryl
reaction conditions for the presented protocol were identified ring are tested. The current catalytic protocol produced the
as the following: 2c (0.1 mol%) and KOH (10 mol%) as the desired α-alkylated ketones 5f and 5g in less than 10% yield
base at 115 °C open to air for 6 h (Table 1, entry 6). Finally, in and the remaining starting materials were recovered when
order to make this process practically viable, we examined a acetophenone reacted with 4-chlorobenzyl alcohol or 2-bromo-
20 mmol scale reaction where 5a was isolated in 71% yield benzyl alcohol under the optimized reaction conditions. A
(2.96 g) in 8 h (Table 1, entry 13).
similar result was observed for the reaction of 4′-chloroaceto-
With the optimized reaction conditions in hand, the sub- phenone with benzyl alcohol where the corresponding product
strate scope and the limitations of the α-alkylation of ketones 5o was detected only in 3% yield by 1H NMR analysis of the
(3) with primary alcohols (4) were studied over different ketone crude reaction mixture. Increasing the catalyst loading to
and primary alcohol derivatives (Table 1, entry 6), and the 1 mol% for these substrates did not improve the yields of the
results are summarized in Table 2. Firstly, the substrate scope desired α-alkylated ketone products 5f, 5g, and 5o. However,
was examined by using acetophenone as ketone and varying these limitations cannot be explained with the apparent low
the primary alcohols. The reaction of acetophenone with a tolerance of substrates substituted with electron-withdrawing
range of para-substituted benzyl alcohols having electron- groups on the aryl ring since –CF3 substituted products 5e and
donating –OMe, –Me, or –iPr groups and electron-withdrawing 5n were obtained in high yields under similar conditions. This
–CF3 groups afforded the desired ketone products (5b–e) in is most likely due to the rapid oxidative addition of aryl
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Table 2 Scope and the limitations of the α-alkylation of ketones with primary alcohols
Reaction conditions: 3 (1.0 mmol), 4 (1.0 mmol), 2c (0.1 mol%), KOH (10 mol%), toluene (2 mL), 115 °C (oil bath temperature), open to air.
1
Reported yields correspond to isolated pure compounds. a Determined by H NMR analysis. b 2c (0.2 mol%), isolated yield. c 2c (0.5 mol%), iso-
lated yield.
halides to the Pd(0) center under basic conditions, the first viously accomplished by the reaction of 4′-bromoacetophe-
step of the Pd-catalyzed cross-coupling reactions such as none, phenylboronic acid, an excess amount of primary
Suzuki–Miyaura,3,4 and the poisoning of the Pd catalyst for the alcohol and Cs2CO3 (3 equiv.) in the presence of triazolyl-diyli-
α-alkylation reaction.
dene bridged heterobimetallic Pd(II)/Ir(III),24a or heterobimetal-
On the basis of the above-mentioned findings and the fact lic Pd(II)/Ir(III) and Pd(II)/Rh(III) NHC complexes.24b In these
that NHC-Pd-PEPPSI type complexes can effectively catalyze studies, the presence of the two different metals allows a
the Suzuki–Miyaura reactions,3,4 we were interested to see tandem process by combined reactions that are typically cata-
whether catalyst 2c could effectively catalyze a tandem reaction lyzed by Pd (Suzuki–Miyaura) and Ir or Rh (α-alkylation).
involving the Suzuki–Miyaura C(sp2)–C(sp2) coupling and Considering the laborious steps in the preparation of these
α-alkylation C(sp3)–C(sp3) coupling. Such reactions were pre- heterobimetallic complexes, using easily prepared NHC-Pd-
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PEPPSI complexes would be highly beneficial for this tandem The reaction of less reactive 4′-chloroacetophenone with
transformation. The initial reaction was performed using 4′- phenylboronic acid resulted in only 11% yield of 3c under the
bromoacetophenone (3b; 0.5 mmol), phenylboronic acid (6; same conditions (Scheme 2b). We were pleased that the reac-
0.55 mmol), 4-methylbenzyl alcohol (4b; 0.5 mmol), and KOH tion of 4′-methylacetophenone (3d), phenylboronic acid (6),
(2 equiv.; 1 mmol) in the presence of 2c (1 mol%) as the cata- and 4-bromobenzyl alcohol (4c) also furnished the corres-
lyst at 115 °C in open air for 3 h (Scheme 2a). The reaction ponding tandem coupling product 5t in good yield
resulted in a complete conversion of 3b into 4-acetylbiphenyl (Scheme 2c). Finally, the reaction of two different aryl bro-
(3c) together with the unreacted primary alcohol 4b where only mides having a ketone or a primary alcohol function, 3b and
a trace amount of α-alkylated biphenyl ketone (5s) was 4c, with phenylboronic acid (6; 2.2 equiv.) afforded the desired
detected (Scheme 2a). Increasing the amount of KOH to α-alkylated ketone 5u, bearing biphenyl handles, in 74% iso-
1.2 mmol resulted in a better outcome and in this case lated yield, indicating the generality of the developed tandem
α-alkylated biphenyl ketone 5s was isolated in 69% yield coupling method (Scheme 2d).
(Scheme 2a). The requirement of more than 2 equiv. of KOH
Next, we performed a series of experiments to get further
for this tandem process can be rationalized by taking into insights into the mechanism of the Pd-catalyzed α-alkylation
account that the Pd-catalyzed Suzuki–Miyaura reaction usually of ketones with primary alcohols. It should be mentioned that
requires 2 equiv. of a base and is faster than the α-alkylation black precipitates were formed at the bottom of the reaction
reaction. To prove the rapid formation of 4-acetylbiphenyl (3c), tube at the end of all the α-alkylation reactions, regardless of
4′-bromoacetophenone (3b) was reacted with phenylboronic the reaction conditions or the type of catalyst used. Therefore,
acid (6) under the conditions given in Scheme 2b, and the we characterized the black precipitates that were obtained
desired product was obtained in 95% yield within just 15 min. from the reaction of acetophenone with benzyl alcohol in the
Scheme 2 Tandem Suzuki–Miyaura coupling/α-alkylation reactions catalyzed by 2c. Yields were determined by 1H NMR analyses of the crude reac-
tion mixtures using 1,3,5-trimethoxybenzene as the internal standard (isolated yields in parentheses).
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presence of complex 2c under the optimized conditions
(Table 1, entry 6) by transmission electron microscopy (TEM),
scanning TEM (STEM) associated electron dispersive X-ray
(EDX), X-ray diffraction (XRD), X-ray photoelectron spec-
troscopy (XPS) and UV-vis spectroscopy analyses. The TEM
images given in Fig. 1a and b show that the well-dispersed Pd
nanoparticles with an average particle size of 3.1
0.6 nm
were formed over a cloudy substrate after the catalytic reac-
tions. To identify the integrity of the cloudy substrate and get
more insights into the structure of the black precipitates,
STEM-HAADF associated EDX elemental mapping analyses
were conducted on the sample. As seen from the elemental
mapping images shown in Fig. S1 (see the ESI†), the Pd atoms
are well-dispersed over a substrate composed of N atoms,
which is most probably attributed to the NHC and pyridine
ligands dissociated into the reaction solution from the dis-
sociation of the Pd(II)-PEPPSI complexes. In this regard, it can
be concluded that the black precipitates that are formed
during the catalytic reactions are the stabilized Pd
nanoparticles.25
Fig. 2 XRD pattern of the Pd nanoparticles formed from complex 2c
under the optimum reaction conditions.
To further support the formation of Pd nanoparticles, the
crystal structure of the black precipitates formed from complex
2c was analyzed by powder XRD. The XRD pattern of the black
precipitates showed four peaks at 2θ = 39.7°, 45.2°, 61.4° and
81.7° (Fig. 2), which are readily assigned to the (111), (200),
(220), and (311) planes of face centered cubic (fcc) metallic
palladium.26 The broad peak observed at 2θ = 30° is most prob-
ably attributed to the amorphous NHC ligand that is a cloudy
substrate seen in the TEM images.
On the other hand, the progress of the reaction of complex
2c (0.001 mmol) with KOH (0.1 mmol) in PhMe (2 mL) at
115 °C over different reaction times was monitored by using a
UV-Vis absorption spectrophotometer and the recorded
spectra are depicted in Fig. 3. The intensity of the absorption
band of complex 2c at 284 nm was decreased during the
course of the reaction and a new absorption continuum
appeared in the wavelength range of 360–300 nm, indicating
that the concentration of 2c is decreased due to the dis-
sociation of complex 2c in the solution and the formation of
NHC-stabilized Pd nanoparticles.
Finally, XPS analysis was conducted on the black precipi-
tates to get more insights into the chemical state of the surface
atoms, especially Pd and N. There are two sets of asymmetric
peaks observable at binding energies (BEs) of 333.6/338.8 eV
and 335.6/340.8 eV in the XPS spectrum of the Pd 3d core-level
(Fig. 4a), which are readily assigned to 3d5/2/3d3/2 core-levels,
respectively.27 Considering the asymmetric shape of the peaks
and the spin–orbit component (Δ) of 5.2 eV, these sets are
attributed to the Pd(0) atoms with different electron density
environments, most probably the ones in the NHC- or pyri-
dine-stabilized Pd NPs.28 The N 1s XPS spectrum (Fig. 4b) also
indicates the presence of two types of nitrogen atoms in the
black precipitates surrounded by different chemical environ-
Fig. 1 (a and b) TEM images of Pd nanoparticles formed from complex 2c under the optimum reaction conditions.
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ments, which are attributed to the pyridine and NHC ligands
at BEs of 397.5 and 394.5 eV, respectively.28a–c
To understand whether the reaction was homogeneously or
heterogeneously catalyzed and to get more insights into the
catalytically active palladium species, mercury poisoning and
hot filtration experiments were performed (Scheme 3). When
50 µL of Hg was added initially into the reaction mixture
under the optimum conditions (Table 1, entry 6), only a 13%
product formation was observed after 6 h (Scheme 3a). This
13% product formation can be attributed to the catalytic
activity of KOH itself. The significant decrease in the catalytic
activity (Scheme 3a compared to Table 1, entry 6) and the inhi-
bition of the α-alkylation reaction due to the deactivation of Pd
nanoparticles indicate the heterogeneous nature of the present
catalytic system. To support this observation, a hot filtration
Fig. 3 UV-vis spectra of complex 2c before (the blue line) and after the
reaction with KOH.
Fig. 4 XPS spectra (a) Pd 3d, (b) N 1s core-levels of the Pd nanoparticles formed from complex 2c under the optimum reaction conditions.
Scheme 3 Mercury poisoning (a) and hot filtration (b) tests for α-alkylation of acetophenone with benzyl alcohol catalyzed by 2c. Yields were deter-
mined by 1H NMR analyses of the crude reaction mixtures using 1,3,5-trimethoxybenzene as the internal standard.
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experiment was also performed. The reaction was carried out 7 with benzyl alcohol as a hydrogen source afforded the
under the optimized conditions, and after 1 h (41% formation desired product 5a in 89% conversion only in 1 h (Scheme 4a).
of 5a), the reaction mixture was filtered off through a pad of In addition, the formation of 1,3,5-triphenylpentane-1,5-dione
Celite® while hot. Then, KOH (10 mol%) was added to the (8), resulting from the 1,4-addition of acetophenone to chal-
reaction mixture and the reaction was further continued for cone, was observed in the early stages of the reaction (∼10% in
5 h (Scheme 3b). After this period, only an 11% increase was 30 min). The 1,4-addition product (8) was consumed during
observed in the product yield (52%), most probably due to the the course of the reaction, suggesting the reversibility of this
catalytic activity of KOH itself. The outcomes of the hot fil- step. Similarly, the formation of 1-phenylethanol (3′a), the
tration experiment also confirm that the active species product of acetophenone reduction, was also observed in the
involved in the α-alkylation reaction are Pd nanoparticles.
initial stages of the reaction. Then 3′a was gradually consumed
Next, we studied the time-dependent progress of the reac- during the progress of the reaction. The slow dehydrogenation
tion of model substrates 3a and 4a under the conditions given of intermediate secondary alcohols was also confirmed by
in Table 1, entry 6 by performing individual experiments over independent control experiments where the secondary alco-
different reaction times (Fig. 5). Control experiments were also hols 5′a and 3′e were dehydrogenated to corresponding
carried out to support the observations obtained from the pro- ketones 5a (23%) and 3e (44%) (Scheme 4b and c). Finally, the
gress of the reaction (Scheme 4). Monitoring the time-depen- dehydrogenation of 4-methoxybenzyl alcohol (4b) was carried
dent reaction profile revealed the complete conversion of the out in a sealed reaction tube for 6 h, resulting in the formation
substrates into the desired product 5a (83%) and over-reduced of 4-methoxybenzaldehyde (9) in 42% yield and the presence
alcohol product 5′a (8%) in 6 h (Fig. 1). The accumulation of of H2 in the gas phase of the reaction was detected by GC ana-
the intermediate chalcone (7) was very low (less than 4%) lysis (Fig. S2, see the ESI†) (Scheme 4d).
during the whole course of the reaction, which suggests that
On the basis of the above-mentioned experimental findings,
the reduction of 7 was very fast. The reduction of intermediate a plausible mechanism for the Pd-catalyzed α-alkylation of
Fig. 5 Time course of the reaction. Reaction conditions: 3a (1 mmol), 4a (1 mmol), 2c (0.1 mol%), KOH (10 mol%), toluene (2 mL), 115 °C (oil bath
temperature), open to air. %Mol values were determined by 1H NMR analyses of the independent reaction mixtures using 1,3,5-trimethoxybenzene
as the internal standard.
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Scheme 4 Control experiments. Conversions were determined by 1H NMR analyses of the crude reaction mixtures.
Scheme 5 Proposed mechanism for the Pd-catalyzed α-alkylation of ketones with primary alcohols.
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ketones with primary alcohols can be proposed as shown in Agilent Cary 60 UV-Vis spectrophotometer. Transmission elec-
Scheme 5. The mechanism involves the formation of NHC- tron microscopy (TEM) images were obtained using a Hitachi
stabilized Pd NPs under basic reaction conditions. Then, the HT7800 equipped with a scanning TEM and the associated
dehydrogenation of primary alcohol into an aldehyde may EDX analyzer working in a high-resolution (HR) mode at 120
generate transient Pd–H species. Next, the condensation of the kV. The crystal structure of the materials was investigated with
ketone and aldehyde gives the intermediate enone (7). Here, a Bruker D8 Advance X-Ray diffractometer using Cu Kα radi-
the reversible 1,4-addition of ketone on 7 may take place. ation (1.54 Å). The chemical states and surface compositions
Finally, 7 is hydrogenated to afford 5 as the major product of the photocatalysts were identified by X-ray photoelectron
accompanied by over-reduced alcohol product 5′.
spectroscopy (XPS, Thermo K-Alpha).
General procedure for the synthesis of NHC-Pd-PEPPSI
complexes (2a–d)
Conclusions
In summary, we reported for the first time the use of A mixture of imidazolium salt (1a–d) (0.5 mmol), PdCl2
[PdCl2(NHC)(py)] complexes as catalyst precursors to promote (0.5 mmol), and K2CO3 (2.5 mmol) was suspended in pyridine
the α-alkylation of ketones with primary alcohols under bor- (3 mL) and stirred at 80 °C for 24 h open to air. The excess of
rowing hydrogen conditions. The variation of the nature of the pyridine was removed under vacuum. The reaction mixture
NHC ligand framework seemed to play an important role in was then diluted with dichloromethane, and filtered through a
catalyst efficiency and complex 2c having 4-methoxyphenyl short pad of Celite. The remaining solid was washed twice
groups at the 4,5-positions and 4-methoxybenzyl substituents with dichloromethane and the solvent of the filtrate was evap-
on the N-atoms of imidazole exhibited the highest activity in orated. The pure complexes were isolated as yellow solids by
this transformation. As a result of mechanistic studies, the column chromatography on silica gel using dichloromethane/
active species involved in the present α-alkylation reaction methanol (95/5).
1
were mainly Pd NPs formed from the NHC-Pd-PEPPSI com-
2a. Yield: 230 mg (%82). H NMR (400 MHz, CDCl3, 25 °C,
plexes. Importantly, this catalytic system also allowed the syn- ppm): δ = 9.02 (d, J = 6.8 Hz, 2H), 7.76 (t, J = 7.8 Hz, 1H), 7.46
thesis of biaryl ketones by tandem Suzuki–Miyaura-coupling/ (d, J = 7.6 Hz, 4H), 7.34 (t, J = 6,2 Hz, 2H), 6.90 (d, J = 7.2 Hz,
α-alkylation reactions. Currently, our studies are focused on 4H), 6.65 (d, J = 1.6 Hz, 2H), 5.79 (s, 4H), 3.78 (s, 6H). 13C{1H}
the development of efficient catalysts and their application in NMR (100.6 MHz, CDCl3, 25 °C, ppm): δ = 159.7, 151.3, 149.0,
these tandem reactions. Considering that NHC-Pd-PEPPSI 138.0, 130.4, 127.4, 124.4, 121.4, 114.3, 55.3, 54.2. HRMS (ESI)
complexes have found widespread applications in catalysis m/z: [M − Cl]+ calcd for C24H25ClN3O2Pd 528.0670; found
chemistry, the results described in this study could be of great 528.0679.
1
importance for further studies.
2b. Yield: 310 mg (%78). H NMR (400 MHz, CDCl3, 25 °C,
ppm): δ = 8.92 (d, J = 5.2 Hz, 2H), 7.74 (t, J = 7.6 Hz, 1H), 7.32
(t, J = 7.2 Hz, 2H) 7.22 (t, J = 7,4 Hz, 6H), 7.15 (t, J = 7,6 Hz,
4H), 6.94 (d, J = 7.2 Hz, 4H), 6.74 (d, J = 8.4 Hz, 4H), 5.82 (s,
4H), 3.75 (s, 6H). 13C{1H} NMR (100.6 MHz, CDCl3, 25 °C,
ppm): δ = 159.0, 151.4, 149.3, 137.9, 133.4, 130.8, 129.6, 128.8,
Experimental
General information
Unless otherwise noted, all reagents and solvents were 128.6, 128.2, 127.8, 124.4, 113.7, 55.2, 52.4. HRMS (ESI) m/z:
obtained commercially and used without further purification. [M − Cl]+ calcd for C36H33ClN3O2Pd 680.1296; found 680.1361.
1
NHC precursors 1a–d were synthesized according to the pre-
2c. Yield: 360 mg (%92). H NMR (400 MHz, CDCl3, 25 °C,
viously developed procedure22 and the physical properties and ppm): δ = 8.89 (d, J = 5.2 Hz, 2H), 7.72 (t, J = 7.6 Hz, 1H),
spectroscopic data of the obtained compounds are in accord- 7.32–7.27 (m, 6H), 6.84 (d, J = 8.8 Hz, 4H), 6.77 (d, J = 8.8 Hz,
ance with previous reports.23 The NMR spectra were recorded 4H), 6.67 (d, J = 9.2 Hz, 4H), 5.77 (s, 4H), 3.76 (s, 6H), 3.73 (s,
on a Varian AS 400 Mercury NMR spectrometer at 298 K. 6H). 13C{1H} NMR (100.6 MHz, CDCl3, 25 °C, ppm): δ = 159.7,
Chemical shifts are reported in units of parts per million 158.9, 151.2, 148.3, 137.9, 133.1, 132.0, 129.5, 128.7, 124.3,
(ppm) relative to tetramethyl silane (δ = 0 ppm) and CDCl3 (δ = 119.9, 113.6, 55.1, 52.1. HRMS (ESI) m/z: [M − Cl]+ calcd for
7.26 ppm for 1H and δ = 77.0 ppm for 13C NMR). Melting C38H37ClN3O4Pd (96.8%) 742.1512; found 742.1523.
1
points were measured on
a
Gallenkamp electrothermal
2d. Yield: 203 mg (%52). H NMR (400 MHz, CDCl3, 25 °C,
melting-point apparatus without correction. High-resolution ppm): δ = 8.91 (d, J = 4.8 Hz, 2H), 7.73 (t, J = 7.8 Hz, 1H), 7.31
mass spectra (HRMS) were recorded on an Agilent 6530 (t, J = 7.0 Hz, 2H), 7.23 (d, J = 8.8 Hz, 4H), 7.13 (d, J = 8.8 Hz,
Accurate-Mass Q-TOF mass spectrometer at the East Anatolia 4H), 6.82 (d, J = 8.8 Hz, 4H), 6.76 (d, J = 8.4 Hz, 4H), 5.83 (s,
High Technology Application and Research Center, Atatürk 4H), 3.75 (s, 6H). 13C{1H} NMR (100.6 MHz, CDCl3, 25 °C,
University. GC analysis for the H2 evolution experiment was ppm): δ = 159.2, 151.3, 138.0, 135.3, 132.5, 131.9, 129.5, 128.6,
performed on an Agilent 7890A GC instrument, and gas pro- 128.1, 126.0, 124.4, 113.8, 55.2, 52.7. HRMS (ESI) m/z: [M −
ducts were identified according to the standard gas mixture Cl]+ calcd for C36H31Cl3N3O2Pd (96.8%) 750.0521; found
(Agilent P/N 5190-0519). The UV spectra were recorded on an 750.0562.
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General procedure for the α-alkylation of ketones with primary determined by H NMR analysis of the crude reaction mixture
alcohols
using 1,3,5-trimethoxybenzene as an internal standard.
To a 10 mL reaction tube with a condenser, ketone (1.0 mmol),
primary alcohol (1.0 mmol), base (0.1 mmol; 10 mol%), and a
solution of the palladium complex (0.1–0.5 mol%) in toluene
(2.0 mL) were added under open air conditions. The reaction
mixture was vigorously stirred under reflux in a preheated oil
bath at 115 °C for 4–6 h. Thereafter, the reaction mixture was
cooled to ambient temperature. For the optimization studies
1,3,5-trimethoxybenzene was added into the reaction mixture
as an internal standard, and the yields were calculated
through 1H NMR analysis. For the substrate scope experi-
ments, the reaction mixture was diluted with 5 mL of dichloro-
methane. After filtration, the solvent was evaporated, and the
crude product was purified by column chromatography on
silica gel using a hexane/ethyl acetate (9/1) mixture as an
eluent to afford the desired product.
Hot filtration experiments
To a 10 mL reaction tube with a condenser, acetophenone
(1.0 mmol), benzyl alcohol (1.0 mmol), KOH (0.1 mmol;
10 mol%), and a solution of 2c (0.1 mol%) in toluene (2.0 mL)
were added under open air conditions. The reaction mixture
was vigorously stirred under reflux in a preheated oil bath at
115 °C for 1 h. Thereafter, the reaction mixture was filtered
while hot into a new reaction tube, which contained KOH
(0.1 mmol; 10 mol%). The reaction mixture was vigorously
stirred under reflux in a preheated oil bath at 115 °C for an
additional 5 h. After completion of the reaction, the yield was
1
determined by H NMR analysis of the crude reaction mixture
using 1,3,5-trimethoxybenzene as an internal standard.
Conflicts of interest
General procedure for the tandem Suzuki–Miyaura coupling/
α-alkylation reactions
There are no conflicts to declare.
To a 10 mL reaction tube with a condenser, ketone (0.5 mmol),
primary alcohol (0.5 mmol), phenylboronic acid (0.55 or
1.1 mmol), base (1.2 or 2.2 mmol), and a solution of the palla-
dium complex (0.005 mmol; 1 mol%) in toluene (2.0 mL) were
added under open air conditions. The reaction mixture was
vigorously stirred under reflux in a preheated oil bath at
115 °C for 3 h. Thereafter, the reaction mixture was cooled to
ambient temperature and diluted with 5 mL of dichloro-
methane. After filtration, the solvent was evaporated, and the
crude product was purified by column chromatography on
silica gel using a hexane/ethyl acetate (9/1) mixture as an
eluent to afford the desired product.
Acknowledgements
We are grateful to the Ege University Scientific Research
Projects Coordination (FYL-2019-21171) and the Turkish
Academy of Science (TUBA) for the financial support. M. O.
thanks the Türkiye Scholarships for the fellowship. Z. E.
thanks to the Council of Higher Education of Turkey for 100/
2000 CoHE Doctoral Scholarship and TUBITAK 2211/C
National Ph.D. Scholarship Program in the Priority Fields in
Science and Technology.
Procedure for the time profile of the α-alkylation reaction
Notes and references
Seven identical reactions were performed in different reaction
tubes for specified times (5, 15, 30, 60, 120, 240, and 360 min).
To a 10 mL reaction tube with a condenser, acetophenone
(1.0 mmol), benzyl alcohol (1.0 mmol), KOH (0.1 mmol;
10 mol%), and a solution of 2c (0.1 mol%) in toluene (2.0 mL)
were added under open air conditions. The reaction mixture
was vigorously stirred under reflux in a preheated oil bath at
115 °C for a specified time. After completion of the reactions,
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10906 | Dalton Trans., 2021, 50, 10896–10908
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