Tandem synthesis of tetrahydroquinolines and identification of the reaction network byoperandoNMR

Article abstract of DOI:10.1039/d1cy00418b

The study of the reaction mechanism and complex network for heterogeneously catalyzed tandem reactions is challenging but can guide reaction design and optimization. Here, we describe a case study using bifunctional metal-organic framework supported Pd nanoparticles (Pd/UiO-66(HCl)) for the one-pot tandem synthesis of substituted tetrahydroquinolinesviathe Claisen-Schmidt condensation and reductive intramolecular cyclization. The directly observed evolution of intermediates and products, including reactive species containing hydroxylamine group and unstable intermediate 2-phenyl-3,4-dihydroquinoline, was enabled byoperandomagic angle spinning nuclear magnetic resonance studies under 50 bar H₂. The reaction network of the tandem reaction is deduced based on reaction kinetic information obtained from theoperandostudy. The optimized procedure was applied to various acetophenone and nitrobenzaldehyde derivatives carrying different functional groups, and eight valuable substituted tetrahydroquinolines were obtained in moderate to good yields. This work provides a molecular-level understanding of the catalytic system and brings up new opportunities for efficient and sustainable synthesis of medicinally relevant building blocks.

Full text of DOI:10.1039/d1cy00418b

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Tandem synthesis of tetrahydroquinolines and
identification of the reaction network by
operando NMR†
Cite this: DOI: 10.1039/d1cy00418b
c
Jingwen Chen, a Long Qi,
b Biying Zhang,c Minda Chen,
*
Takeshi Kobayashi, b Zongbi Bao,ad Qiwei Yang,ad Qilong Ren,ad
c
ad
*
*
Wenyu Huang
and Zhiguo Zhang
The study of the reaction mechanism and complex network for heterogeneously catalyzed tandem
reactions is challenging but can guide reaction design and optimization. Here, we describe a case study
using bifunctional metal–organic framework supported Pd nanoparticles (Pd/UiO-66(HCl)) for the one-pot
tandem synthesis of substituted tetrahydroquinolines via the Claisen–Schmidt condensation and reductive
intramolecular cyclization. The directly observed evolution of intermediates and products, including
reactive species containing hydroxylamine group and unstable intermediate 2-phenyl-3,4-
dihydroquinoline, was enabled by operando magic angle spinning nuclear magnetic resonance studies
under 50 bar H2. The reaction network of the tandem reaction is deduced based on reaction kinetic
information obtained from the operando study. The optimized procedure was applied to various
acetophenone and nitrobenzaldehyde derivatives carrying different functional groups, and eight valuable
substituted tetrahydroquinolines were obtained in moderate to good yields. This work provides a
molecular-level understanding of the catalytic system and brings up new opportunities for efficient and
sustainable synthesis of medicinally relevant building blocks.
Received 9th March 2021,
Accepted 20th April 2021
DOI: 10.1039/d1cy00418b
rsc.li/catalysis
Other approaches, like oxidative cyclization of amino
Introduction
alcohols,23 Cα–H activation, and intramolecular nucleophilic
1,2,3,4-Tetrahydroquinolines (THQs) widely exist in bioactive
natural products1 and artificial molecules like fragrances,
dyes, pharmaceuticals, and hydrogen-storage materials.2–7
2-substituted-THQs,8 especially the 2-phenyl analogues
(PTHQs), have attracted great interest as medicinal scaffolds
for treating diseases like estrogen-responsive cancer and
osteoporosis.9,10 Therefore, numerous protocols have been
developed for the preparation of PTHQs.11 The most
commonly employed method for generating PTHQs is the
hydrogenation of quinolines with various homogeneous and
heterogeneous catalysts (Scheme 1).12–21 However, harsh
reaction conditions are usually required because of the high
reaction energy barrier in the hydrogenation of quinolines.22
substitution,24,25 have been developed for the synthesis of
PTHQs, but the tedious synthetic procedures for the complex
starting materials, multiple reaction steps, and harsh reaction
conditions significantly restrict their further applications.
a Key Laboratory of Biomass Chemical Engineering of Ministry of Education,
College of Chemical and Biological Engineering, Zhejiang University, Hangzhou
310027, China. E-mail: zhiguo.zhang@zju.edu.cn
b U.S. DOE Ames Laboratory, Iowa State University, Ames, Iowa 50011, USA.
E-mail: lqi@iastate.edu
c Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA.
E-mail: whuang@iastate.edu
d Institute of Zhejiang University-Quzhou, Quzhou 324000, China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1cy00418b
Scheme 1 Representative approaches for the preparation of PTHQs.
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Cascade or tandem reactions have attracted tremendous
interest continuously because they provide rapid, low cost
and simple approaches for preparing complex molecules.26,27
Many tandem catalysis approaches have been developed for
the synthesis of PTHQs.28–31 Bunce and co-workers32 reported
a reduction–reductive amination reaction of nitro keto esters
to prepare 1,2,3,4-tetrahydroquinoline-3-carboxylic esters.
Feng's33 and Kim's groups31 developed the tandem
Catalysis Science & Technology
(ACPs) for the synthesis of PTHQs (Scheme 1). The tandem
reaction involves multiple intermediates resulting from the
simultaneous existence of easily reducible functional groups,
which may cause unsatisfactory selectivity toward PTHQs.
Understanding the reaction network by monitoring the
heterogeneously catalyzed system composed of reactants,
intermediates, and favored/disfavored products is critical in
directing the species evolution towards the desired product.
The first step of such efforts is to deconvolute individual
reaction paths among all existing species and understand their
reversibility of interconversions. However, probing a molecular-
level reaction pathway is challenging because of the co-
existence of solid catalysts, reaction solutions, and reactive
gases, particularly when intermediates are not stable during
sampling and quantification processes. Even if intermediates
are stable, limited number of sampling results in low-density
data points that prevent the accurate delineation of the
reaction network.
Operando magic-angle spinning nuclear magnetic resonance
(MAS-NMR) spectroscopy can operate at high temperature and
pressure,56 and shows exceptional advantages in acquiring
kinetic and structural information of multiphasic reaction
systems.57–59 To elucidate the complex reaction network, we
employ operando MAS-NMR to detect various stable and
unstable reaction intermediates in the tandem reaction for the
synthesis of PTHQs. Multiple transient intermediates, including
the unstable 2-phenyl-3,4-dihydroquinoline and intermediates
with a hydroxylamine group, were identified by the operando
MAS-NMR study under 50 bar H2. The obtained kinetic
information on the molecules has been utilized to construct the
reaction network of the Pd/UiO-66(HCl) catalyzed tandem
reaction. The deep insight into the mechanism provides us the
opportunity to tune the selectivity to PTHQs. Under the
optimized reaction conditions, eight functionalized PTHQs were
obtained in moderate to good yields by the tandem reaction.
This work provides guidance on the rational design of
multifunctional heterogeneous catalysts to efficiently
manufacture complex bioactive molecules.
1,5-hydride
transfer/cyclization
reaction
to
afford
tetrahydroquinolines. An enantioselective reaction has also
been discovered by Han and co-workers,34 using chiral gold
phosphate to catalyze the tandem hydroamination/transfer
hydrogenation of 2-(3-phenyl-2-propyl)aniline, and PTHQs
were obtained in good yield and enantioselectivity.
Furthermore, the tandem conjugate addition/cyclization,
Michael/Aza-Henry tandem reaction, oxidative cyclization of
amino alcohols, etc.29 have been developed to synthesize
tetrahydroquinolines. However, the complicated substrates
and tedious separation process of the catalyst and products
hinder the practical application of those tandem catalysis
approaches. Therefore, the design and development of
multifunctional heterogeneous catalysts that can help
construct THQ heterocycles from readily available starting
materials in one pot are highly desired. Nevertheless, such
tandem catalysis is rather demanding because the formation
and cleavage of multiple bonds need to be orchestrated
simultaneously and under the same reaction conditions.
Additionally, multiple reaction intermediates are typically
involved, and by-products may form during the reaction
process, posing challenges in mechanistic investigation and
reaction optimization.
Metal–organic frameworks (MOFs) are constructed from
metal ions and organic ligands, and multiple functional groups
can co-exist and work cooperatively within the porous
framework.35–37 Hence, MOFs have great potential in tandem
catalysis,38–43 and multifunctional MOFs have been reported
for obtaining quinoline derivatives by the Friedländer reaction
or
cascade
hydrogenation–intramolecular
reductive
amination.44–46 Among various MOFs reported, UiO-66,
featuring a 12-coordinated Zr6 cluster Zr6(μ3-O)4(μ3-OH)4, has
been a promising material for catalysis, with excellent chemical
and thermal stability.47 The coordinatively unsaturated Zr and
μ3-OH work as Lewis and Brønsted acid sites, respectively.48–50
Corma and coworkers found that UiO-66 and UiO-66-NH2 were
efficient in catalyzing the Povarov reaction of in situ formed
imine and dihydropyran, and the trans-pyrano[3,2-c]quinoline
was formed in high diastereoselectivity.51 Besides, our previous
work has demonstrated that Pt or Pd nanoparticle-supported
UiO-66 can regulate the selective hydrogenation of nitro groups
in the tandem reaction for the synthesis of bioactive
compounds like quinoline N-oxides.52,53 In this work, we
synthesized a bifunctional catalyst with UiO-66(HCl)-supported
Pd nanoparticles (Pd/UiO-66(HCl)),54,55 which was anticipated
to catalyze the one-pot sequential Claisen–Schmidt
condensation and reductive intramolecular cyclization reaction
between the 2-nitrobenzaldehydes (NBAs) and acetophenones
Results and discussion
Synthesis and characterization
UiO-66 was prepared with ZrCl4 and terephthalic acid via a
solvothermal reaction with HCl as the modulator in the
growth of MOF materials.60 The resulting sample is denoted
UiO-66(HCl). The powder X-ray diffraction (PXRD) pattern of
UiO-66(HCl) is identical to that of the simulation (Fig. 1A).
Pd nanoparticles (NPs) were introduced to UiO-66(HCl) by an
impregnation method.54 The PXRD pattern of Pd/UiO-66(HCl)
indicates that the crystal structure of UiO-66(HCl) was kept
after loading the Pd precursor and the subsequent reduction
process. The Pd amount in Pd/UiO-66(HCl) was 1.6 wt%
(Table S2†), determined by inductively coupled plasma
optical emission spectrometry (ICP-OES). The nitrogen
sorption isotherms indicate that both UiO-66(HCl) and Pd/
UiO-66(HCl) display a type I isotherm (Fig. 1B) according to
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Fig. 2 (A) TEM and (B) HRTEM images of Pd/UiO-66(HCl).
Mechanistic investigation with operando MAS-NMR
The construction of PTHQ moieties can be achieved via the
tandem reaction of readily accessible feedstocks:
2-nitrobenzaldehyde (NBA) and acetophenone (ACP).53
Several reactive functionalities (–NO2, CO, CN, CC, and
arenes) exist in NBA and ACP, and hence a complex reaction
network will be present, involving multiple parallel and
consecutive pathways composed of intermediates, products,
and by-products. Traditionally, the exploration of desired
reaction selectivity was achieved by laborious trial-and-error
experiments. Therefore, it is vital to rapidly identify
intermediates and accurately elucidate the complex reaction
network promptly for the on-demand control and switch of
selectivity. Operando high-pressure and high-temperature
MAS-NMR spectroscopy enables the detection of both stable
and metastable species under reaction conditions. In this
context, we employed operando MAS-NMR to acquire kinetic
and mechanistic information on the multiphasic catalytic
production of PTHQs.
Firstly, the Claisen–Schmidt condensation reaction between
NBA and ACP was investigated by operando MAS-NMR. Our
previous work has demonstrated that UiO-66(HCl) possesses a
large surface area and high catalytic activity for the
condensation reaction,53 hence, the Pd-supported UiO-66(HCl)
was chosen as the catalyst for the tandem reaction in the
operando MAS-NMR studies. To fast-track molecular evolution
by 13C NMR, the isotopically labelled ACP with 13C at the acetyl
group (195.2 and 24.9 ppm) was used as the substrate (Fig. 3).
Therefore, both intermediates and products derived from ACP
can be detected as two doublets of the 13C labels while the
unlabeled positions remained invisible in the 13C NMR spectra.
The Claisen–Schmidt condensation reaction was conducted
at 60 °C in air. The intensity of ACP resonance decreased
immediately upon heating (Fig. 3). At the same time, two new
sets of doublets appeared, which can be assigned to
β-hydroxyketone intermediate 3 (198.0 and 45.9 ppm) and
product 2-nitrochalcone 4 (188.4 and 127.3 ppm), respectively.
The β-hydroxyketone intermediate 3 was not observed at higher
reaction temperatures due to shorter residence time.53 The
concentration profiles of ACP, intermediate 3, and product 4
were extracted from the NMR array, and the overall
concentration remains constant over the reaction course. After
Fig.
1 (A) Powder X-ray diffraction patterns and (B) N2 sorption
isotherms of UiO-66(HCl) and Pd/UiO-66(HCl) (1.6 wt%) at −196 °C.
the IUPAC classification.61 The Brunauer–Emmett–Teller
(BET) surface area of Pd/UiO-66(HCl) is 1687 m2 g−1 with a
micropore volume of 0.55 cm3 g−1, which are smaller than
those of UiO-66(HCl) (a BET surface area of 2027 m2 g−1 and
a micropore volume of 0.66 cm3 g−1, Table S1†). The results
of microscopic study and textural analysis indicated that only
a small portion of the internal pore volume of UiO-66(HCl)
was occupied by Pd NPs, and Pd/UiO-66(HCl) remains highly
porous allowing the free diffusion of reactants and products.
The transmission electron microscopy (TEM) image shows
that Pd NPs are dispersed uniformly on UiO-66(HCl) with a
mean size of 3.9 nm (Fig. 2A). The high-resolution TEM
(HRTEM) image shows an interplanar spacing of 0.23 nm
(Fig. 2B), which corresponds to the (111) lattice spacing of
the face-centered cubic (fcc) Pd structure. Besides, another
three UiO-66 samples have been prepared, including UiO-66
(prepared without an acid modulator),47 UiO-66(AcOH)
(prepared with AcOH as the additive),62 and UiO-66-NH2(0.5)
(prepared with a mixed linker of terephthalic acid and
2-aminoterephthalic acid; molar ratio 1 : 1).60 These three
materials are synthesized to investigate the influence of
structural modification63–66 on the catalytic activity, with
characterization results shown in Fig. S1–S6.†
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ACP was curve-fitted with
a second-order reaction rate
equation, and the pseudo-second-order rate constant of ACP
was 0.31 M−1 h−1.
To accelerate the conversion of ACP and reduce the possible
influence of the unreacted ACP on the next step, the mixture
was further heated at a higher reaction temperature (100 °C).
After an additional 2.5 h, 74% yield of 4 from ACP was reached,
and the selectivity to 4 remained >99% (Fig. S7†).
After the Claisen–Schmidt condensation reaction, the
high-pressure MAS rotor was further charged with 50 bar H2;
the reaction was carried out at room temperature, monitored
by MAS-NMR (Fig. 4). The chalcone 4 reacted rapidly, and its
resonances disappeared within 1 h along with multiple new
sets of doublets. The emergence of new signals is due to the
reactions of several reducible functionalities in 4,
intermediates, products, and by-products. The signals of PQ
(155.9 and 117.5 ppm) only became visible in ∼4.5 h, and its
concentration maintained below 0.02 mol L−1 (Fig. S8†);
hence, PQ is unlikely the intermediate for the formation of
PTHQs (55.2 and 30.2 ppm), even though PQ has been
suggested as a precursor for the production of PTHQs in
several previous reports.3,11
Multiple resonances can be identified in the range of 190.5
to 188.4 ppm, attributed to the a-carbon of nitrochalcone 4 and
its nitro-reduced intermediates: hydroxylamine 9 and amine 12.
At the same time, the carbonyl and CC are untouched. The
signals of the corresponding b-carbons appear at 122.0 and
121.2 ppm for 9 and 12, respectively, which have been verified
Fig. 3 Kinetic studies of the Pd/UiO-66(HCl) catalyzed Claisen–Schmidt
condensation of NBA and ACP at 60 °C with operando MAS-NMR. Direct
polarization 13C MAS-NMR spectra (eight scans per transient) were
collected at the MAS rate of 5 kHz. Reaction conditions: ACP-α,β-13C2
(1.48 mg, 12.3 μmol), NBA (3.0 mg, 19.8 μmol), toluene (50 μL), 1.6 wt%
Pd/UiO-66(HCl) (1.22 mg). The rate of ACP was obtained by fitting the
second-order rate equation.
14.5 h, the yield of 4 from ACP was 44% with a nearly
quantitative selectivity. Furthermore, the reaction kinetics of
Fig. 4 Time evolution of direct polarization 13C MAS-NMR spectra acquired during the reductive cyclization of the reaction mixture after the Claisen–
Schmidt condensation step (5 kHz MAS rate and eight scans per transient). Reaction conditions: 1.6 wt% Pd/UiO-66(HCl) (1.22 mg), H2 (50 bar), room
temperature, 16 h.
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in our recent study.53 The doublets at 197.5 and 39.4 ppm
represent intermediate 7 when CC is hydrogenated.
The intensities of 164.2 and 22.9 ppm doublets, assigned
to 2-phenyl-3,4-dihydroquinoline (13), are high throughout
the reaction. The detection and quantification of the key
intermediate 13 have been a challenge using ex situ analysis
due to its air instability. The concentration of 13 increased
first and decreased after 4 h, which was proved to be the key
intermediate for the formation of PTHQs in the reductive
cyclization reaction.53 Compound 11, as
a
necessary
compound between 7 and 13, can not be identified in the
NMR spectra; it is because of its high reactivity towards
cyclization leading to 13.
Compound 14 was previously postulated as the
intermediate when hydrogenating PQ to PTHQs, and can be
isomerized from 13.12,67 However, we did not detect 14
because the reduction of PQ or the isomerization of 13 is
limited under the reaction conditions.
Moreover, a new set of doublets at 139.7 and 26.6 ppm
was observed even in the starting spectrum, which has been
assigned to the a and b carbons of the imine intermediates
(15), the condensation product of intermediate 7 or 11 with
2-aminobenzyl alcohol (reduced from NBA, Scheme S1†). This
compound was only observed in this study when NBA was in
excess of ACP. The peak at 139.7 ppm shifted to a low
frequency gradually, which may be caused by the interaction
with by-product water. Signals of 15 disappeared after 6 h,
caused by the hydrolysis to 7 or 11. The relatively large
Fig. 5 (A) Time-dependent concentrations of PTHQ, 4, and other
quantifiable intermediates (7, 9, 12, 13, and 15) during the reaction
derived from the MAS-NMR data (Fig. 4). Only intermediates with
concentrations higher than 0.02 mol L−1 are shown. (B) Curve fitting of
the concentration profiles of PTHQ, key intermediate 13, and the sum
of other quantifiable species (4, 7, 9, 12, and 15).
coupling constant (13C–13C 1J
= 44.6 ppm, Table S3†)
confirms the double bond functionality. The internal
hydrogen bonding of imine N and OH may explain the
relatively low frequency of the imine signal.68,69
In addition, two new resonances between 66.3 and 72.0
ppm (Fig. S9†) were assigned to the carbons in hydroxyl-
containing compounds (such as 8 and 10), which were not
observed at a lower hydrogen pressure (27.6 bar).
Using ex situ gas chromatography–mass spectrometry (GC-
MS), we further confirmed the identities of PTHQ, PQ, 7, 10,
12, etc. (Fig. S10–S12†). Along with the formation of PTHQ,
intermediates 4, 9, 12, and 15 rapidly disappeared. The
concentration profiles of the quantifiable species in the
reductive cyclization are shown in Fig. 5 for those with
concentration higher than that of PQ, and the production of
PTHQs was curve-fitted with the pseudo first-order reaction
equation (0.25 0.03 h−1).
The above MAS-NMR studies indicated that under 50 bar
H2, the nitro group and CC bonds could be reduced to
generate 7, 9, and 12. The PTHQ product was formed via
intermediates 11 and 13 as the major reaction pathway
(Scheme 2). Other condensation intermediates and by-
products were formed as well, from the residual ACP or NBA,
but they are not relevant to the production of PTHQs. Based
on the assignment from operando MAS-NMR and ex situ GC-
MS, the plausible reaction routes of these extra species
derived from ACP and NBA are shown in Scheme S1.† Both
spectroscopic and chromatographic studies indicate that NBA
can undergo side reactions, generating side products 20 and
15, and therefore in the following reaction studies, an
excessive amount of ACP was added to ensure full conversion
of NBA.
One-pot synthesis of PTHQs
The identification of reaction intermediates by operando
MAS-NMR allows us to gain deep understanding of the
tandem reaction at the molecular level. Accordingly, the
reaction conditions were optimized to maximize the PTHQ
selectivity.
We first carried out the Claisen–Schmidt condensation
reaction with different MOFs as the catalysts at 80 °C. As
shown in Fig. 6, UiO-66(HCl) shows a high catalytic activity
toward the Claisen–Schmidt condensation reaction. UiO-66
prepared without an acid modulator shows the lowest activity
for the condensation reaction. Compared to HCl, acetic acid
as a modulator also enhances the rate in a similar fashion.
After introducing –NH2 groups into UiO-66(HCl), the catalytic
activity decreased obviously. It should be noted that the TON
of UiO-66(HCl) is two orders of magnitude larger than that of
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Scheme 2 Reaction network of the Pd/UiO-66(HCl) catalyzed reductive cyclization of 2-nitrochalcone (4) in the production of PTHQ based on
the operando MAS-NMR study. Compound 20 (2-aminobenzylalcohol) is the reduction product of NBA, see Scheme S1.†
UiO-66 (Table S4†), which illustrated the vital role of acid
modulators in the formation of active sites within the UiO-66
framework. Based on the above experimental results, UiO-
66(HCl) was employed for further studies.
To optimize the reaction conditions for the hydrogenation
step, we first carried out the Claisen–Schmidt condensation
reaction at 80 °C for 5 h to completely convert NBA and ACP
to 2-nitrochalcone (4) since the reaction selectivity is
relatively insensitive to temperature. After that, the reaction
mixture was directly charged with H2 for the reductive
cyclization (step 2) without any additional treatment.
Lowering the pressure below 50 bar was attempted to allow
sufficient reduction of 13 to PTHQ without over-reduction of
carbonyls in the reaction mixture.
The catalytic properties of the MOF-supported Pd catalysts
were evaluated for the hydrogenation reaction of
2-nitrochalcone (Fig. S13†). High catalytic activity and selectivity
to PTHQ were achieved with Pd/UiO-66(HCl) as the catalyst. The
activity of Pd/UiO-66(AcOH) is slightly lower, followed by Pd/
UiO-66-NH2(0.5) and Pd/UiO-66. The results demonstrated the
beneficial effect of UiO-66(HCl) on the supported Pd sites.
Besides, the low synthetic temperature for UiO-66(HCl) is
attractive for practical applications; hence, Pd/UiO-66(HCl) was
chosen as the catalyst for further reaction optimization and
study of the substrate scope.
The influence of reaction temperature on the reductive
cyclization step was firstly investigated. As shown in Table 1,
PTHQ was obtained in 90% yield in the reductive cyclization of
4 after 8 h (entry 1). The yield of PTHQ decreased to 63% when
the reaction temperature was decreased to 40 °C (entry 2).
Lowering the H2 pressure from 27.6 bar to 6.9 bar has mimimal
effect on the reductive cyclization reaction, and 86% yield of
PTHQ was obtained after 19 h under 6.9 bar of H2 (entry 3). It
should be noted that PTHQ can be formed smoothly even under
ambient-pressure H2, though with a lower yield (78%, entry 4).
Changing the Pd loading from 1.6 wt% to 0.8 wt%, the yield of
PTHQ decreased from 86% to 54% (entry 5). Hence, the
optimized reaction conditions are (1) 5 h at 80 °C catalyzed by
1.6 wt% Pd/UiO-66(HCl) in air for the Claisen–Schmidt
condensation, and then (2) 80 °C under 6.9 bar H2 for 19 h in
the reductive cyclization step. The above-described procedure
permits the production of PTHQ from simple and readily
available precursors under relatively mild reaction conditions.
Fig.
6 The Claisen–Schmidt condensation reaction catalyzed by
different MOFs. Reaction conditions: NBA (0.2 mmol), ACP (0.4 mmol),
MOF (with 18 mol% of metal), toluene (1 mL), 80 °C.
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Table 1 Pd/UiO-66(HCl) catalyzed tandem reaction for the synthesis of PTHQa
Yield (%)b
PTHQ
Entry
H2 (bar)
Time (h)
PQ
1
27.6
27.6
6.9
1
8
8
19
19
19
90
63
86
78
54
<1
7
2
5
7
2c
3
4
5d
6.9
a
Reaction conditions: (1) NBA (0.2 mmol), ACP (0.4 mmol), 1.6 wt% Pd/UiO-66(HCl) (10 mg), toluene (1 mL), 80 °C, 5 h; (2) 80 °C with H2
b
c
d
under different pressures. Yields were calculated by GC analysis with mesitylene as the internal standard. 40 °C. 0.8 wt% Pd/UiO-66(HCl)
as the catalyst.
No work-up or separation of intermediates is needed, and water
is formed as the only innocuous by-product.
With the optimized reaction conditions in hand, we further
explored the substrate scope of the Pd/UiO-66(HCl) catalyzed
synthesis of PTHQs from NBAs and ACPs bearing different
substituents (Table 2). The reaction went smoothly with both
electron-donating (R1
= 4-OCH3, entry 2) and electron-
withdrawing (R1 = 4-NO2, 4-F, entries 3–4) substituents on
acetophenone. However, the nitro group was reduced to amine
under the standard reaction conditions as expected when
4-nitroacetophenone (entry 3) was used as the substrate.
Electron-withdrawing substituents (R2 = 5-F, 4-F, and 4-Cl,
Table 2 Substrate scope of the Pd/UiO-66(HCl) catalyzed synthesis of PTHQsa
Entry
1
Ketone
ACP
Aldehyde
NBA
Product
Yield (%)b
71
2
3
4
5
6
NBA
NBA
NBA
60
74
57
69
ACP
ACP
ACP
ACP
89
64
62
7
c
8
a
Reaction conditions: (1) NBA (0.2 mmol), ACP (0.4 mmol), 1.6 wt% Pd/UiO-66(HCl) (10 mg), toluene (1 mL), 80 °C, 5 h; (2) 6.9 bar H2, 80 °C,
19 h. Yields of isolated products. c 1.6 wt% Pd/UiO-66(HCl) (20 mg); step (1): 80 °C, 10 h and step (2): H2 (27.6 bar), 80 °C, 38 h.
b
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Table 3 The size-selective Claisen–Schmidt condensation of NBA and
spectroscopy, clearly demonstrate that a complex tandem
chemical transformation could be enabled by catalyst design.
This protocol provides a simple and convenient approach for
the selective preparation of diverse PTHQs as shown in the
substrate-scope study, avoiding tedious separation and
purification processes of the reaction intermediates. This
reaction mechanism study provides valuable references and
guides us to design better multifunctional catalysts for
preparing valuable bioactive cyclic compounds.
different ketones catalyzed by Pd/UiO-66(HCl)a
Entry
1
Ketone
ACP
Conversion (%)b
85
2
38
Conflicts of interest
3
6
There are no conflicts to declare.
a
Acknowledgements
Reaction conditions: NBA (0.2 mmol), ketone (2.0 equiv), 1.6 wt%
b
Pd/UiO-66(HCl) (10 mg), toluene (1 mL), 80 °C, 5 h. Conversion of
J. C., Z. B., Q. Y., Q. R., and Z. Z. are grateful for financial
support from the National Key R&D Program of China
(2016YFA0202900), the National Natural Science Foundation
of China (21878266 and 22078288) and the China
Postdoctoral Science Foundation (2020M680077). L. Q. and T.
K. are supported by the U.S. Department of Energy (DOE),
Office of Basic Energy Sciences, Division of Chemical
Sciences, Geosciences, and Biosciences. The Ames Laboratory
is operated for the U.S. DOE by Iowa State University under
Contract No. DE-AC02-07CH11358. B. Z., M. C., and W. H.
appreciate the support from the National Science Foundation
(NSF) grant CHE-1566445 and from the Iowa State University.
NBA determined by GC with mesitylene as the internal standard.
entries 5–7) on NBAs have a minor effect on the yield of PTHQs,
but the electron-donating group (R2 = 4,5-(OCH2O), entry 8)
reduced the reactivity of NBA and higher H2 pressure and longer
reaction time are needed to improve the product yield.
A final set of experiments was conducted to investigate the
impact of substrate size on the Pd/UiO-66(HCl) catalyzed
Claisen–Schmidt condensation. Ketones with different kinetic
diameters,
acetophenone,
1-acetonaphthone,
and
9-acetylanthracene, were employed for this investigation.
As shown in Table 3, the conversion of NBA reacted with
different ACPs was in the following order: acetophenone >
1-acetonaphthone> 9-acetylanthracene, indicating that Pd/
UiO-66(HCl) is size-selective in catalysis. The observation of
drastically different activities also provides evidence that the
Claisen–Schmidt condensation reaction occurs in the pores
of Pd/UiO-66(HCl) rather than on the external surface or by
the leached catalytic species. The effect of size selectivity was
also observed in the reductive cyclization reaction catalyzed
by Pd/UiO-66(HCl) (Fig. S14†).
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