An efficient synthesis of aryl-substituted pyrroles by the Suzuki–Miyaura coupling reaction of SEM-protected pyrroles

Article abstract of DOI:10.3390/molecules24081594

An efficient arylation of SEM-protected pyrroles by the Suzuki–Miyaura coupling reaction has been developed. The reaction can be carried out under mild conditions to provide aryl-substituted pyrroles in moderate to excellent yields. The scope and limitations of the methodology were evaluated, and the reaction was tolerant of a wide range of functionalities. Compared to the reported methods, the protocol has some advantages, such as commercially available materials, no debrominated by-products being formed, and the amine-protecting group being stable under the reaction conditions. The synthetic utility of the product has also been demonstrated, with several common transformations of the aryl-substituted pyrrole product being conducted. This protocol will offer the opportunity to explore other metal-catalyzed cross-coupling reactions employing SEM-protected pyrroles.

Full text of DOI:10.3390/molecules24081594

molecules
Article
An Efficient Synthesis of Aryl-Substituted Pyrroles
by the Suzuki–Miyaura Coupling Reaction of
SEM-Protected Pyrroles
Keli Cui 1, Meng Gao 2, Hongyi Zhao 2, Dongfeng Zhang 2,
* *
, Hong Yan 1,
and Haihong Huang 2,
*
1
College of Life Science and Bio-engineering, Beijing University of Technology, 100 Ping Le Yuan,
Chaoyang District, Beijing 100124, China; ckl0615@163.com
State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Beijing Key Laboratory of
Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union
Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, China;
gaomengss@imm.ac.cn (M.G.); zhaohongyicool@imm.ac.cn (H.Z.)
2
*
Correspondence: zdf@imm.ac.cn (D.Z.); hongyan@bjut.edu.cn (H.Y.); joyce@imm.ac.cn (H.H.)
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 19 March 2019; Accepted: 20 April 2019; Published: 22 April 2019
Abstract: An efficient arylation of SEM-protected pyrroles by the Suzuki–Miyaura coupling reaction
has been developed. The reaction can be carried out under mild conditions to provide aryl-substituted
pyrroles in moderate to excellent yields. The scope and limitations of the methodology were evaluated,
and the reaction was tolerant of a wide range of functionalities. Compared to the reported methods,
the protocol has some advantages, such as commercially available materials, no debrominated
by-products being formed, and the amine-protecting group being stable under the reaction conditions.
The synthetic utility of the product has also been demonstrated, with several common transformations
of the aryl-substituted pyrrole product being conducted. This protocol will offer the opportunity to
explore other metal-catalyzed cross-coupling reactions employing SEM-protected pyrroles.
Keywords: aryl-substituted pyrroles; Suzuki–Miyaura coupling reaction; SEM-protected pyrroles
1. Introduction
Aryl-substituted pyrroles are an important structural motif in both pharmaceuticals and natural
products alike, and display a wide range of interesting biological activities [
an ester functional group are commonly used in organic synthesis and medicinal chemistry as
synthetic intermediates [ ]. There are a great deal of methods for the preparation of aryl-substituted
pyrroles with this pendant ester group, and generally, the pyrrole core is formed from functionalized
precursors with complex structures employing various catalysts and ligands [ 14]. As our aim
1]. Aryl pyrroles bearing
2–6
7
–
was to construct a small library of aryl-substituted pyrroles for biological activity assays, we found
that it was inefficient to build these required pyrrole structures from some non-commercial starting
materials. If the aryl-substituted pyrroles could be synthesized from commercially available pyrrole
compounds, the approach will be simple, straightforward, and efficient. The coupling reaction is a
powerful method in the formation of C(sp2)–C(sp2) bonds, and the aryl-substituted pyrroles could be
synthesized by the Stille–Migita cross-coupling reaction [15,16], decarboxylative coupling reaction [16,
17], metal-catalyzed desulfitative coupling reaction [18], and Suzuki–Miyaura coupling reaction [16].
Considering the availability of materials and the operability of the reaction, the Suzuki–Miyaura
coupling reaction may be the most suitable method to prepare aryl pyrroles from arylboronic acids
and bromopyrroles. However, without protection of the nitrogen of the pyrrole moiety, debromination
readily occurs, and the debrominated compounds are generally obtained in a large percentage [19,20].
Molecules 2019, 24, 1594; doi:10.3390/molecules24081594
www.mdpi.com/journal/molecules

Molecules 2019, 24, 1594
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A t-butyloxy carbonyl (BOC) group is the traditional choice for an amine-protecting group; however,
it is well known that these groups are often unstable under general Suzuki–Miyaura coupling reaction
conditions [3,19,21]. Therefore, the development of a high-throughput synthesis of aryl-substituted
pyrroles with protection for subsequent application via a Suzuki–Miyaura coupling reaction is highly
desirable. SEM (2-(trimethylsilyl)ethoxymethyl) represents a versatile and robust protecting group for
nitrogen heterocycles that can readily be removed under a variety of deprotection conditions [22–27].
Herein, we present a method that allows for the efficient arylation of SEM-protected pyrroles via the
Suzuki–Miyaura coupling reaction. This methodology provides the desired products in high yields for
a wide range of substrates.
2. Results and Discussion
Initially, phenylboronic acid (1a) and 4-bromopyrrole (2a) were chosen as the model substrates
for the Suzuki–Miyaura coupling reaction. In the presence of Pd(PPh3)4 (0.1 equiv.) and Na2CO3
(2 equiv.), the reaction between 1a and 2a in dioxane/H2O (4:1) at 90 ◦C afforded the desired coupling
product (3a) in 61% yield (Table 1, entry 1). However, the use of Pd(II) salts, such as Pd(PPh3)2Cl2,
Pd(AcO)2, and Pd(dppf)Cl2 as the catalysts reduced the yield of the product (Table 1, entries 2–4).
Although the temperature was increased to 110 ◦C, almost no desired product was gained in DMF
(N,N-dimethyl formamide) (Table 1, entry 5). We observed that the main by-product of the reaction was
the homocoupling of the arylboronic acid. Therefore, we increased the amount of 1a to two equivalents;
however, the product 3a was obtained in almost the same yield (Table 1, entry 6 versus entry 1).
Moreover, increasing the amount of Na2CO3 (6 equiv.) did not lead to a discernible effect on the yield
(Table 1, entry 7 versus entry 1). We further optimized the reaction conditions by reducing the amount
of H2O, but the product was obtained in only 5% yield (Table 1, entry 8). For further improvement of
the reaction, other bases such as K2CO3, KF, and Cs2CO3 were also examined (Table 1, entries 9–11).
To our delight, the product was obtained in 85% yield with Cs2CO3 as the base. Furthermore, we
observed that an increase or reduction of the reaction temperature were both unfavorable for the
transformation (Table 1, entries 12 and 13). When the amount of Pd(PPh3)4 was reduced to 5 mol%,
the product 3a was obtained in a slightly lower yield (Table 1, entry 14). From the above-mentioned
results, it was concluded that the optimized conditions for this Suzuki–Miyaura coupling reaction
protocol were 10 mol% Pd(PPh3)4, Cs2CO3 (2 equiv.) in dioxane/H2O (4:1) at 90 ◦C (Table 1, entry 11);
especially, we have observed no dehalogenation in the reaction. To assess the effect of SEM-protected
and BOC-protected pyrroles, BOC-protected pyrrole (2a’) was selected as the substrate. The reaction
gave the product 3a in good yield, but the deprotected by-product (4a) was obtained in 5% yield
(Table 1, entry 15). The result was confirmed with the assay conducted using Na2CO3 as the base,
which led to 4a in 11% yield (Table 1, entry 16). In conclusion, the SEM-protecting group was stable
under the optimal reaction conditions compared to the BOC protecting group, and a cross-coupling
product was obtained in very good yield.
Table 1. Screening reaction conditions of Suzuki coupling a.
Yield (%) b
T
Base
(equiv.)
Time
(h)
Entry
Catalyst
R
Solvent
(◦C)
3a (3a0)
4a
1
2
3
SEM
SEM
SEM
Pd(PPh3)4
Pd(PPh3)2Cl2
Pd(AcO)2
90
90
90
Na2CO3 (2)
Na2CO3 (2)
Na2CO3 (2)
Dioxane/H2O (4:1)
Dioxane/H2O (4:1)
Dioxane/H2O (4:1)
1
1
6
61
45
13
0
0
0

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Table 1. Cont.
Yield (%) b
3a (3a0)
4a
T
Base
(equiv.)
Time
(h)
Entry
R
Catalyst
Solvent
(◦C)
4
5
SEM
SEM
SEM
SEM
SEM
SEM
SEM
SEM
SEM
SEM
SEM
BOC
BOC
Pd(dppf)Cl2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
90
110
90
90
90
90
90
90
110
60
90
90
90
Na2CO3 (2)
Na2CO3 (2)
Na2CO3 (2)
Na2CO3 (6)
Na2CO3 (2)
K2CO3 (2)
KF (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Na2CO3 (2)
Dioxane/H2O (4:1)
DMF
6
6
1
1
6
5
6
5
3
5
2
2
2
28
trace
57
57
5
45
32
85
75
53
78
76
64
0
0
0
0
0
0
0
0
0
0
0
5
11
6 c
7 c
8
Dioxane/H2O (4:1)
Dioxane/H2O (4:1)
Dioxane/H2O (4:0.1)
Dioxane/H2O (4:1)
Dioxane/H2O (4:1)
Dioxane/H2O (4:1)
Dioxane/H2O (4:1)
Dioxane/H2O (4:1)
Dioxane/H2O (4:1)
Dioxane/H2O (4:1)
Dioxane/H2O (4:1)
9
10
11
12
13
14 d
15
16
a
General conditions: 1a (1.5 mmol), 2a (1 mmol), catalyst (10 mol %), and base in 10 mL of the indicated solvent
b
c
d
under Ar2 atmosphere. Isolated yield. The equivalent ratio of 1a:2a = 2:1. 5 mol% Pd(PPh3)4.
With these conditions in hand, we next evaluated the substrate scope of the reaction (Scheme 1).
Overall, it was found that all the attempted phenylboronic acid analogues produced the desired
aryl-substituted pyrroles in moderate to excellent yields. To evaluate the effect of boronic acid
substituents, we first studied the reaction of the substrate bearing the electron-withdrawing groups
such as Cl, F, NO2, and CF3 (3b−i). When phenylboronic acid with Cl and F substituents were used in
the ortho position, the target compounds (3c and 3f) were isolated in 93% and 77% yield, respectively.
In contrast, para substitution resulted in a decreased yield (3b and 3e). The same behavior was
observed with the 2,4-dichloro or 2,4-difluro phenylboronic acid (3d and 3g). The presence of the
strong electron-withdrawing NO2 and CF3 groups on the phenylboronic acid did not drastically affect
the efficiency of the reaction (3h and 3i).
Then, we focused our attention on the reactivity of the phenylboronic acid with the
electron-donating groups. When the phenylboronic acid was substituted with an OMe group at the C-4
position, the reaction gave the product 3j in 77% yield, while the OMe in the ortho position afforded the
desired product in 87% yield (3k). The results displayed that this reaction followed the same behavior
as the cross-coupling reaction compared to 2-fluorophenylboronic acid and 2-chlorophenylboronic
acid as the substrate. Nevertheless, the Me group in the ortho position of phenylboronic acid lowered
the efficiency of the reaction (3l versus 3m). The reaction with the fused aromatic compounds gave
the corresponding products in good yields as well (3n and 3o). Notably, the reaction can also be
carried out successfully with the heterocyclic substrates to furnish the desired products (3p and 3q).
Finally, 5-bromopyrrole and 3-bromopyrrole (2b and 2c) were chosen as the substrates to document
the potential of the method. The reactions worked very smoothly, giving the corresponding products
in excellent yields (3r and 3s).
To further explore this synthetic potential, several common transformations of the product 3a were
conducted (Scheme 2). First, the SEM-protecting group was removed smoothly in the presence of TBAF
(tetrabutyl ammonium fluoride) to provide the N-H-4-phenyl pyrrole 4a in 83% yield. Hydrolysis
and reduction reactions readily occurred, leading to the fascinating pyrrole-2-carboxylic acid 4b and
2-hydroxymethyl substituted pyrrole compound 4c in good yields, respectively. No SEM deprotection
of pyrrole was observed in the aforementioned hydrolysis and reduction reactions as anticipated.

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Scheme 1. Scope of the Suzuki coupling reaction. Yields refer to the isolated yields.
Scheme 2. The application of SEM-protected pyrroles. Yields refer to the isolated yields.
3. Materials and Methods
3.1. General Methods
All the starting materials were obtained from commercial suppliers and were used without
further purification unless stated otherwise. Reactions were monitored by Thin Layer Chromatography
(silica gel GF254). Products were purified by column chromatography on silica gel (300–400 mesh).
1H and 13
C
spectra were recorded on a Varian (Palo Alto, CA, USA) 400 NMR or 500 NMR spectrometer
using DMSO-d6 as a solvent and tetramethylsilane (TMS) as an internal standard. Chemical shifts

Molecules 2019, 24, 1594
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(δ) are reported in parts per million (ppm), and coupling constants (J) are reported in Hertz (Hz).
Data are represented as follows: chemical shift, multiplicity (br = broad, s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet), coupling constants in Hertz (Hz), and integration. All the
melting points were measured with a microscope melting point apparatus (MP-J3, Yanaco, Kyoto,
Japan) and were uncorrected. High-resolution mass spectra were determined on ThermoExactive
Orbitrap plus mass spectrometer (Waltham, MA, USA). 1H-NMR and HRMS spectra are available in
Supplementary Materials.
3.2. Typical Procedure to Synthesize Compounds 2a–c
First, t-BuOK (330 mg, 2.94 mmol) was added to a solution of bromopyrroles (500 mg, 2.45 mmol)
in anhydrous DMF (5 mL) in an ice-bath, and the mixture was stirred for 0.5 h. SEM-Cl (449 mg,
2.7 mmol) was added to the resulting mixture. The reaction mixture was stirred at rt for 2 h, and then
quenched with H2O. The mixture was extracted with EtOAc (15 mL
layer was washed with sat. NaHCO3 and brine, dried with Na2SO4, and concentrated. The product
×
3), and the combined organic
was obtained by flash chromatography (EtOAc in PE = 3%).
Methyl 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (2a). Colorless oil, 71% yield.
1H-NMR (400 MHz, DMSO-d6)
δ
: 7.50 (d, J = 2.0 Hz, 1H, Pyrrole-5H), 6.94 (d, J = 2.0 Hz, 1H, Pyrrole-3H),
5.58 (s, 2H, NCH2O), 3.74 (s, 3H, CH3), 3.46 (t, J = 8.0 Hz, 2H, OCH2CH2Si), 0.79 (t, J = 8.0 Hz, 2H,
OCH2CH2Si),
0.07 (s, 9H, Si(CH3)3). HRMS (ESI): m/z [M + H]+ calcd for C12H21BrNO3Si: 334.0469;
found: 334.0448.
−
Methyl 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (2b). Colorless oil, 96% yield.
1H-NMR (400 MHz, DMSO-d6)
: 6.99 (d, J = 4.0 Hz, 1H, Pyrrole-3H), 6.40 (d, J = 4.0 Hz, 1H, Pyrrole-4H),
5.71 (s, 2H, NCH2O), 3.75 (s, 3H, CH3), 3.51 (t, J = 8.0 Hz, 2H, OCH2CH2Si), 0.80 (t, J = 8.0 Hz, 2H,
OCH2CH2Si),
0.07 (s, 9H, Si(CH3)3). HRMS (ESI): m/z [M + H]+ calcd for C12H21BrNO3Si: 334.0469;
found: 334.0463.
δ
−
Methyl 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (2c). Colorless oil, 81% yield.
1H-NMR (500 MHz, DMSO-d6)
: 7.33 (d, J = 2.5 Hz, 1H, Pyrrole-5H), 6.35 (d, J = 2.5 Hz, 1H, Pyrrole-4H),
5.57 (s, 2H, NCH2O), 3.78 (s, 3H, CH3), 3.41 (t, J = 7.5 Hz, 2H, OCH2CH2Si), 0.78 (t, J = 7.5 Hz, 2H,
OCH2CH2Si),
0.08 (s, 9H, Si(CH3)3). HRMS (ESI): m/z [M + H]+ calcd for C12H21BrNO3Si: 334.0469;
found: 334.0460.
δ
−
3.3. Typical Procedure to Synthesize Products 3a–s
Dioxane (8 mL) and H2O (2 mL) were added to the mixture of 1a–q (1.5 mmol), 2a–c (1 mmol),
Cs2CO3 (652 mg, 2 mmol), and Pd(PPh3)4 (116 mg, 0.1 mmol) under Ar2 atmosphere. The reaction
mixture was stirred at 90 ◦C for about 5 h (monitored by Thin Layer Chromatography) and cooled to rt.
Then, the mixture was filtered to remove the solids, and the filtrate was concentrated. Purification by
flash chromatography (EtOAc in PE = 3%) gave the desired product.
Methyl 4-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (3a). Colorless oil, 85% yield.
1H-NMR (400 MHz, DMSO-d6)
δ
: 7.80 (d, J = 1.2 Hz, 1H, Pyrrole-5H), 7.61 (d, J = 8.0 Hz, 2H, Ar-2,6H),
7.36–7.32 (m, 3H, Ar-3,5H, Pyrrole-3H), 7.19 (t, J = 8.0 Hz, 1H, Ar-4H), 5.64 (s, 2H, NCH2O), 3.77 (s, 3H,
CH3), 3.50 (t, J = 7.6 Hz, 2H, OCH2CH2Si), 0.82 (t, J = 7.6 Hz, 2H, OCH2CH2Si), 0.07 (s, 9H, Si(CH3)3).
−
13C-NMR (100 MHz, DMSO-d6)
δ: 161.0, 134.2, 129.2, 127.4, 126.6, 125.2, 123.9, 122.7, 116.1, 76.9, 65.6,
51.6, 17.6, −1.0. HRMS (ESI): m/z [M + H]+ calcd for C18H26NO3Si: 332.1677; found: 332.1662.
Methyl 4-(4-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (3b). Colorless oil,
1
66% yield. H-NMR (500 MHz, DMSO-d6)
δ: 7.84 (s, 1H, Pyrrole-5H), 7.65 (d, J = 8.5 Hz, 2H, Ar-2,6H),
7.39 (d, J = 8.5 Hz, 2H, Ar-3,5H), 7.35 (s, 1H, Pyrrole-3H), 5.64 (s, 2H, NCH2O), 3.77 (s, 3H, CH3), 3.50
(t, J = 8.0 Hz, 2H, OCH2CH2Si), 0.82 (t, J = 8.0 Hz, 2H, OCH2CH2Si),
−
0.07 (s, 9H, Si(CH3)3). 13C-NMR

Molecules 2019, 24, 1594
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(100 MHz, DMSO-d6)
δ
: 160.9, 133.2, 130.9, 129.2, 127.7, 126.9, 122.9, 122.6, 116.2, 76.9, 65.6, 51.7, 17.5,
−1.0. HRMS (ESI): m/z [M + H]+ calcd for C18H25ClNO3Si: 366.1287; found: 366.1271.
Methyl 4-(2-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (3c). Colorless oil,
1
93% yield. H-NMR (500 MHz, DMSO-d6)
δ
: 7.75 (s, 1H, Pyrrole-5H), 7.56 (d, J = 7.5 Hz, 1H, Ar-3H),
7.50 (d, J = 7.5 Hz, 1H, Ar-6H), 7.36 (t, J = 7.0 Hz, 1H, Ar-5H), 7.29–7.27 (m, 2H, Ar-4H, Pyrrole-3H),
5.68 (s, 2H, NCH2O), 3.77 (s, 3H, CH3), 3.52 (t, J = 7.5 Hz, 2H, OCH2CH2Si), 0.82 (t, J = 7.5 Hz, 2H,
OCH2CH2Si),
−
0.07 (s, 9H, Si(CH3)3). 13C-NMR (100 MHz, DMSO-d6)
δ
: 160.9, 133.0, 131.1, 130.7,
130.0, 128.5, 128.0, 121.9, 120.8, 119.1, 77.0, 65.6, 51.7, 17.6,
C18H25ClNO3Si: 366.1287; found: 366.1274.
−
1.0. HRMS (ESI): m/z [M + H]+ calcd for
Methyl 4-(2,4-dichlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (3d). Colorless
1
oil, 67% yield. H-NMR (500 MHz, DMSO-d6)
δ 7.78 (d, J = 1.5 Hz, 1H, Pyrrole-5H), 7.65 (d, J = 1.5 Hz,
1H, Ar-3H), 7.60 (d, J = 8.5 Hz, 1H, Ar-6H), 7.43 (dd, J = 8.0, 1.5 Hz, 1H, Ar-5H), 7.28 (d, J = 1.5 Hz, 1H,
Pyrrole-3H), 5.68 (s, 2H, NCH2O), 3.78 (s, 3H, CH3), 3.52 (t, J = 8.0 Hz, 2H, OCH2CH2Si), 0.82 (t, J = 8.0
Hz, 2H, OCH2CH2Si),
131.8, 130.1, 130.0, 128.1, 122.0, 119.7, 119.0, 77.0, 65.6, 51.7, 17.6,
for C18H24Cl2NO3Si: 400.0897; found: 400.0892.
−
0.07 (s, 9H, Si(CH3)3). 13C-NMR (100 MHz, DMSO-d6)
δ
: 160.8, 132.0, 131.9,
−
1.0. HRMS (ESI): m/z [M + H]+ calcd
Methyl 4-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (3e). Colorless oil,
1
70% yield. H-NMR (400 MHz, DMSO-d6)
δ
: 7.77 (d, J = 2.0 Hz, 1H, Pyrrole-5H), 7.66–7.63 (m, 2H,
Ar-2,6H), 7.31 (d, J = 2.0 Hz, 1H, Pyrrole-3H), 7.17 (t, J = 8.8 Hz, 2H, Ar-3,5H), 5.63 (s, 2H, NCH2O),
3.77 (s, 3H, CH3), 3.50 (t, J = 8.0 Hz, 2H, OCH2CH2Si), 0.81 (t, J = 8.0 Hz, 2H, OCH2CH2Si), 0.08 (s,
9H, Si(CH3)3). 13C-NMR (100 MHz, DMSO-d6)
: 161.2 (d, J = 241.1 Hz), 160.9, 130.8 (d, J = 2.9 Hz),
−
δ
127.3, 127.1 (d, J = 7.8 Hz), 122.8 (d, J = 23.6 Hz), 116.1, 116.0, 115.9, 76.9, 65.6, 51.6, 17.6,
−
1.0. HRMS
(ESI): m/z [M + H]+ calcd for C18H25FNO3Si: 350.1582; found: 350.1565.
Methyl 4-(2-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (3f). Colorless oil,
77% yield. 1H-NMR (500 MHz, DMSO-d6)
: 7.76–7.72 (m, 2H, Pyrrole-5H, Ar-6H), 7.36 (s, 1H,
Pyrrole-3H), 7.26–7.21 (m, 3H, Ar-3,4,5H), 5.68 (s, 2H, NCH2O), 3.78 (s, 3H, CH3), 3.51 (t, J = 7.5 Hz,
2H, OCH2CH2Si), 0.81 (t, J = 7.5 Hz, 2H, OCH2CH2Si),
0.07 (s, 9H, Si(CH3)3). 13C-NMR (100 MHz,
DMSO-d6) : 160.9, 159.3 (d, J = 244.4 Hz), 129.3 (d, J = 8.6 Hz), 128.3 (d, J = 4.2 Hz), 128.2 (d, J = 8.4
δ
−
δ
Hz), 125.2 (d, J = 3.1 Hz), 122.4, 121.8 (d, J = 12.8 Hz), 117.5, 117.4, 116.5 (d, J = 22.1 Hz), 76.9, 65.6, 51.7,
17.5, −1.0. HRMS (ESI): m/z [M + H]+ calcd for C18H25FNO3Si: 350.1582; found: 350.1572.
Methyl 4-(2,4-difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (3g). Colorless
1
oil, 70% yield. H-NMR (500 MHz, DMSO-d6)
δ: 7.78 (dd, J = 16.0, 9.0 Hz, 1H, Ar-3H), 7.74 (s, 1H,
Pyrrole-5H), 7.34 (s, 1H, Pyrrole-3H), 7.28 (t, J = 9.5 Hz, 1H, Ar-6H), 7.10 (t, J = 8.5 Hz, 1H, Ar-5H),
5.68 (s, 2H, NCH2O), 3.79 (s, 3H, CH3), 3.51 (t, J = 8.0 Hz, 2H, OCH2CH2Si), 0.82 (t, J = 8.0 Hz, 2H,
OCH2CH2Si), δ: 161.1 (dd, J = 244.0, 12.2 Hz),
0.07 (s, 9H, Si(CH3)3). 13C-NMR (100 MHz, DMSO-d6)
−
160.8, 159.3 (dd, J = 247.3, 11.9 Hz), 129.4 (dd, J = 9.3, 5.9 Hz), 129.0 (d, J = 8.5 Hz), 122.4, 118.5 (dd, J =
13.0, 3.6 Hz), 117.3 (d, J = 3.5 Hz), 116.8, 112.3 (dd, J = 21.0, 3.2 Hz), 104.8 (t, J = 26.1 Hz), 76.9, 65.6, 51.6,
17.5, −1.1. HRMS (ESI): m/z [M + H]+ calcd for C18H24F2NO3Si: 368.1488; found: 368.1480.
Methyl 4-(4-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (3h). Yellow solid,
62% yield. M.p. 82–83 ◦C. 1H-NMR (400 MHz, DMSO-d6)
δ: 8.20 (d, J = 8.4 Hz, 2H, Ar-3,5H), 8.08
(d, J = 1.6 Hz, 1H, Pyrrole-5H), 7.91 (d, J = 8.4 Hz, 2H, Ar-2,6H), 7.51 (d, J = 2.0 Hz, 1H, Pyrrole-3H),
5.66 (s, 2H, NCH2O), 3.79 (s, 3H, CH3), 3.52 (t, J = 8.0 Hz, 2H, OCH2CH2Si), 0.83 (t, J = 8.0 Hz, 2H,
OCH2CH2Si),
124.7, 123.5, 121.8, 116.8, 77.2, 65.8, 51.8, 17.5,
377.1527; found: 377.1545.
−
0.07 (s, 9H, Si(CH3)3). 13C-NMR (100 MHz, DMSO-d6)
δ
: 160.8, 145.7, 141.3, 129.4, 125.8,
−
1.0. HRMS (ESI): m/z [M + H]+ calcd for C18H25N2O5Si:
Methyl 4-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (3i).
Colorless oil, 68% yield. 1H-NMR (500 MHz, DMSO-d6)
: 7.95 (s, 1H, Pyrrole-5H), 7.83 (d, J =
δ

Molecules 2019, 24, 1594
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5.0 Hz, 2H, Ar-3,5H), 7.67 (brs, 2H, Ar-2, 6H), 7.43 (s, 1H, Pyrrole-3H), 5.65 (s, 2H, NCH2O), 3.78 (s,
3H, CH3), 3.51 (t, J = 7.5 Hz, 2H, OCH2CH2Si), 0.82 (t, J = 7.5 Hz, 2H, OCH2CH2Si), 0.08 (s, 9H,
Si(CH3)3). 13C-NMR (100 MHz, DMSO-d6)
: 160.9, 138.4, 128.5, 126.9, 126.1 (q, J = 3.7 Hz), 125.6, 125.1
−
δ
(q, J = 236.0 Hz), 123.2, 122.3, 116.5, 77.1, 65.7, 51.7, 17.5,
1.0. HRMS (ESI): m/z [M + H]+ calcd for
−
C19H25F3NO3Si: 400.1550; found: 400.1567.
Methyl 4-(4-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (3j). Colorless oil,
1
77% yield. H-NMR (400 MHz, DMSO-d6)
δ: 7.68 (d, J = 1.6 Hz, 1H, Pyrrole-5H), 7.53 (d, J = 8.8 Hz,
2H, Ar-2,6H), 7.25 (d, J = 2.0 Hz, 1H, Pyrrole-3H), 6.92 (d, J = 8.8 Hz, 2H, Ar-3,5H), 5.63 (s, 2H, NCH2O),
3.76 (s, 3H, CH3), 3.75 (s, 3H, CH3), 3.50 (t, J = 8.0 Hz, 2H, OCH2CH2Si), 0.81 (t, J = 8.0 Hz, 2H,
OCH2CH2Si),
−
0.07 (s, 9H, Si(CH3)3). 13C-NMR (100 MHz, DMSO-d6)
δ
: 161.0, 158.3, 126.8, 126.6,
126.4, 123.8, 122.5, 115.8, 114.6, 76.8, 65.5, 55.5, 51.5, 17.6,
C19H28NO4Si: 362.1782; found: 362.1792.
−
1.0. HRMS (ESI): m/z [M + H]+ calcd for
Methyl 4-(2-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (3k). Colorless
1
oil, 87% yield. H-NMR (400 MHz, DMSO-d6)
δ: 7.76 (d, J = 2.0 Hz, 1H, Pyrrole-5H), 7.59 (dd, J = 8.0,
2.0 Hz, 1H, Ar-6H), 7.37 (d, J = 2.0 Hz, 1H, Pyrrole-3H), 7.20 (td, J = 7.6, 1.6 Hz, 1H, Ar-4H), 7.05 (d, J =
7.6 Hz, 1H, Ar-3H), 6.95 (td, J = 7.6, 1.2 Hz, 1H, Ar-5H), 5.67 (s, 2H, NCH2O), 3.86 (s, 3H, CH3), 3.77
(s, 3H, CH3), 3.51 (t, J = 7.6 Hz, 2H, OCH2CH2Si), 0.82 (t, J = 7.6 Hz, 2H, OCH2CH2Si),
Si(CH3)3). 13C-NMR (100 MHz, DMSO-d6)
: 161.1, 156.3, 129.9, 127.7, 122.6, 121.6, 121.2, 120.0, 118.0,
1.0. HRMS (ESI): m/z [M + H]+ calcd for C19H28NO4Si: 362.1782;
−
0.06 (s, 9H,
δ
112.1, 76.7, 65.4, 55.8, 51.5, 17.6,
found: 362.1784.
−
Methyl 4-(p-tolyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (3l). Colorless oil, 73%
1
yield. H-NMR (400 MHz, DMSO-d6)
δ: 7.74 (d, J = 2.0 Hz, 1H, Pyrrole-5H), 7.49 (d, J = 8.0 Hz, 2H,
Ar-2,6H), 7.28 (d, J = 2.0 Hz, 1H, Pyrrole-3H), 7.16 (d, J = 8.0 Hz, 2H, Ar-3,5H), 5.63 (s, 2H, NCH2O),
3.76 (s, 3H, CH3), 3.50 (t, J = 8.0 Hz, 2H, OCH2CH2Si), 2.29 (s, 3H, CH3), 0.81 (t, J = 8.0 Hz, 2H,
OCH2CH2Si),
−
0.07 (s, 9H, Si(CH3)3). 13C-NMR (100 MHz, DMSO-d6)
δ
: 161.0, 135.7, 131.4, 129.8,
127.1, 125.1, 123.9, 122.6, 116.0, 76.8, 65.5, 51.6, 21.1, 17.6,
C19H28NO3Si: 346.1833; found: 346.1839.
−
1.0. HRMS (ESI): m/z [M + H]+ calcd for
Methyl 4-(o-tolyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (3m). Colorless oil, 52%
1
yield. H-NMR (400 MHz, DMSO-d6)
δ
: 7.52 (d, J = 2.0 Hz, 1H, Pyrrole-5H), 7.32 (dd, J = 7.6, 2.0 Hz,
1H, Ar-6H), 7.25–7.16 (m, 3H, Ar-3,4,5H), 7.09 (d, J = 2.0 Hz, 1H, Pyrrole-3H), 5.66 (s, 2H, NCH2O), 3.76
(s, 3H, CH3), 3.51 (t, J = 8.0 Hz, 2H, OCH2CH2Si), 2.37 (s, 3H, CH3), 0.81 (t, J = 8.0 Hz, 2H, OCH2CH2Si),
−
0.07 (s, 9H, Si(CH3)3). 13C-NMR (100 MHz, DMSO-d6)
δ
: 161.0, 135.1, 134.2, 131.1, 129.5, 129.2,
127.0, 126.5, 123.4, 121.8, 119.1, 76.9, 65.5, 51.6, 21.5, 17.6,
C19H28NO3Si: 346.1833; found: 346.1843.
−
1.0. HRMS (ESI): m/z [M + H]+ calcd for
Methyl 4-(naphthalen-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (3n). Colorless
oil, 76% yield. 1H-NMR (400 MHz, DMSO-d6)
: 8.16 (dd, J = 7.2, 2.4 Hz, 1H, Ar-5H), 7.98–7.95
δ
(m, 1H, Ar-4H), 7.87 (d, J = 8.0 Hz, 1H, Ar-8H), 7.65 (d, J = 2.0 Hz, 1H, Pyrrole-5H), 7.54–7.46 (m,
4H, Ar-1,3,6,7H), 7.18 (d, J = 2.0 Hz, 1H, Pyrrole-3H), 5.73 (s, 2H, NCH2O), 3.79 (s, 3H, CH3), 3.57 (t,
J = 7.6 Hz, 2H, OCH2CH2Si), 0.84 (t, J = 7.6 Hz, 2H, OCH2CH2Si),
−
0.05 (s, 9H, Si(CH3)3). 13C-NMR
(100 MHz, DMSO-d6) : 161.0, 134.1, 132.8, 131.3, 129.9, 128.9, 127.5, 127.0, 126.7, 126.3, 126.2, 125.5,
δ
122.4, 122.2, 119.7, 77.0, 65.6, 51.7, 17.6,
382.1833; found: 382.1839.
−
1.0. HRMS (ESI): m/z [M + H]+ calcd for C22H28NO3Si:
Methyl 4-(quinolin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (3o). Colorless solid,
66% yield. M.p. 52–54 ◦C. 1H-NMR (400 MHz, DMSO-d6 )
: 9.21 (d, J = 2.0 Hz, 1H, Ar-2H), 8.53
δ
(d, J = 2.0 Hz, 1H, Ar-4H), 8.06 (d, J = 2.0 Hz, 1H, Pyrrole-5H), 7.94 (d, J = 8.4 Hz, 1H, Ar-8H), 7.89
(d, J = 7.2 Hz, 1H, Ar-5H), 7.65 (td, J = 7.2, 1.6 Hz, 1H, Ar-6H), 7.57–7.53 (m, 2H, Ar-7H, Pyrrole-3H),
5.65 (s, 2H, NCH2O), 3.77 (s, 3H, CH3), 3.51 (t, J = 8.0 Hz, 2H, OCH2CH2Si), 0.80 (t, J = 8.0 Hz, 2H,
OCH2CH2Si), δ: 160.9, 149.0, 146.7, 130.1, 129.2,
0.1 (s, 9H, Si(CH3)3). 13C-NMR (100 MHz, DMSO-d6)
−

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129.1, 128.4, 128.3, 128.2, 127.5, 127.4, 123.2, 120.8, 116.5, 77.1, 65.7, 51.8, 17.6,
+ H]+ calcd for C21H27N2O3Si: 383.1786; found: 383.1783.
−
1.0. HRMS (ESI): m/z [M
Methyl 4-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (3p). Colorless oil,
1
41% yield. H-NMR (500 MHz, DMSO-d6)
δ: 8.88 (s, 1H, Py-2H), 8.40 (d, J = 3.5 Hz, 1H, Py-6H), 8.01
(d, J = 7.5 Hz, 1H, Py-4H), 7.93 (s, 1H, Pyrrole-5H), 7.43 (s, 1H, Pyrrole-3H), 7.36 (dd, J = 7.5, 5.0 Hz,
1H, Py-5H), 5.65 (s, 2H, NCH2O), 3.78 (s, 3H, CH3), 3.51 (t, J = 8.0 Hz, 2H, OCH2CH2Si), 0.82 (t, J = 8.0
Hz, 2H, OCH2CH2Si),
132.3, 130.0, 127.9, 124.2, 123.1, 120.6, 116.2, 77.0, 65.7, 51.7, 17.5,
for C17H25N2O3Si: 333.1629; found: 333.1622.
−
0.07 (s, 9H, Si(CH3)3). 13C-NMR (100 MHz, DMSO-d6)
δ
: 160.9, 147.6, 146.5,
−
1.0. HRMS (ESI): m/z [M + H]+ calcd
Methyl 4-(furan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (3q). Colorless oil, 45%
1
yield. H-NMR (500 MHz, DMSO-d6)
δ
: 7.61 (s, 1H, Furan-5H), 7.58 (s, 1H, Pyrrole-5H), 7.16 (s, 1H,
Furan-4H), 6.57 (d, J = 2.5 Hz, 1H, Furan-3H), 6.49 (s, 1H, Pyrrole-3H), 5.64 (s, 2H, NCH2O), 3.76 (s, 3H,
CH3), 3.49 (t, J = 8.0 Hz, 2H, OCH2CH2Si), 0.81 (t, J = 8.0 Hz, 2H, OCH2CH2Si), 0.08 (s, 9H, Si(CH3)3).
: 160.8, 149.6, 141.5, 126.1, 122.6, 115.6, 115.1, 111.9, 104.1, 76.9, 65.6,
−
13C-NMR (100 MHz, DMSO-d6)
δ
51.7, 17.5, −1.0. HRMS (ESI): m/z [M + H]+ calcd for C16H24NO4Si: 322.1469; found: 322.1483.
Methyl 5-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (3r). Colorless oil, 95% yield.
1H-NMR (500 MHz, DMSO-d6)
δ
: 7.55 (d, J = 7.5 Hz, 2H, Ar-2,6H), 7.49–7.44 (m, 3H, Ar-3,4,5H), 7.03
(d, J = 3.5 Hz, 1H, Pyrrole-3H), 6.33 (d, J = 4.0 Hz, 1H, Pyrrole-4H), 5.62 (s, 2H, NCH2O), 3.77 (s, 3H,
CH3), 3.36 (t, J = 8.0 Hz, 2H, OCH2CH2Si), 0.73 (t, J = 8.0 Hz, 2H, OCH2CH2Si), 0.10 (s, 9H, Si(CH3)3).
: 161.2, 142.5, 131.8, 129.5, 129.2, 128.8, 123.3, 119.3, 110.3, 73.4, 65.3,
−
13C-NMR (100 MHz, DMSO-d6)
δ
51.6, 17.9, −1.0. HRMS (ESI): m/z [M + H]+ calcd for C18H26NO3Si: 332.1677; found: 332.1661.
Methyl 3-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (3s). Colorless solid, 99%
yield. M.p. 87–88 ◦C. 1H-NMR (500 MHz, DMSO-d6)
δ
: 7.35–7.30 (m, 6H, Ar-2,3,4,5,6H, Pyrrole-5H),
6.24 (d, J = 2.0 Hz, 1H, Pyrrole-4H), 5.60 (s, 2H, NCH2O), 3.58 (s, 3H, CH3), 3.46 (t, J = 7.5 Hz, 2H,
OCH2CH2Si), 0.81 (t, J = 7.5 Hz, 2H, OCH2CH2Si),
0.06 (s, 9H, Si(CH3)3). 13C-NMR (100 MHz,
1.0. HRMS
−
DMSO-d6)
δ
: 161.8, 136.3, 134.2, 129.4, 129.2, 128.2, 127.1, 118.1, 110.6, 77.6, 65.5, 51.3, 17.6,
−
(ESI): m/z [M + H]+ calcd for C18H26NO3Si: 332.1677; found: 332.1663.
3.4. Procedure for the Preparation of Methyl 4-phenyl-1H-pyrrole-2-carboxylate (4a)
A mixture of 3a (500 mg, 1.5 mmol) and TBAF (3 mL, 1 mol/L THF) was stirred at 80 ◦C for 2 h
and cooled to rt. Then, the reaction mixture was diluted with EtOAc and H2O. The aqueous phase was
extracted with EtOAc, and the combined organic layer was washed with brine, dried with Na2SO4,
and concentrated. Purification by flash chromatography (EtOAc in PE = 14%) gave 4a (251 mg, 83%)
as a colorless solid. M.p. 198–200 ◦C. 1H-NMR (500 MHz, DMSO-d6)
δ: 12.07 (s, 1H, NH), 7.62 (d, J =
7.0 Hz, 2H, Ar-2,6H), 7.51 (s, 1H, Pyrrole-5H), 7.32 (t, J = 7.0 Hz, 2H, Ar-3,5H), 7.19–7.16 (m, 2H, Ar-4H,
1
Pyrrole-3H), 3.79 (s, 3H, CH3). H-NMR data was in agreement with the literature [28]. 13C-NMR (100
MHz, DMSO-d6) δ: 161.3, 135.0, 129.1, 126.2, 125.6, 125.2, 123.2, 121.7, 112.4, 51.6. HRMS (ESI): m/z [M +
H]+ calcd for C12H12NO2: 202.0863; found: 202.0856.
3.5. Procedure for the Preparation of 4-Phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylic
acid (4b)
A mixture of 3a (250 mg, 0.75 mmol) and NaOH (60 mg, 1.5 mmol) in ethanol (6 mL) and H2O
(4 mL) was stirred at 100 ◦C for 6 h. Then, the reaction mixture was concentrated to remove ethanol,
and the residue was adjusted to pH 7 with HCl (2M). The aqueous phase was extracted with EtOAc,
and the combined organic layer was washed with brine, dried with Na2SO4, and concentrated to give
4b (200 mg, 84%) as a colorless solid. M.p. 83–85 ◦C. 1H-NMR (400 MHz, DMSO-d6)
δ: 12.44 (s, 1H,
COOH), 7.72 (d, J = 1.6 Hz, 1H, Pyrrole-5H), 7.59 (d, J = 7.2 Hz, 2H, Ar-2,6H), 7.34 (t, J = 7.6 Hz, 2H,
Ar-3,5H), 7.26 (d, J = 2.0 Hz, 1H, Pyrrole-3H), 7.18 (t, J = 7.6 Hz, 1H, Ar-4H), 5.66 (s, 2H, NCH2O), 3.51

Molecules 2019, 24, 1594
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(t, J = 8.0 Hz, 2H, OCH2CH2Si), 0.82 (t, J = 8.0 Hz, 2H, OCH2CH2Si),
−
0.07 (s, 9H, Si(CH3)3). 13C-NMR
(100 MHz, DMSO-d6)
δ: 162.2, 134.4, 129.2, 126.8, 126.5, 125.1, 123.9, 123.6, 115.9, 76.7, 65.5, 17.6, 0.9.
−
HRMS (ESI): m/z [M + H]+ calcd for C17H24NO3Si: 318.1520; found: 318.1489.
3.6. Procedure for the Preparation of (4-Phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrol-2-yl)methanol (4c
)
First, LiAlH4 (35 mg, 0.94 mmol) was added to a solution of 3a (155 mg, 0.47 mmol) in anhydrous
THF (6 mL) at rt. After stirring overnight, the reaction mixture was quenched with 15% NaOH (0.11
mL) and extracted with EtOAc/H2O, and the organic layer was washed with brine, dried with Na2SO4,
and concentrated. Purification by flash chromatography (EtOAc in PE = 14%) gave 4c (127 mg, 89%)
1
as a yellow oil. H-NMR (500 MHz, DMSO-d6)
δ: 7.49 (d, J = 7.5 Hz, 2H, Ar-2,6H), 7.31–7.28 (m, 3H,
Ar-3,5H, Pyrrole-5H), 7.11 (t, J = 7.5 Hz, 1H, Ar-4H), 6.41 (s, 1H, Pyrrole-3H), 5.29 (s, 2H, NCH2O), 4.98
(brs, 1H, OH), 4.47 (d, J = 4.0 Hz, 2H, CH2OH), 3.50 (t, J = 8.0 Hz, 2H, OCH2CH2Si), 0.84 (t, J = 8.0 Hz,
2H, OCH2CH2Si),
124.7, 122.6, 120.0, 107.1, 76.0, 65.2, 55.3, 17.6,
304.1727; found: 304.1708.
−
0.04 (s, 9H, Si(CH3)3). 13C-NMR (100 MHz, DMSO-d6)
δ
: 135.9, 134.7, 129.1, 125.5,
−
0.9. HRMS (ESI): m/z [M + H]+ calcd for C17H26NO2Si:
4. Conclusions
In summary, we have developed an efficient Suzuki–Miyaura coupling reaction of SEM-protected
bromopyrroles and arylboronic acids under mild conditions leading to aryl-substituted pyrroles.
This methodology is a practical and straightforward way to synthesize various pyrrole building
blocks for delivering novel compounds with broad functional group compatibility. The protocol
displays some advantages compared to the reported methods, such as commercially available materials,
no debrominated by-products being formed, and the SEM-protecting group being more tolerant
than the BOC-protecting group under the reaction conditions. Around the privileged SEM-protected
aryl-substituted pyrroles, we demonstrate the versatility of the pyrrole ring framework in synthetic
transformations for constructing new structures. This protocol will offer the opportunity to explore
other metal-catalyzed cross-coupling reactions using SEM-protected pyrroles and generate new
bioactive compounds containing polyfunctionalized pyrroles.
Supplementary Materials: The following are available online: 1H-NMR and HRMS of compounds 2a
–c
, 1H-NMR,
13C-NMR and HRMS of compounds 3a–s and 4a–c.
Author Contributions: K.C. and M.G. performed the experiments. H.Z. supervised the study. D.Z. and H.H.
conceived and designed the study. D.Z., H.Y., and H.H. interpreted the results, and wrote the paper.
Funding: This research was funded by the CAMS Innovation Fund for Medical Sciences (CIFMS) (Grant No.
2016-I2M-1-013) and National Science & Technology Major Project of China (Grant No. 2015ZX09102007-012).
Conflicts of Interest: The authors declare no conflict of interest.
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2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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