Hexafluoroisopropanol as solvent and promotor in the Paal-Knorr synthesis of N-substituted diaryl pyrroles

Article abstract of DOI:10.1016/j.tet.2021.131985

An additive-free synthesis of challenging N-substituted aryl pyrroles from the often poorly soluble corresponding 1,4-diketones by means of the Paal-Knorr pyrrole synthesis is reported, which makes use of the unique properties of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as a solvent and reaction promotor. Our procedure offers simple execution and purification as well as easy scale-up and can be applied in the Paal-Knorr synthesis of a large number of structurally diverse pyrroles including the synthetically challenging tetra- and penta-substituted pyrroles in moderate to excellent yields. HFIP can also be used as solvent in the Paal-Knorr synthesis of furans and thiophenes; however, the solvent effect is more pronounced in synthesis of pyrroles.

Full text of DOI:10.1016/j.tet.2021.131985

Tetrahedron 83 (2021) 131985
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Hexafluoroisopropanol as solvent and promotor in the Paal-Knorr
synthesis of N-substituted diaryl pyrroles
,
d
c
,
, b, c, d, *
Robert H.E. Schirmacher c , Daniel Rosch d, Franziska Thomas a
€
a
€
Institute of Organic Chemistry, Ruprecht-Karls-Universitat Heidelberg, Im Neuenheimer Feld 270, Heidelberg, 69120, Germany
b Centre for Advanced Materials, Im Neuenheimer Feld 225, Heidelberg, 69120, Germany
c
€
€
Institute of Organic and Biomolecular Chemistry, Georg-August-Universitat, Gottingen, Tammanstr. 2, 37077, Germany
Center for Biostructural Imaging of Neurodegeneration, Gottingen, Von-Siebold-Straße 3a, 37075, Germany
d
€
a r t i c l e i n f o
a b s t r a c t
Article history:
An additive-free synthesis of challenging N-substituted aryl pyrroles from the often poorly soluble
corresponding 1,4-diketones by means of the Paal-Knorr pyrrole synthesis is reported, which makes use
of the unique properties of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as a solvent and reaction promotor.
Our procedure offers simple execution and purification as well as easy scale-up and can be applied in the
Paal-Knorr synthesis of a large number of structurally diverse pyrroles including the synthetically
challenging tetra- and penta-substituted pyrroles in moderate to excellent yields. HFIP can also be used
as solvent in the Paal-Knorr synthesis of furans and thiophenes; however, the solvent effect is more
pronounced in synthesis of pyrroles.
Received 15 December 2020
Received in revised form
16 January 2021
Accepted 23 January 2021
Available online 6 February 2021
Keywords:
Fluorinated solvents
Heterocycles
© 2021 Elsevier Ltd. All rights reserved.
Pyrroles
Paal-knorr synthesis
1. Introduction
1A). However, solvent-free methods [12] or the use of green sol-
vents such as naturally occurring mild organic acids [13], ionic
Aryl substituted pyrroles are found in a plethora of natural
products and are key structural motifs in many pharmaceuticals,
pesticides and fluorescent dyes [1,2]. For instance, Rutecarpine is a
non-basic alkaloid with COX-2 inhibitory properties [3]; Lukianol A
consists of a 3,4-diaryl substituted pyrrole backbone and has been
discussed as an antitumor agent [4]; many structurally diverse
pyrroles have been employed as antibacterial, anti-inflammatory or
antioxidant agents [5], Chlorfenapyr, a 2-(4-chlorophenyl)-pyrrole,
is a widely applied insecticide [6]. Furthermore, aryl-pyrroles have
been used in materials science; for instance, in the functionaliza-
tion of carbon nanotubes [7], or as biomarkers in diagnostics [8].
This list could continue endlessly displaying the vast diversity of
applications and, therefore, clearly emphasizing the need of good
synthetic access to these chemically valuable compounds.
liquids or deep eutectic solvents have been increasingly promoted
[14e18]. Recent developments include cascade reaction protocols
that provide convenient access to b-functionalized or polycyclic or
1,2-annulated pyrroles [19,20] or the use of chiral acid additives for
the atroposelective synthesis of arylpyrroles [21].
During our recent work we have become interested in the 2,5-
diphenyl-substituted pyrrole as a central structural motif in the
design of potential aggregation inhibitors of the amyotrophic
lateral sclerosis (ALS)-related superoxide dismutase 1 (SOD1) [22].
In order to create a library of suitable inhibitor candidates, we
envisaged a modular synthesis strategy to access 2,5-diarylpyrroles
with varying substituents at the pyrrole nitrogen as well as the
phenyl rings. We identified 2,5-bis(4-cyanophenyl)pyrrole (4) as a
suitable inhibitor precursor, as the nitrile groups can be readily
converted into carboxylic acids, esters, amines, amides or alde-
hydes. Literature known syntheses of N-substituted 2,5-bis(4-
Pyrroles can be readily obtained via the established Paal-Knorr
pyrrole synthesis, which involves the condensation reaction of a
1,4-diketone and a primary amine [9e11]. Usually, the reaction is
carried out in polar organic solvents with acid additives (Scheme
cyanophenyl)pyrrole (4), which would match our idea of
a
modular synthesis approach, include palladium-catalyzed CH-
activation of N-substituted pyrroles and activated benzonitriles at
elevated temperatures [23e26]. However, only few N-substituted
pyrroles are commercially available, and, on top of that, expensive.
Paal-Knorr pyrrole synthesis starting from the 4,40-
* Corresponding author. Institute of Organic Chemistry, Ruprecht-Karls-Uni-
€
versitat Heidelberg, Im Neuenheimer Feld 270, 69120, Heidelberg, Germany.
E-mail address: franziska.thomas@oci.uni-heidelberg.de (F. Thomas).
https://doi.org/10.1016/j.tet.2021.131985
0040-4020/© 2021 Elsevier Ltd. All rights reserved.

€
R.H.E. Schirmacher, D. Rosch and F. Thomas
Tetrahedron 83 (2021) 131985
Scheme 1. Synthesis of 2,5-bis(4cyanophenyl) pyrrole (LA: Lewis acid, DES: deep eutectic solvent, IL: ionic liquid).
succinyldibenzonitrile (1) and inexpensive commercially available
primary amines would allow easy variation of the N-substituent
and hence facilitate molecule library synthesis. However, although
the Paal-Knorr synthesis is largely established, protocols for the
reaction of 1,4-diketones with electron-deficient aromatic sub-
stituents are relatively scarce. Taking the few reported examples,
the yields are moderate at best, with the exception of a reaction of
bis(4-nitrophenyl)butane-1,4-dione with methylamine in acetic
acid, which gave excellent 98% yield [27e29].
pyrrole (4) by using N,N-dimethylformamide (DMF) or dime-
thylsulfoxide (DMSO) and catalytic amounts of p-toluenesulfonic
acid (PTSA) in the reaction of 1,4-diketone 1 and benzyl amine (3a).
Yet, even under reflux conditions, only poor solubility of 1 was
observed and, hence, no or little conversion was obtained (Table 1,
Table 1
Optimization of the reaction Conditions.
This report centers on the development of a Paal-Knorr pyrrole
synthesis protocol using 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as
solvent and as sole promotor of the reaction. These conditions are
suitable for a broad range of amines and various 1,4-diketones
including those with aromatic substituents. Whereas elevated
temperatures and long reaction times are required in the conver-
sion of aryl-1,4-diketones, aliphatic 1,4-diketones react instantly.
Out of curiosity, we also tested HFIP in the Paal-Knorr synthesis of
various furans and thiophenes. Whereas furans could be success-
fully synthesized upon the addition of catalytic amounts of hy-
drochloric acid, thiophenes were partly obtained as mixtures of
furans and thiophenes using Lawesson’s reagent as sulfur source. To
reveal the opportunities of the HFIP-promoted Paal-Knorr pyrrole
synthesis in the generation of a library of N-substituted 2,5-
diarylpyrroles, we end our report with exemplary chemical func-
tionalization of the 2,5-bis(4-cyanophenyl)pyrrole (4) core
structure.
entry
1/2
3a eq
solvent
cat.
t (h)
T (ꢀC)
yield (%)a
1
2
3
4
5
6
1
1
1
1
1
1
5
5
neat
2.5
2.5
1.5
DMF
DMSO
e
[BmIm]Ib
CC/Uc
HFIP
PTSA
PTSA
e
12
24
96
24
24
48
100
130
80
100
80
0
12
25
0
0
74
PTSA
e
e
60
7
8
9
10
11
2
2
2
2
2
1.5
1.5
1.5
1.5
1.5
HFIP
e
e
e
e
e
<0.1
0.5
12
1
r.t.
100
80
95
100
99
99
98
98
99
H2O [31]
CC/Uc[16]
[BmIm]Ib[15]
None [32]
2. Results and discussion
1
2.1. HFIP promotes the Paal-Knorr pyrrole synthesis
We started our efforts in the synthesis of 2,5-bis(4-cyanophenyl)
a
Yields refer to isolated compounds.
b
c
[BmIm]I ¼ 1-Butyl-3-methylimidazolium Iodide.
CC/U ¼ 1:1 equimolar mixture of Cholin Chloride and Urea.
2

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R.H.E. Schirmacher, D. Rosch and F. Thomas
Tetrahedron 83 (2021) 131985
Table 2
entries 1e2). As 1 appeared to be poorly soluble in any common
organic solvent, we tried solvent-free conditions (Table 1, entry 3).
This led to a slight increase in yield; however, the removal of excess
2a proved to be difficult. Furthermore, this approach is impractical
for expensive or solid amines. Solvent alternatives such as the ionic
liquid 1-butyl-3-methylimidazolium iodide [15] (entry 4) or the
deep eutectic solvent choline chloride/urea [16] (CC/U, entry 5)
were similarly unsuitable as the solubility of 1 was poor and no
conversion was observed even at elevated temperatures.
Optimization of the catalytic activity of HFIP.
entry
3a eq
solvent
cat.
yield (%)a
1
2
3
4
1.5
1.5
1.5
1.5
1.5
1.5
1.5
DCM
EtOAc
Et2O
Toluene
EtOH
EtOH
HFIP
e
e
e
e
e
45
41
39
46
56
The low solubility of compounds like 1 could be explained by
strong aromatic or polar interactions such as hydrogen bonds be-
tween the hydroxyl groups of the enol form of 1 and the nitrile
groups. Therefore, fluorinated solvents or, more precisely, HFIP
should be a suitable alternative due to its very potent hydrogen
bonding donor properties, strong ionizing power but low nucleo-
philicity [30]. Hence, polar interactions such as hydrogen bonds
should be disrupted. As HFIP is slightly acidic (pKa ¼ 9.3), it serves
as an acid catalyst and solvent at the same time. The low boiling
point of 59 ꢀC ensures easy removal at the end of the reaction.
When performing the Paal-Knorr synthesis of 1 and 3a in HFIP at
reflux conditions but without any further additives desired 4a was
obtained in 74% yield. However, the reaction was slow and was
stopped after two days (entry 6). Since HFIP is relatively expensive,
the reaction was carried out at 0.5 M concentration of 1,4-diketone,
the maximum concentration, at which 1 was still completely
soluble.
As HFIP worked well with aryl-1,4-diketone 1, we wanted to
compare this procedure with literature-reported Paal-Knorr pyr-
role synthesis protocols. Therefore, we performed the reaction in
HFIP with 2,5-hexanedione (2), a commonly used “work horse” in
the optimization of Paal-Knorr conditions, and benzyl amine (3a,
entries 7e11). The reaction with HFIP was completed instantly
giving almost quantitative yields of the desired pyrrole 5a (entry 7).
The very same reaction was then carried out under literature
known conditions with all procedures giving excellent yields
(Table 1, entries 8e11) [15,16,31,32]. In comparison, Paal-Knorr
synthesis in HFIP proceeded by far most rapidly.
5
6
HFIP (5-mol%)
e
82
99
7b
a
Yields refer to isolated compounds.
Reaction was complete within 5 min.
b
diketone 2. Generally, Paal-Knorr synthesis with 4,40-succinyldi-
benzonitrile (1) was performed under reflux conditions and
stopped after two days giving yields of 41e76%, and showing the
expected functional-group tolerance (Table 3) [33]. The use of
aliphatic amines 3b to 3f and diketone 1 resulted in isolated yields
of 50e76%. Interestingly, a- and b-branched amines 3f and 3e gave
higher isolated yields than the sterically less demanding amines 3c
and 3d (50% and 56%, Table 3, entries 4 and 5). The use of anilines
3g, 3h and 3i resulted in lower yields, in general, as they are less
nucleophilic. Aniline 3g gave a respectable isolated yield of 61%.
However, Paal-Knorr synthesis of 1 with 4-aminophenol 3h did not
lead to full conversion and, in the case of 4-nitroaniline 3i, no re-
action was observed (Table 3, entries 8 and 9).
Paal-Knorr syntheses of the more reactive aliphatic 1,4-diketone
2 were performed at room temperature and completed within few
minutes, when aliphatic amines were used. Reactions with alkyl
amines 3b to 3f (Table 3, entries 11 to 15) gave excellent yields of
94% (3d) to almost quantitative 99% (3b). The use of less reactive
anilines 3g, 3h and 3i still resulted in very good yields of about 90%;
however, reflux conditions were required.
2.2. HFIP can be used as an acid catalyst
Next, we continued our study by applying our reaction condi-
tions to various 1,4-diketones (Table 4) including symmetric aro-
matic diketones (6e9, entries 3e6), asymmetric non-branched
diketones (10e12, entries 7e9) and branched diketones (13e16,
entries 10e13). We found that all 1,4-diketones resulted in isolated
yields of 62%e82%, whilst a range of functional groups such as
thioesters, sulfones, esters and nitro groups were tolerated. Inter-
estingly, and somewhat to our surprise, non-substituted aromatic 6
gave the lowest yields. Aliphatic substituents accelerate the reac-
tion, whereas electron-poor diketones such as 9 (Table 4, entry 6)
show slower conversion. The synthesis of tetra- or penta-
substituted pyrroles using Paal-Knorr synthesis is generally
described as synthetically challenging [34,35]. We found that Paal-
Knorr synthesis in HFIP provided poly-substituted 24 to 26 in good
to very good yields (Table 4, entries 11e12). We also tested the Paal-
Knorr synthesis of diketone 16 with 3a. 16 is a literature-known
precursor of Atorvastatin, one of the most commonly prescribed
drugs targeting cardiovascular disease. Atorvastatin can be pre-
pared in large quantities and high purity from 16 by means of a
Paal-Knorr synthesis in a toluene/heptane solvent mixture with
Pivalic Acid as a catalyst under Dean-Stark-conditions [36]. Hence,
we were interested in examining the suitability of our protocol in
the Paal-Knorr synthesis of 16 and 3a as the primary amine.
However, no product formation could be observed when carrying
out the described reaction and the starting material was reisolated.
This was probably due to the low boiling point of HFIP, which did
As HFIP is relatively expensive compared to more commonly
used organic solvents, we have been interested in exploring the
possibility of using only catalytic amounts of HFIP in order to
accelerate the Paal-Knorr synthesis. This would be useful in case of
well-soluble 1,4-diketones and represent an interesting alternative
to typical Lewis-acid and Brønstedt-acid additives [9,10]. We chose
the conversion of 2,5-hexanedione (2) with benzyl amine (3a) as
our model reaction and initially tested the Paal-Knorr synthesis in
various commonly applied organic solvents without HFIP additive
(Table 2). Ethanol as protic solvent gave 5a in the highest yield of
56% after 1h reaction time at room temperature (Table 2, entry 5).
When repeating the reaction in ethanol under similar conditions
but in the presence of 5-mol% HFIP, the yield had significantly been
increased to 82% (Table 2, entry 6) indicating an accelerating effect
on the Paal-Knorr synthesis most likely due to the acidic properties
of HFIP. However, the reaction proceeds most rapidly in pure HFIP
(Table 2, entry 7), and if the unique solubilizing properties of HFIP
are required, the catalytic approach are less suitable.
2.3. HFIP-promoted Paal-Knorr pyrrole synthesis is broadly
applicable
With the optimized reaction procedure in hand, we started to
explore its scope and limitations. Initially, a series of amines (3) was
reacted with the less reactive diketone 1 as well as the aliphatic 1,4-
3

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R.H.E. Schirmacher, D. Rosch and F. Thomas
Tetrahedron 83 (2021) 131985
Table 3
Reaction scope of Paal-Knorr-pyrrole synthesis with varying Amines.
4

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R.H.E. Schirmacher, D. Rosch and F. Thomas
Tetrahedron 83 (2021) 131985
Table 4
Reaction scope of Paal-Knorr-pyrrole synthesis with varying 1,4-Diketones.
5

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R.H.E. Schirmacher, D. Rosch and F. Thomas
Tetrahedron 83 (2021) 131985
not allow sufficient energy to be added to the reaction to overcome
the severe steric hindrance. Nevertheless, the desired product
could be obtained in 34% yield when carrying out the reaction in a
pressure tube at 90 ꢀC, with all other conditions remaining un-
changed (Table 4, entry 13).
acidic conditions. As HFIP is acidic on its own, we initially tried an
acid-additive-free HFIP-promoted protocol using diketones 1 to 15.
However, no conversion was observed even under reflux condi-
tions. Hence, we added catalytic amounts of HCl and obtained the
desired furans in good to very good 70e91% yield (Table 5). Even
the tetra-substituted furan 37, using the Atorvastatin precursor 16,
was accessible by this protocol (Table 5, entry 10). This is compa-
rable to previously reported methods, which have usually been
performed in organic acids such as acetic acid or corrosive tri-
fluoroacetic acid [37]. In contrast, Paal-Knorr thiophene synthesis
2.4. HFIP as solvent in the Paal-Knorr synthesis of furans and
thiophenes
The Paal-Knorr-furan synthesis is usually performed under
Table 5
Reaction scope of Paal-Knorr-furan synthesis with varying 1,4-Diketones.
6

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R.H.E. Schirmacher, D. Rosch and F. Thomas
Tetrahedron 83 (2021) 131985
Table 6
Reaction scope of Paal-Knorr-thiophene synthesis with varying 1,4-Diketones.
has proved to be more challenging as the formation of the corre-
sponding furan has found to be a significant side reaction in some
cases. We used Lawesson’s reagent as a thiol source and refluxed
diarylpyrroles. As stated in the introduction, we were mainly
interested in 2,5-bis(4-cyanophenyl)pyrrole, as this compound can
be readily converted into the respective amides, amines, carboxylic
acids or aldehydes, which are intended to be explored as potential
inhibitors of the aggregation of ALS-related SOD1. To demonstrate
the versatility of our approach in the generation of a library of
structurally diverse pyrroles, we converted 4a to the respective
dicarboxylic acid 43, diamide 44 and diamine 45 (Scheme 2). These
functionalizations are of special interest as compounds 43 to 45 can
participate in electrostatic interactions and hydrogen bonding with
our protein of interest SOD1. The conversion of 4a to the corre-
sponding dicarboxylic acid 43 was performed by basic hydrolysis
using potassium hydroxide and succeeded in excellent 96% yield.
However, refluxing for three days was required in order to avoid
undesired and difficult to separate mixtures of nitriles, amides and
carboxylic acids. The diamide 44 was obtained in 64% yield by
the respective diketone at 0.17
M concentration in HFIP overnight
(Table 6). The relatively low concentration was due to the reduced
solubility of Lawesson’s reagent in HFIP. Whereas diketones 8, 9 and
11 reacted cleanly and in good yields to the desired thiophenes
(Table 6, entries 2e4), diketone 6 and the trisubstituted diketone 13
gave inseparable mixtures of the respective thiophenes 38 and 42
and furans 29 and 35, respectively (Table 6, entries 1 and 5).
2.5. 2,5-bis(4-Cyanophenyl)pyrrole is a precursor for functionalized
aromatic pyrroles
The development of suitable reaction conditions for the Paal-
Knorr synthesis with deactivated aromatic 1,4-diketones provided
an excellent tool for the modular synthesis of a range of 2,5-
following
a literature reported procedure, which includes
Scheme 2. Functionalization of 2,5-bis(4-cyanophenyl)pyrroles.
7

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R.H.E. Schirmacher, D. Rosch and F. Thomas
Tetrahedron 83 (2021) 131985
equilibration of the nitrile compound (4a) with sodium perborate
in a methanol-water-mixture for two days at elevated tempera-
tures [38]. Finally, full reduction of 4a with lithium aluminum hy-
dride gave the diamine 45 in an isolated yield of 90%.
4. Experimental Section
4.1. General
1,1,1,3,3,3-Hexafluoroisopropanol was purchased from ChemPur
GmbH (Karlsruhe, Germany) and used without further purification.
Amines were purchased from ChemPur GmbH (Karlsruhe, Ger-
many), Thermo Fischer GmBH (Kandel, Germany), TCI Germany
GmbH (Eschborn, Germany) and Merck (Darmstadt, Germany) and
used without further purification. Yields correspond to isolated
compounds unless stated otherwise. Purity is estimated to be >95%
based on 1H-NMR spectroscopy. Reactions were monitored by thin
layer chromatography (TLC) using standard silica gel pre-coated
plates provided by Merck (Darmstadt, Germany) and impregnated
with a fluorescent indicator (254 nm). TLC plates were visualized by
exposure to ultraviolet light (UV) and/or staining with a 2% etha-
nolic ninhydrin solution or a 3% aqueous solution of potassium
permanganate followed by heating. Flash column chromatography
was performed on silica gel 60 (230e300 mesh) purchased from
Macherey-Nagel (Düren, Germany). Reaction work-up and flash
chromatography was performed using analytical grade solvents.
Analytical grade solvents were purchased from Th. Geyer GmbH
(Renningen, Germany), Fisher Scientific GmbH (Schwerte, Germany)
and Thermo Fischer GmbH (Kandel, Germany) and used without
further purification. 1H- and 13C- NMR spectra were recorded on a
Bruker Avance III 500 spectrometer at 70.49 kG (1H: 300 MHz, 13C:
3. Conclusion
In summary, we have presented a new protocol for the well-
established Paal-Knorr synthesis, which provides good access to
synthetically demanding N-substituted 2,5-diarylpyrroles and
higher substituted pyrroles that are interesting compounds for
pharmaceutical purposes. Key to synthetic success is the use of
HFIP as solvent and, as it is acidic, as catalyst at the same time.
Hence, the work-up of the reaction is facilitated as HFIP can easily
be removed from the reaction mixture if compared to DMF or
DMSO. Our synthetic protocol is broadly applicable, as it was
demonstrated by Paal-Knorr synthesis with various primary
amines and di- to tetra-substituted 1,4-diketones. The optimized
reaction conditions can be applied in gram scale as we have shown
in the synthesis of 4a (Experimental Section). To compare the ef-
ficiency of Paal-Knorr synthesis in HFIP with other established
methods, we tested aliphatic 2,5-hexanedione 2 as diketone com-
pound and found that the reaction proceeded instantly and at room
temperature to give quantitative yields of the desired 2,5-
bis(methyl)pyrrole 5a. However, Paal-Knorr synthesis of 1,4-
diaryl-1,4-diketones and electron-poor anilines as well as steri-
cally demanding tetra-substituted 1,4-diketones remains chal-
lenging. Additionally, we could show that HFIP can also be applied
in Paal-Knorr-furan or -thiophene synthesis; though catalytic
amounts of hydrochloric acid have been required to promote the
Paal-Knorr synthesis of furans.
Paal-Knorr synthesis is a modular synthesis using 1,4-diketones
and primary amines, which are often commercially available and
inexpensive. This makes it attractive for the generation of libraries
of structurally diverse pyrroles. The successful synthesis of N-
substituted 2,5-bis(4-cyanophenyl)-pyrroles has previously been
reported, but uses palladium-catalyzed CH-activation of N-
substituted pyrroles [23e26], which, compared to primary amines,
are less well accessible. In contrast, Paal-Knorr synthesis of 2,5-
diarylpyrroles bearing electron-withdrawing functional groups
has scarcely been reported. We believe, this was due to the poor
solubility of the 1,4-diketone precursors, an issue, which could be
solved by using HFIP as solvent. In the last years, fluorinated alco-
hols such as trifluoroethanol (TFE) and HFIP have experienced
increasing use as solvents in organic synthesis [39]. For instance,
the positive effects of fluorinated solvents on chemoselectivity,
stereoselectivity, yield and functional group tolerance have been
reported in the halogenation of BODIPYs, cross-coupling reactions
or various other stereoselective reactions [40e44]. Furthermore, a
reaction-accelerating effect in several classical syntheses of het-
erocyclic compounds has been reported [45]. Although HFIP is
more expensive than commonly used organic solvents, it is less
expensive than many ionic liquids and, hence, could be more often
considered as alternative solvent. In our case, the use of HFIP not
only improved the solubility of an otherwise more or less insoluble
1,4-diketone and, in this way, expanded the scope of Paal-Knorr
synthesis, it also led to fast conversions in the case of aliphatic
1,4-diketones and generally provided good to excellent yields. In
the case of well-soluble compounds, we have shown the possibility
of using small quantities of HFIP to catalyze the Paal-Knorr syn-
thesis in ethanol. Therefore, we find our Paal-Knorr synthesis in
HFIP to be a valuable addition to the literature-known Paal-Knorr
synthesis protocols.
75 MHz, 19F-NMR: 282 MHz) at 25 ꢀC. The chemical shifts
d are
expressed in parts per million (ppm) and referred to the solvent
residue proton signals: CDCl3 7.26 ppm, CD2Cl2 5.32 ppm, DMSO-d6
2.50 ppm, acetone-d6 2.10 ppm (1H-NMR); CDCl3 77.2 ppm, CD2Cl2
53.8 ppm, DMSO-d6 39.5 ppm, acetone-d6 29.8, 206.3 ppm (13C-
NMR). Data are reported as follows: chemical shift, multiplicity
(s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet, br
s ¼ broad singlet), coupling constants in Hz, integration multi-
plicator. Please note the following clarification for 1H-NMR: In 1,4-
disubstituted benzenes the two aromatic proton signals can be
assigned to an AA’XX’ spin system, which leads to coupling patterns
of higher order. For clarity reasons these signals are regarded as
doublets and only one coupling constant is given. Infrared spec-
troscopy was performed on a JASCO FT/IR-4100 spectrometer;
analysis was performed using JASCO Spectra Manager. The spectra
were recorded in the range of 4000e400 cmꢁ1 and absorption
bands are given in wave numbers (cm-1). High-resolution mass
spectrometry data (HR-MS) were recorded on a BRUKER microTOF
(ESI) or JEOL AccuTOF (EI) device.
4.2. 4,40-Succinyldibenzonitrile (1)
ZnCl2 (5.92 g, 43.4 mmol, 2 equiv), Et3N (4.6 mL, 32.6 mmol, 1.5
equiv) and absolute ethanol (2.0 mL, 32.6 mmol, 1.5 equiv) were
suspended in anhydrous toluene (50 mL) in an atmosphere of
argon. The reaction mixture was stirred for 60 min. Then, 4-
acetylbenzonitrile (4.73 g, 32.6 mmol, 1.5 equiv) and 4-(2-
bromoacetyl)benzonitrile (4.84 g, 21.7 mmol, 1 equiv) were added
and the suspension was stirred at room temperature for 7 days. The
resulting yellow precipitate was filtered off, dissolved in hot DMF
(150 mL, 80 ꢀC) and crystallized by slow addition of methanol
(20 mL). After storing at 0 ꢀC for 12 h the crystals were filtered off
and dried in air. The product was obtained as a light yellow,
microcrystalline powder. 3.75 g, 70% yield. m.p.: 261 ꢀC; 1H-NMR
(300 MHz, DMSO-d6):
d
[ppm] ¼ 8.16 (d, 4 H, J ¼ 8.61 Hz, 3-H, 30-H),
8.02 (d, 4 H, J ¼ 8.61 Hz, 4-H, 40-H), 3.47 (s, 4 H, 7-H, 70-H); 13C-NMR
could not be measured because the product was not soluble enough
in common organic solvents (DCM-d2, DMSO-d6, acetone-d6); FT-
IR (solid): ṽ (cmꢁ1) ¼ 2225, 1680, 1402, 1319, 1304, 1381, 1191, 1172,
8

€
R.H.E. Schirmacher, D. Rosch and F. Thomas
Tetrahedron 83 (2021) 131985
1010, 860, 840, 783, 713, 694. HR-MS (ESI): m/z calculated for
C
4.6. 4,4’-(1-Benzyl-1H-pyrrole-2,5-diyl)dibenzonitrile (4a)
18H12N2O2þNaþ: 311.0791 [MþNa]þ; observed 311.0786.
The reaction mixture was refluxed for 2 days and worked-up
according to the general procedure. For purification, column
chromatography (n-hexane/EtOAc 4:1, Rf ¼ 0.40) was performed.
Yellow crystals, 338 mg, 74% yield. Large scale synthesis
(10 mmol): 72% yield. m.p.: 168 ꢀC; 1H-NMR (300 MHz, CDCl3):
4.3. 1,4-bis(4-Bromophenyl)butane-1,4-dione (8)
ZnCl2 (5.11 g, 37.5 mmol, 2 equiv), Et3N (4.0 mL, 28.1 mmol, 1.5
equiv) and absolute ethanol (1.72 mL, 28.1 mmol, 1.5 equiv) were
suspended in anhydrous toluene (50 mL) in an atmosphere of
argon. The reaction mixture was stirred for 60 min. Then, 1-(4-
bromophenyl)ethan-1-one (5.56 g, 28.1 mmol, 1.5 equiv) and 2-
d
¼ 7.58 (d, 4H, J ¼ 6.2 Hz, 8-H, 80-H), 7.42 (d, 4H, J ¼ 6.2 Hz, 7-H, 70-
H), 7.17e7.12 (m, 3H, 13-H, 130-H, 15-H), 6.66e6.60 (m, 2H, 14-H,
140-H), 6.47 (s, 2H, 3-H, 4-H), 5.21 (s, 2H, 11-H); 13C-NMR (75 MHz,
CD2Cl2):
d
¼ 137.9 (C-2, C-5), 137.3 (C-6, C-60), 136.6 (C-12), 132.2 (C-
bromo-1-(4-bromophenyl)ethan-1-one (5.17 g, 17.8 mmol,
1
8, C-80), 128.8 (C-7, C-70), 128.7 (C-14, C-140), 127.5 (C-15), 125.5 (C-
13, C-130), 118.7 (C-10, C-100), 112.1 (C-9, C-90), 110.6 (C-3, C-4), 49.4
(C-11); FT-IR (solid): ṽ (cmꢁ1) ¼ 2922, 2221, 1599, 1178, 796, 706;
HR-MS (ESI): m/z calculated for C25H17N3þNaþ: 382.1315
[MþNa]þ; observed 382.1314.
equiv) were added and the resulting suspension was stirred for 7
days at room temperature. The reaction mixture was washed with
10% H2SO4 (50 mL) and a saturated solution of NaHCO3 (50 mL). The
aqueous phase was extracted with EtOAc (2 ꢂ 50 mL) and the
combined organic phases were dried over Na2SO4. The solvent was
evaporated under reduced pressure. The residue was recrystallized
from EtOAc (ca.100 mL) and the product was obtained as a colorless
crystalline solid. 4.98 g, 71% yield. m.p.: 289 ꢀC; 1H-NMR (300 MHz,
4.7. 1-Benzyl-2,5-dimethyl-1H-pyrrole (5a)
The reaction mixture was stirred at room temperature for 5 min
and worked-up according to the general procedure. Light brown
solid, 363 mg, 99% yield. m.p.: 48 ꢀC; 1H-NMR (300 MHz, CD2Cl2):
DMSO-d6):
d
[ppm] ¼ 7.95 (d, 4H, J ¼ 8.85 Hz, 2-H, 20-H), 7.76 (d, 4H,
J ¼ 8.85 Hz, 3-H, 30-H), 3.39 (2, 4H, 6-H, 60-H); 13C-NMR could not
be measured because the product was not soluble enough in
common organic solvents (DCM-d2, DMSO-d6, acetone-d6); FT-IR
(solid): ṽ (cmꢁ1) ¼ 2896, 1667, 1583, 1568, 1482, 1406, 1389, 1279,
1189, 1104, 1071, 977, 742, 783, 760, 658; HR-MS (ESI): m/z calcu-
lated for C16H12Br2O2þHþ: 394.9277 [MþH]þ; observed 394.9289.
d
[ppm] ¼ 7.35e7.19 (m, 3H, 10-H, 100-H, 11-H), 6.91 (d, 2H,
J ¼ 8.43 Hz, 9-H, 90-H), 5.81 (s, 2H, 3-H, 4-H), 5.03 (2, 2H, 7-H), 2.14
(s, 6H, 6-H, 60-H); 13C-NMR (75 MHz, CD2Cl2):
d
[ppm] ¼ 138.9 (C-
8), 128.6 (C-11), 127.7 (C-2, C-5), 126.9 (C-10, C-100), 125.7 (C-9, C-
90), 105.4 (C-3, C-4), 46.6 (C-7), 12.2 (C-6, C-60); FT-IR (solid): ṽ
(cmꢁ1): 2918, 1652, 1493, 1408, 1355, 1303, 754, 725, 701, 689; HR-
MS (ESI): m/z calculated for C13H15N þ Hþ: 186.1277 [MþH]þ;
observed 186.1275.
4.4. 1,4-bis(4-Nitrophenyl)butane-1,4-dione (9)
ZnCl2 (5.62 g, 41.2 mmol, 2 equiv), Et3N (4.4 mL, 30.9 mmol, 1.5
equiv) and absolute ethanol (1.81 mL, 30.9 mmol, 1.5 equiv) were
suspended in anhydrous toluene (50 mL) in an atmosphere of
argon. The reaction mixture was stirred for 60 min. Then, 1-(4-
nitrophenyl)ethan-1-one (5.00 g, 30.9 mmol, 1.5 equiv) and 2-
bromo-1-(4-nitrophenyl)ethan-1-one (5.05 g, 20.6 mmol, 1 equiv)
were added and the resulting suspension was stirred for 7 days at
room temperature. The precipitated product was isolated by
decantation and recrystallized from DMF (ca. 100 mL, 90 ꢀC). The
product was obtained as light orange needles. 4.33 g, 64% yield.
4.8. 4,4’-(1-Propyl-1H-pyrrole-2,5-diyl)dibenzonitrile (4b)
The reaction mixture was refluxed for 2 days and worked-up
according to the general procedure. For purification column chro-
matography (n-hexane/EtOAc 4:1, Rf ¼ 0.57) was performed. Yellow
crystals, 432 mg, 76% yield. m.p.: 144 ꢀC; 1H-NMR (300 MHz,
CDCl3):
d
[ppm] ¼ 7.72 (d, 4H, J ¼ 6.2 Hz, 8-H, 80-H), 7.55 (d, 4H,
J ¼ 6.2 Hz, 7-H, 70-H), 6.38 (s, 2H, 3-H, 4-H), 4.06 (7, 2H, J ¼ 7.1 Hz,
11-H), 1.18 (sex, 2H, J ¼ 7.2 Hz, 12-H), 0.43 (t, 3H, J ¼ 7.4 Hz, 13-H);
13C-NMR (75 MHz, CDCl3):
d
[ppm] ¼ 138.0 (C-2, C-5), 136.7 (C-6, C-
m.p.: 243 ꢀC; 1H-NMR (300 MHz, DMSO-d6):
d
[ppm] ¼ 8.39 (d, 4H,
60), 132.5 (C-8, C-80), 128.8 (C-7, C-70), 118.8 (C-10, C-100), 112.1 (C-9,
C-90), 110.5 (C-3, C-4), 47.5 (C-11), 24.1 (C-12), 10.6 (C-13); FT-IR
(solid): ṽ (cmꢁ1) ¼ 2922, 2358, 2341, 2220, 1600, 834, 777. HR-MS
(ESI): m/z calculated for C21H17N3þHþ: 312.1495 [MþH]þ; observed
312.1492.
J ¼ 8.88 Hz, 2-H, 20-H), 8.27 (d, 4H, J ¼ 8.88 Hz, 3-H, 30-H), 3.54 (s,
4H, 6-H, 60-H); 13C-NMR could not be measured because the
product was not soluble enough in common organic solvents
(DCM-d2, DMSO-d6, acetone-d6); FT-IR (solid): ṽ (cmꢁ1) ¼ 1683,
1602, 1517, 1397, 1341, 1317, 1222, 1172, 997, 942, 848, 737, 700, 682;
HR-MS (EI): m/z calculated for
C
16H12N2O6: 328.0690 [M]þ;
4.9. 2,5-Dimethyl-1-propyl-1H-pyrrole (5b)
observed 328.0688.
The reaction mixture was stirred at room temperature for 5 min
and worked-up according to the general procedure. Brown oil,
269 mg, 99% yield. m.p.: 192 ꢀC; 1H-NMR (300 MHz, CD2Cl2):
4.5. General procedure for the synthesis of tri-to penta-substituted
pyrroles
d
[ppm] ¼ 5.68 (s, 2H, 3-H, 4-H), 3.69 (t, 2H, J ¼ 7.5 Hz, 7-H), 2.20 (s,
The 1,4-diketone (2 mmol) was dissolved in 4e10 mL of
1,1,1,3,3,3-hexafluoroisopropanol at ambient temperature. The
respective amine (3 mmol) was added slowly and the mixture was
stirred for the indicated time either at room temperature or under
reflux conditions. The reaction mixture was allowed to cool to room
temperature and the solvent was removed by means of a rotary
evaporator or distilled for reuse. The residue was dissolved in
6 H, 6-H, 60-H),1.63 (m, 2 H, J ¼ 7.5 Hz, 8-H), 0.94 (t, 3H, J ¼ 7.5 Hz, 9-
H); 13C-NMR (75 MHz, CD2Cl2):
d
[ppm] ¼ 127.0 (C-2, C-5), 104.9 (C-
3, C-4), 45.1 (C-7), 24.3 (C-8), 12.2 (C-6, C-60), 11.0 (C-9); FT-IR
(solid): ṽ (cmꢁ1) ¼ 2962, 1660, 1518, 1406, 1298, 1018, 892, 742; HR-
MS (ESI): m/z calculated for C9H15N þ Hþ 138.1277 [MþH]þ;
observed 138.1273.
dichloromethane (10 mL) and washed with 4
M
HCl (20 mL) to
4.10. 4,4’-(1-(3,3-Dimethylbutyl)-1H-pyrrole-2,5-diyl)
dibenzonitrile (4c)
remove excess amine. The organic phase was dried over MgSO4 and
the solvent was removed under reduced pressure. The products
were mostly pure; however, in some cases column chromatography
was necessary using n-hexane/EtOAc as eluents.
The reaction mixture was refluxed for 2 days and worked-up
according to the general procedure. For purification column
9

€
R.H.E. Schirmacher, D. Rosch and F. Thomas
Tetrahedron 83 (2021) 131985
chromatography (n-hexane/EtOAc 4:1, Rf ¼ 0.73) was performed.
Yellow crystals, 378 mg, 56% yield. m.p.: 192 ꢀC; 1H-NMR
CD2Cl2):
d
[ppm] ¼ 7.70 (d, 4H, J ¼ 6.2 Hz, 8-H, 80-H), 7.53 (d, 4H,
J ¼ 6.2 Hz, 7-H, 70-H), 6.35 (s, 2H, 3-H, 4-H), 3.92 (d, 2H, 11-H), 1.55
(s, 1H, 12-H), 1.41 (m, 2H, 13-H, 130-H), 1.09e0.73 (m, 6H, 14-H, 140-
H, 15-H), 0.37 (m, 2H, 13-H, 130-H); 13C-NMR (75 MHz, CD2Cl2):
(300 MHz, CDCl3):
d
[ppm] ¼ 7.73 (d, 4H, J ¼ 6.2 Hz, 8-H, 80-H), 7.56
(d, 4H, J ¼ 6.2 Hz, 7-H, 70-H), 6.38 (s, 2H, 3-H, 4-H), 4.07 (t, 2H,
J ¼ 7.0 Hz, 11-H), 1.02 (t, 2H, J ¼ 7.0 Hz, 12-H), 0.56 (s, 9H, 14-H, 140-
d
[ppm] ¼ 138.0 (C-2, C-5), 137.3 (C-6, C-60), 132.4 (C-8, C-80), 128.6
H, 1400-H); 13C-NMR (75 MHz, CDCl3):
d
[ppm] ¼ 137.9 (C-2, C-5),
(C-7, C-70), 118.8 (C-10, C-100), 112.0 (C-9, C-90), 110.4 (C-3, C-4), 52.4
(C-11), 39.4 (C-12), 30.1 (C-13, C-130), 25.9 (C-15), 25.4 (C-14, C-140);
FT-IR (solid): ṽ (cmꢁ1) ¼ 2922, 2226, 1604, 1490, 1179, 836, 771;
136.1 (C-6, C-60), 132.4 (C-8, C-80), 129.0 (C-7, C-70), 118.8 (C-10, C-
100), 112.1 (C-9, C-90), 110.7 (C-3, C-4), 44.0 (C-12), 42.5 (C-11), 29.6
(C-13), 28.7 (C-14); FT-IR (solid): ṽ (cmꢁ1) ¼ 2959, 2222,1602,1491,
1476, 1332, 1268, 1249, 1234, 1178, 1113, 1062, 850, 839, 769, 677;
HR-MS (ESI): m/z calculated for C24H23N3þNaþ: 376.1784 [MþNa]þ;
observed 376.1785.
HR-MS (ESI): m/z calculated for
[MþNa]þ; observed 388.1783.
C
25H23N3þNaþ: 388.1784
4.15. 1-(Cyclohexylmethyl)-2,5-dimethyl-1H-pyrrole (5e)
4.11. 1-(3,3-Dimethylbutyl)-2,5-dimethyl-1H-pyrrole (5c)
The reaction mixture was stirred at room temperature for
10 min and worked-up according to the general procedure. Brown
The reaction mixture was stirred at room temperature for 5 min
and worked-up according to the general procedure. Red-brown
solid, 341 mg, 97% yield. m.p.: 49 ꢀC; 1H-NMR (300 MHz,
oil, 375 mg, 98% yield. 1H-NMR (300 MHz, CD2Cl2):
d
[ppm] ¼ 5.68
(s, 2H, 3-H, 4-H), 3.54 (d, 2H, J ¼ 7.14 Hz, 7-H), 2.18 (s, 6H, 6-H, 60-H),
1.80e1.55 (m, 6H, C-8, C-9, C-90, C-10, C-100, C-11), 1.30e1.11 (m, 3H,
C-10, C-100, C-11), 1.06e0.88 (m, 2H, C-9, C-90); 13C-NMR (75 MHz,
CD2Cl2):
d
[ppm] ¼ 5.67 (s, 2H, 3-H, 4-H), 3.74 (m, 2H, J ¼ 4.56 Hz, 7-
H), 2.19 (s, 6H, 6-H, 60-H), 1.46 (m, 2H, J ¼ 4.56 Hz, 8-H), 1.01 (s, 9H,
CD2Cl2):
d
[ppm] ¼ 127.6 (C-2, C-5), 104.9 (C-3, C-4), 49.8 (C-7), 39.5
10-H,100-H,1000-H); 13C-NMR (75 MHz, CD2Cl2):
d
[ppm] ¼ 126.7 (C-
(C-8), 31.0 (C-9, C-90), 26.5 (C-11), 26.0 (C-10, C-10‘), 12.6 (C-6, C-6‘);
FT-IR (solid): ṽ (cmꢁ1) ¼ 2919, 2848, 1511, 1446, 1403, 1353, 1291,
1018, 966, 738; HR-MS (ESI): m/z calculated for C13H21N þ Hþ:
192.1747 [MþH]þ; observed 192.1747.
2, C-5),104.9 (C-3, C-4), 44.5 (C-8), 39.8 (C-7), 29.7 (C-9), 28.9 (C-10,
C-100, C-1000), 12.0 (C-6, C-60); FT-IR (solid): ṽ (cmꢁ1) ¼ 2954, 1515,
1464, 1442, 1410, 1636, 1296, 1247, 1216, 1179, 1015, 975, 740; HR-
MS (ESI): m/z calculated for C12H21N þ Hþ: 180.1747 [MþH]þ;
observed 180.1747.
4.16. 4,4’-(1-Cyclohexyl-1H-pyrrole-2,5-diyl)dibenzonitrile (4f)
4.12. 4,4’-(1-(4,4,4-Trifluorobutyl)-1H-pyrrole-2,5-diyl)dibenzo-
nitrile (4d)
The reaction mixture was refluxed for 2 days and worked-up
according to the general procedure. For purification column chro-
matography (n-hexane/EtOAc 4:1, Rf ¼ 0.61) was performed. Light
yellow solid, 537 mg, 76% yield. m.p.: 189 ꢀC; 1H-NMR (300 MHz,
The reaction mixture was refluxed for 2 days and worked-up
according to the general procedure. For purification column chro-
matography (n-hexane/EtOAc 2:1, Rf ¼ 0.79) was performed. Yellow
crystals, 338 mg, 50% yield. m.p.: 136 ꢀC; 1H-NMR (300 MHz,
CD2Cl2):
d
[ppm] ¼ 7.72 (d, J ¼ 8.43 Hz, 4H, 8-H, 8’-H), 7.55 (d, 2H
J ¼ 8.43 Hz, 7-H, 70-H), 6.24 (s, 2H, 3-H, 4-H), 3.93 (tt, 1H,
J ¼ 3.33 Hz, J ¼ 12.15 Hz, 11-H), 1.85 (d, 2H, J ¼ 12.27 Hz, 12-H, 120-
H), 1.70e1.41 (m, 5H, 12-H, 120-H, 13-H, 130-H, 14-H), 1.17e0.99 (m,
2H, (13-H, 130-H), 0.89e0.69 (m, 1H, 14-H); 13C-NMR (75 MHz,
CD2Cl2):
d
[ppm] ¼ 7.75 (d, 4H, J ¼ 6.2 Hz, 8-H, 80-H), 7.58 (d, 4H,
J ¼ 6.2 Hz, 7-H, 70-H), 6.44 (s, 2H, 3-H, 4-H), 4.20 (m, 2H, 11-H),
1.56e1.29 (m, 4H, 12-H, 13-H); 13C-NMR (75 MHz, CD2Cl2):
CD2Cl2):
d
[ppm] ¼ 139.3 (C-2, C-5), 136.3 (C-6, C-60), 131.9 (C-8, C-
d
[ppm] ¼ 137.3 (C-2, C-5), 137.0 (C-6, C-60), 132.7 (C-8, C-80), 128.7
80), 130.4 (C-7, C-70), 118.8 (C-10), 111.9 (C-3, C-4), 110.8 (C-9, C-9‘),
59.5 (C-11), 34.6 (C-12, C-12‘), 26.4 (C-13, C-13‘), 25.1 (C-14); FT-IR
(solid): ṽ (cmꢁ1) ¼ 2923, 2857, 2222, 1603, 1489, 1451, 1410, 1397,
1376, 1320, 1265, 1225, 1198, 1177, 1110, 1017, 843, 833, 770, 692;
HR-MS (EI): m/z calculated for C24H21N3: 351.1730 [M]þ; observed
351.1730.
(C-7, C-70), 118.7 (C-10, C-100), 112.6 (C-9, C-90), 110.8 (C-3, C-4), 44.5
(C-11), 30.0 (q, C-13), 23.0 (d, C-12); 19F-NMR (282 MHz):
d
¼ ꢁ66.90; FT-IR (solid): ṽ (cmꢁ1) ¼ 2224, 1599, 1492, 1250, 1244,
1151, 1019, 1010, 841, 774, 677; HR-MS (ESI): m/z calculated for
C
22H16F3N3þHþ: 380.1369 [MþH]þ; observed 380.1364.
4.13. 2,5-Dimethyl-1-(4,4,4-trifluorobutyl)-1H-pyrrole (5d)
4.17. 1-Cyclohexyl-2,5-dimethyl-1H-pyrrole (5f)
The reaction mixture was stirred at room temperature for 5 min
and worked-up according to the general procedure. Red solid,
386 mg, 94% yield. m.p.: 51 ꢀC; 1H-NMR (300 MHz, CD2Cl2):
The reaction mixture was stirred at room temperature for
10 min and worked-up according to the general procedure. Yellow
solid, 340 mg, 96% yield. m.p.: 56 ꢀC; 1H-NMR (300 MHz, CD2Cl2):
d
[ppm] ¼ 5.71 (s, 2H, 3-H, 4-H), 3.81 (t, 2H, J ¼ 5.22 Hz, 7-H), 2.20
(s, 6H, 6-H, 60-H), 2.18e2.03 (m, 2H, 8-H), 1.93e1.81 (m, 2H, 9-H);
13C-NMR (75 MHz, CD2Cl2):
[ppm] ¼ 127.2 (q, C-10), 127.0 (C-2, C-
5), 105.5 (C-3, C-4), 42.0 (C-7), 30. 9 (q, C-8), 23.4 (C-8), 12.1 (C-6, C-
d
[ppm] ¼ 5.64 (s, 2H, 3-H, 4-H), 3.99e3.79 (m, 1H, 7-H), 2.26 (s, 6H,
6-H, 6’-H), 1.98e1.67 (m, 7H, 8-H, 80-H, 9-H, 90-H, 10-H), 1.49e1.14
d
(m, 3H, 9-H, 90-H, 10-H); 13C-NMR (75 MHz, CD2Cl2):
d
[ppm] ¼ 127.5 (C-2, C-5), 106.0 (C-3, C-4), 56.3 (C-7), 32.5 (C-8, C-
60); 19F-NMR (282 MHz):
d
¼
ꢁ66.52; FT-IR (solid):
ṽ
8‘), 26.6 (C-9, C-9‘), 25.6 (C-10), 14.1 (C-6, C-6‘); FT-IR (solid): ṽ
(cmꢁ1) ¼ 2927, 2852, 1654, 1446, 1396, 1344, 1293, 1260, 1215, 1188,
1145, 1057, 1019, 994, 891, 777, 744; HR-MS (ESI): m/z calculated for
(cmꢁ1) ¼ 2939, 1402, 1380, 1290, 1251, 1135, 1032, 751; HR-MS
(ESI):. m/z calculated for C10H14F3N þ Hþ: 206.1151 [MþH]þ;
observed 206.1151.
C
12H19N þ Hþ: 178.1590 [MþH]þ; observed 178.1594.
4.14. 4,4’-(1-(Cyclohexylmethyl)-1H-pyrrole-2,5-diyl)dibenzonitrile
(4e)
4.18. 4,4’-(1-Phenyl-1H-pyrrole-2,5-diyl)dibenzonitrile (4g)
The reaction mixture was refluxed for 2 days and worked-up
according to the general procedure. For purification column chro-
matography (n-hexane/EtOAc 6:1, Rf ¼ 0.43) was performed. Yellow
solid, 421 mg, 61% yield. m.p.: 192 ꢀC; 1H-NMR (300 MHz, CD2Cl2):
The reaction mixture was refluxed for 2 days and worked-up
according to the general procedure. For purification column chro-
matography (n-hexane/EtOAc 4:1, Rf ¼ 0.75) was performed. Yellow
crystals, 436 mg, 65% yield. m.p.: 161 ꢀC; 1H-NMR (300 MHz,
d
[ppm] ¼ 7.46 (d, 4H, J ¼ 8.52 Hz, 8-H, 8’-H), 7.41e7.30 (m, 3H, 13-
10

€
R.H.E. Schirmacher, D. Rosch and F. Thomas
Tetrahedron 83 (2021) 131985
H, 130-H, 14-H), 7.14 (d, 2H, J ¼ 8.52 Hz, 7-H, 70-H), 7.06 (d, 2H,
J ¼ 7.86 Hz, 12-H, 120-H), 6.63 (s, 2H, 3-H, 4-H); 13C-NMR (75 MHz,
4.23. 1-Benzyl-2,5-diphenyl-1H-pyrrole (17)
CD2Cl2):
d
[ppm] ¼ 138.0 (C-2, C-5), 137.1 (C-6, C-6‘), 135.3 (C-11),
The reaction mixture was refluxed for 2 days and worked-up
according to the general procedure. For purification column chro-
matography (n-hexane/EtOAc 9:1, Rf ¼ 0.76) was performed.
Colorless crystals, 381 mg, 62% yield. m.p.: 131 ꢀC; 1H-NMR
131.8 (C-8, C-8‘), 129.4 (C-13, C-13‘), 128.7 (C-12, C-12‘), 128.6 (C-7,
C-7‘), 128.4 (C-14), 118.8 (C-10, C-10‘), 112.2 (C-3, C-4), 109.7 (C-9, C-
9‘); FT-IR (solid): ṽ (cmꢁ1) ¼ 2361, 2222, 1599, 1491, 1428, 1346,
1179, 842, 778, 698. HR-MS (ESI): m/z calculated for C24H15N3þNaþ:
368.1158 [MþNa]þ; observed 368.1153.
(300 MHz, CD2Cl2):
d
[ppm] ¼ 7.42e7.23 (m, 10H, 7-H, 70-H, 8-H, 80-
H, 9-H, 90-H), 7.14e7.05 (m, 3H, 13-H, 130-H, 14-H), 6.63e6.58 (m,
2H, 12-H, 120-H), 6.35 (s, 2H, 3-H, 4-H), 5.28 (s, 2H, 10-H); 13C-NMR
4.19. 2,5-Dimethyl-1-phenyl-1H-pyrrole (5g)
(75 MHz, CD2Cl2):
d
[ppm] ¼ 139.2 (C-11), 136.9 (C-2, C-5), 133.7 (C-
6, C-60), 128.9 (C-8, C-80), 128.3 (C-7, C-70), 128.2 (C-13, C-130), 127.0
(C-9, C-90), 126.7 (C-14), 125.8 (C-12, C-120), 109.8 (C-3, C-4), 48.6
(C-10); FT-IR (solid): ṽ (cmꢁ1) ¼ 2357, 1599, 1480, 1448, 1360, 1321,
1024, 752, 731, 699, 663; HR-MS (ESI): m/z calculated for
The reaction mixture was stirred at room temperature for
15 min and worked-up according to the general procedure. Yellow
solid, 308 mg, 90% yield. m.p.: 51 ꢀC; 1H-NMR (300 MHz, CD2Cl2):
d
[ppm] ¼ 7.51e7.36 (m, 3H, 9-H, 9’-H, 10-H), 7.25e7.16 (m, 2H, 8-H,
C
23H19N þ Hþ: 310.1590 [MþH]þ; observed 310.1595.
80-H), 5.83 (s, 2H, 3-H, 4-H), 2.00 (s, 6H, 6-H, 60-H); 13C-NMR
(75 MHz, CD2Cl2):
d
[ppm] ¼ 139.1 (C-7), 128.9 (C-9, C-90), 128.4 (C-
4.24. 1-Benzyl-2,5-di-p-tolyl-1H-pyrrole (18)
2, C-5), 128.3 (C-10), 127.51 (C-8, C-80), 105.7 (C-3, C-4), 12.7 (C-6, C-
60); FT-IR (solid): ṽ (cmꢁ1) ¼ 2920, 1596, 1495, 1401, 1318, 1067,
1037, 1006, 772, 746, 716, 684; HR-MS (ESI): m/z calculated for
The reaction mixture was refluxed for 2 days and worked-up
according to the general procedure. For purification column chro-
matography (n-hexane/EtOAc 19:1, Rf ¼ 0.72) was performed.
Colorless crystals, 550 mg, 82% yield. m.p.: 144 ꢀC; 1H-NMR
C
12H13N þ Hþ: 172.1121 [MþH]þ; observed 172.1123.
4.20. 4,4’-(1-(4-Hydroxyphenyl)-1H-pyrrole-2,5-diyl)
dibenzonitrile (4h)
(300 MHz, CD2Cl2):
d
[ppm] ¼ 7.25 (d, 4H, J ¼ 8.1 Hz, 7-H, 70-H),
7.17e7.07 (m, 7H, 8-H, 80-H, 14-H, 140-H, 15-H), 6.64e6.60 (m, 2H,
13-H, 130-H), 6.28 (2, 2H, 3-H, 4-H), 5.24 (s, 2H, 11-H), 2.34 (s, 6H,
The reaction mixture was refluxed for 2 days in an atmosphere
of argon, was protected from sunlight and was worked-up ac-
cording to the general procedure. For purification column chro-
matography (n-hexane/EtOAc 3:1, Rf ¼ 0.54) was performed. Yellow
solid, 296 mg, 41% yield. m.p.: 195 ꢀC; 1H-NMR (300 MHz, DMSO-
10-H, 100-H); 13C-NMR (75 MHz, CD2Cl2):
d
[ppm] ¼ 139.5 (C-11),
136.8 (C-2, C-5), 136.5 (C-9, C-90), 130.8 (C-6, C-60), 129.0 (C-7, C-70),
128.8 (C-8, C-80), 128.2 (C-14, C-140), 126.7 (C-15), 125.7 (C-13, C-
130), 109.4 (C-3, C-4), 48.4 (C-11), 20.8 (C-10, C-100); FT-IR (solid): ṽ
(cmꢁ1) ¼ 2967, 2357, 2340,1736,1436,1365,1216; HR-MS (ESI): m/z
d6):
d
[ppm] ¼ 9.86 (2, 1H, OH), 7.68 (d, 2H, J ¼ 8.58 Hz, 8-H, 80-H),
calculated for
338.1902.
C
25H23
N
þ
Hþ: 338.1903 [MþH]þ; observed
7.23 (d, 2H, J ¼ 8.58 Hz, 7-H, 70-H), 6.99 (d, 2H, J ¼ 8.70 Hz,12-H,120-
H), 6.75e6.73 (m, 4H, 3-H, 4-H, 13-H, 130-H); 13C-NMR (75 MHz,
DMSO-d6):
d
[ppm] ¼ 157.8 (C-14), 137.4 (C-2, C-5), 135.7 (C-6, C-60),
4.25. 1-Benzyl-2,5-bis(4-bromophenyl)-1H-pyrrole (19)
132.5 (C-8, C-80), 130.3 (C-12, C-120), 129.3 (C-11), 128.7 (C-7, C-70),
119.3 (C-10, C-100), 116.5 (C-13, C-130), 112.6 (C-3, C-4), 109.1 (C-9, C-
90); FT-IR (solid): ṽ (cmꢁ1) ¼ 3335, 2922, 2237, 2222, 1596, 1515,
1259,1220,1014, 836, 797, 781, 656; HR-MS (ESI): m/z calculated for
The reaction mixture was refluxed for 2 days and worked-up
according to the general procedure. For purification column chro-
matography (n-hexane/EtOAc 8:1, Rf ¼ 0.56) was performed.
Colorless crystals, 735 mg, 79% yield. m.p.: 174 ꢀC; 1H-NMR
C
24H14N3Oꢁ: 360.1142 [M ꢁ H]-; observed 360.1133.
(300 MHz, CD2Cl2):
d
[ppm] ¼ 7.46 (d, 4H, J ¼ 8.46 Hz, 7-H, 70-H),
4.21. 4-(2,5-Dimethyl-1H-pyrrole-1-yl)phenol (5h)
7.24 (d, 4H, J ¼ 8.46 Hz, 8-H, 80-H), 7.17e7.08 (m, 3H, 13-H, 130-H,14-
H), 6.64e6.57 (m, 2H, 12-H, 120-H), 6.35 (s, 2H, 3-H, 4-H), 5.20 (s,
The reaction mixture was refluxed for 15 min and worked-up
2H, 10-H); 13C-NMR (75 MHz, CD2Cl2):
d
[ppm] ¼ 138.8 (C-11),
according to the general procedure. Yellow solid, 329 mg, 88%
136.0 (C-2, C-5), 132.5 (C-6, C-60), 131.5 (C-7, C-70), 130.4 (C-8, C-8‘),
128.4 (C-13, C-13‘),127.0 (C-14),125.7 (C-12, C-12‘),121.0 (C-9, C-9‘),
110.3 (C-3, C-4), 48.7 (C-10); FT-IR (solid): ṽ (cmꢁ1) ¼ 2962, 2031,
1477, 1409, 1358, 1322, 1259, 1097, 1068, 1008, 820, 776, 762, 715;
HR-MS (ESI): m/z calculated for C23H17Br2N þ Hþ: 465.9801
[MþH]þ; observed 465.9800.
yield. m.p.: 103 ꢀC; 1H-NMR (300 MHz, CD2Cl2):
d
[ppm] ¼ 7.07 (d,
2H, J ¼ 8.7 Hz, 8-H, 80-H), 6.91 (d, 2H, J ¼ 8.7 Hz, 9-H, 90-H), 5.81 (s,
2H, 3-H, 4-H), 5.16 (s, 1H, OH), 1.99 (s, 6H, 6-H, 60-H); 13C-NMR
(75 MHz, CD2Cl2):
d
[ppm] ¼ 155.1 (C-10), 131.9 (C-7), 129.5 (C-8, C-
80), 128.7 (C-2, C-5), 115.6 (C-9, C-90), 105.3 (C-3, C-4), 12.6 (C-6, C-
60); FT-IR (solid): ṽ (cmꢁ1) ¼ 3242,1512,1440,1408,1217,1095, 999,
838, 820, 751; HR-MS (ESI): m/z calculated for C12H13NO þ Hþ:
188.1070 [MþH]þ; observed 188.1070.
4.26. 1-Benzyl-2,5-bis(4-nitrophenyl)-1H-pyrrole (20)
The reaction mixture was refluxed for 2 days and worked-up
according to the general procedure. For purification column chro-
matography (n-hexane/EtOAc 6:1, Rf ¼ 0.43) was performed. Brown
solid, 528 mg, 66% yield. m.p.: 139 ꢀC; 1H-NMR (300 MHz, CD2Cl2):
4.22. 2,5-Dimethyl-1-(4-nitrophenyl)-1H-pyrrole (5i)
The reaction mixture was refluxed for 15 min and worked-up
according to the general procedure. Brown solid, 389 mg, 90%
d
[ppm] ¼ 8.20 (d, 4H, J ¼ 8.88 Hz, 8-H, 8’-H), 7.56 (d, 4H,
yield. m.p.: 143 ꢀC; 1H-NMR (300 MHz, CD2Cl2):
d
[ppm] ¼ 8.33 (d,
J ¼ 8.88 Hz, 7-H, 70-H), 7.17e7.10 (m, 3H, 13-H, 130-H, 14-H),
6.67e6.61 (m, 2H, 12-H, 120-H), 6.59 (s, 2H, 3-H, 4-H), 5.32 (s, 2H,
10-H, the signal overlaps with the solvent residue proton signal);
2H, J ¼ 6 Hz, 9-H, 90-H), 7.39 (d, 2H, J ¼ 6 Hz, 8-H, 80-H), 5.91 (s, 2h;
3-H, 4-H), 2.06 (s, 6H, 6-H, 60-H); 13C-NMR (75 MHz, CD2Cl2):
d
[ppm] ¼ 128.9 (C-9, C-90), 128.4 (C-2, C-5), 124.4 (C-8, C-80), 107.3
13C-NMR (75 MHz, CD2Cl2):
d
[ppm] ¼ 146.6 (C-9), 139.3 (C-11),
(C-3, C-4), 12.8 (C-6, C-60); FT-IR (solid): ṽ (cm¡1) ¼ 1594, 1516,
137.9 (C-6, C-6‘), 137.0 (C-2, C-5), 128.9 (C-7, C-7‘), 128.6 (C-13, C-
13‘), 127.4 (C-14), 125.7 (C-10), 123.8 (C-8, C-8‘), 112.9 (C-3, C-4),
49.5 (C-10); FT-IR (solid): ṽ (cmꢁ1) ¼ 2960, 2921, 2851, 1590, 1508,
1337, 1258, 1012, 792, 750, 697, 678. HR-MS (EI): m/z calculated for
1490, 1396, 1335, 1223, 1094, 1000, 853, 776, 764, 718, 689; HR-MS
(ESI): m/z calculated for
C
12H12N2O2þHþ: 217.0972 [MþH]þ;
observed 217.0977.
11

€
R.H.E. Schirmacher, D. Rosch and F. Thomas
Tetrahedron 83 (2021) 131985
C23H17N3O4: 399.1214 [M]þ; observed 399.1212.
135.6 (C-19), 133.5 (C-6), 133.1 (C-14), 132.4 (C-5), 131.3 (C-8, C-80),
129.0 (C-12, C-120), 128.4 (C-16, C-160), 128.4 (C-7, C-70), 128.1 (C-15,
C-150), 128.0 (C-21, C-210), 127.7 (C-9), 127.6 (C-11, C-110), 127.1 (C-
13), 126.7 (C-17), 125.9 (C-20, C-200), 125.2 (C-22), 123.3 (C-3), 109.6
(C-4), 48.3 (C-18); FT-IR (solid): ṽ (cmꢁ1) ¼ 1600, 1450, 1341, 805,
766, 750, 740, 695; HR-MS (EI): m/z calculated for C29H23N:
385.1830 [M]þ; observed 385.1835.
4.27. 1-Benzyl-2-methyl-5-phenyl-1H-pyrrole (21)
The reaction was refluxed for 2 days and worked-up according
to the general procedure. For purification column chromatography
(Hexane/EtOAc, 20:1, Rf ¼ 0.46) was performed. Light yellow oil,
175 mg, 71% yield. 1H-NMR (300 MHz, CD2Cl2):
d
[ppm] ¼ 7.35e7.19
(m, 9H, 7-H, 7’-H, 8-H, 80-H, 9-H, 13-H, 130-H, 14-H), 6.89 (d, 2H,
J ¼ 8.19 Hz, 12-H, 120-H), 6.18 (d, 1H, J ¼ 3.45 Hz, 3-H), 6.01 (dd, 1H,
J ¼ 3.45 Hz, J ¼ 0.84 Hz, 4-H), 5.15 (s, 2H, 10-H), 2.14 (s, 3H, 15-H);
4.31. Ethyl 1-benzyl-5-(4-bromophenyl)-2-phenyl-1H-pyrrole-3-
carboxylate (25)
13C-NMR (75 MHz, CD2Cl2):
d
[ppm] ¼ 139.1 (C-2), 134.4 (C-11),
The reaction was refluxed for 3 days and worked-up according
to the general procedure. For purification column chromatography
(n-hexane/EtOAc, 10:1, Rf ¼ 0.30) was performed. Colorless oil,
133.9 (C-6), 130.5 (C-5), 128.6 (C-8), 128.5 (C-9), 128.3 (C-7), 126.9
(C-14), 126.5 (C-12), 125.6 (C-13), 108.0 (C-3), 107.2 (C-4), 47.5 (C-
10), 12.3 (C-15); FT-IR (solid): ṽ (cmꢁ1) ¼ 2914, 1601, 1512, 1495,
1474, 1452, 1444, 1406, 1354, 1310, 1073, 1026, 748, 726, 695, 574,
536, 458; HR-MS (ESI): m/z calculated for C18H17N þ Hþ: 248.1434
[MþH]þ; observed 248.1437.
377 mg, 82% yield. 1H-NMR (300 MHz, CD2Cl2):
d
[ppm] ¼ 7.47 (d,
2H, J ¼ 8.55 Hz, 14-H, 140-H), 7.40e7.20 (m, 7H, 7-H, 70-H, 8-H, 80-H,
9-H, 15-H, 150-H), 7.19e7.07 (m, 3H, 20-H, 200-H, 21-H), 6.79 (s, 1H,
4-H), 6.66e6.57 (m, 2H, 19-H, 190-H), 5.05 (s, 2H, 17-H), 4.10 (q, 2H,
J ¼ 7.12 Hz, 11-H), 1.12 (t, 3H, J ¼ 7.12 Hz, 12-H); 13C-NMR (75 MHz,
4.28. 1-Benzyl-2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrole (22)
CD2Cl2):
d
[ppm] ¼ 164.2 (C-10), 140.2 (C-13), 138.0 (C-18), 133.8 (C-
6), 132.0 (C-2), 131.7 (C-5), 131.6 (C-14, C-140), 130.8 (C-7, C-70, C-8,
C-80), 128.3 (C-20, C-200), 128.3 (C-9), 127.7 (C-15, C-150), 127.1 (C-
21), 125.7 (C-19, C-190), 121.7 (C3), 114.4 (C-4), 111.2 (C-16), 59.4 (C-
11), 48.5 (C-17), 13.9 (C-12); FT-IR (solid): ṽ (cmꢁ1) ¼ 1712, 1474,
1454, 1413, 1267, 1176, 1100, 1073, 1035, 984, 836, 823, 778, 759,
736, 720, 706, 696; HR-MS (EI): m/z calculated for C26H22BrNO2:
459.0834 [M]þ; observed 459.0830.
The reaction was refluxed for 2 days and worked-up according
to the general procedure. For purification column chromatography
(n-hexane/EtOAc, 20:1, Rf ¼ 0.64) was performed. Off-white solid,
232 mg, 79% yield. m.p.: 87.9 ꢀC; 1H-NMR (300 MHz, CD2Cl2):
d
[ppm] ¼ 7.33e7.14 (m, 7H, C-8, C-13, C-130, C-14, C-140, C-15), 6.89
(d, 2H, J ¼ 6.84 Hz, 7-H, 7‘-H), 6.16 (d, 1H, J ¼ 3.45 Hz, 3-H), 6.00 (dd,
1H, J ¼ 3.45 Hz, J ¼ 0.78 Hz, 4-H), 5.12 (s, 2H, 11-H), 2.45 (s, 3H, 10-
H), 2.13 (s, 3H, 16-H); 13C-NMR (75 MHz, CD2Cl2):
d
[ppm] ¼ 139.1
4.32. 1-Benzyl-2,3,4,5-tetramethyl-1H-pyrrole (26)
(C-2), 130. 7 (C-5), 130.3 (C-12), 128.8 (C-14), 128.6 (C-7), 126.9 (C-
15), 126.4 (C-13), 125.8 (C-8), 125.4 (C-6), 107.9 (C-3), 107.2 (C-4),
47.5 (C-11), 15.5 (C-10), 12.3 (C-16); FT-IR (solid): ṽ (cmꢁ1) ¼ 2917,
1510, 1496, 1434, 1414, 1356, 1311, 1105, 1029, 818, 760, 727, 694;
HR-MS (ESI): m/z calculated for C19H19NS þ Hþ: 294.1311 [MþH]þ;
observed 294.1314.
The reaction was stirred for 5 min and worked-up according to
the general procedure. For purification column chromatography (n-
hexane/EtOAc, 10:1, Rf ¼ 0.85) was performed. Reddish oil, 175 mg,
82% yield. 1H-NMR (300 MHz,CD2Cl2):
d
[ppm] ¼ 7.32e7.19 (m, 3H,
9-H, 90-H, 10-H), 6.88 (d, 2H, J ¼ 6.9 Hz, 8-H, 80-H), 4.96 (s, 2H, 6-H),
2.03 (s, 6H, 11-H, 110-H),1.94 (s, 6H,12-H, 120-H); 13C-NMR (75 MHz,
4.29. 1-Benzyl-2-methyl-5-(4-(methylsulfonyl)phenyl)-1H-pyrrole
(23)
CD2Cl2):
d
[ppm] ¼ 139.6 (C-7), 128.5 (C-9, C-90), 126.7 (C-2, C-5),
125.8 (C-8, C-80), 122.3 (C-10), 113.0 (C-3, C-4), 46.7 (C-6), 9.5 (C-11,
C-110), 9.2 (C-12, C-120); FT-IR (solid): ṽ (cmꢁ1) ¼ 2916, 2857, 1643,
1495, 1453, 1393, 1351, 1215, 1190, 1101, 1029, 729, 695; HR-MS
(ESI): m/z calculated for C15H19N þ Hþ: 214.1590 [MþH]þ; observed
214.1589.
The reaction was refluxed for 2 days and worked-up according
to the general procedure. For purification column chromatography
(n-hexane/EtOAc, 2:1, Rf ¼ 0.55) was performed. Yellow solid,
254 mg, 78% yield. m.p.: 140.4 ꢀC; 1H-NMR (300 MHz, CD2Cl2):
d
[ppm] ¼ 7.80 (d, 2H, J ¼ 8.31 Hz, 7-H, 7’-H), 7.46 (d, 2H, J ¼ 8.31 Hz,
4.33. 1-Benzyl-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-
pyrrole-3-carboxamide (27)
8-H, 80-H), 7.35e7.21 (m, 3H, 14-H, 140-H, 15-H), 6.91 (d, 2H,
J ¼ 7.29 Hz, 13-H, 130-H), 6.36 (d, 1H, J ¼ 3.57 Hz, 3-H), 6.08 (d, 1H,
J ¼ 3.57 Hz, 4-H), 5.19 (s, 2H, 11-H), 3.00 (s, 3H, 10-H), 2.17 (s, 3H,16-
The reaction mixture was heated for 3 days in a pressure tube at
95 ꢀC. Afterwards, the reaction mixture was diluted with iPrOH and
acetone (1:1, ca. 15 mL) and cooled to 0 ꢀC. The precipitated solid
was isolated by filtration, washed with cold water to remove trace
solvents, and dried in vacuo to afford the desired product. Yellow
crystalline solid, 344 mg, 34% yield. m.p.: 219 ꢀC; 1H-NMR
H); 13C-NMR (75 MHz, CD2Cl2):
d
[ppm] ¼ 139.1 (C-2), 138.5 (C-9),
137.9 (C-6), 132.9 (C-12), 132.5 (C-5), 128.8 (C-14, C-140), 128.3 (C-8,
C-80), 127.5 (C-78, C-70), 127.2 (C-15), 125.5 (C-13, C-130), 110.3 (C-3),
108.1 (C-4), 47.8 (C-11), 44.4 (C-10), 12.3 (C-16); FT-IR (solid): ṽ
(cmꢁ1) ¼ 2922, 1593, 1316, 1302, 1147, 964, 776, 761, 738, 726, 697;
HR-MS (ESI): m/z calculated for C19H19NO2S þ Hþ: 326.1209
[MþH]þ; observed 326.1211.
(300 MHz, CD2Cl2):
d
[ppm] ¼ 7.37e6.84 (m, 19, H, 6-H, 60-H, 7-H,
70-H, 10-H, 100-H, 11-H, 110-H, 12-H, 15-H, 150-H, 16-H, 160-H, 17-H,
22-H, 220-H, 23-H, 230-H, 24-H), 5.09 (s, 2H, 20-H), 3.24 (sept, 1H,
18-H), 1.36 (d, 6H, J ¼ 6.81 Hz, 19-H, 190-H); 13C-NMR (75 MHz,
4.30. 1-Benzyl-2,3,5-triphenyl-1H-pyrrole (24)
CD2Cl2):
d
[ppm] ¼ 160.68 (C-13), 141.31 (C-4), 138.53 (C-9), 138.47
The reaction was refluxed for 3 days and worked-up according
to the general procedure. For purification column chromatography
(n-hexane/EtOAc, 10:1, Rf ¼ 0.63) was perfomed. White solid,
285 mg, 74% yield. m.p.: 167.5 ꢀC; 1H-NMR (300 MHz, CD2Cl2):
(C-14), 134.83 (C-21), 133.17 (C-7, C-70), 130.46 (C-11, C-110), 129.34
(C-1), 128.63 (C-6, C-60), 128.29 (C-10, C-100), 128.04 (C-5), 127.20
(C-12), 126.54 (C-17), 125.52 (C-23, C-230), 123.47 (C-22, C-220),
121.80 (C-2), 119.46 (C-16, C-160), 116.12 (C-3), 115.16 (C-24), 114.87
(C-15, C-150), 47.91 (C-20), 26.63 (C-18), 21.13 (C-19, C-190); 19F-
d
[ppm] 7.55e7.00 (m,18H, 7-H, 70-H, 8-H, 80-H, 9-H,11-H,110-H,12-
H, 120-H, 13-H, 15-H, 150-H, 16-H, 160-H, 17-H, 21-H, 210-H, 22-H),
NMR (282 MHz, CD2Cl2):
d
[ppm] ¼ ꢁ114.44; FT-IR (solid): ṽ
6.66e6.61 (m, 2H, 20-H, 200-H), 6.57 (s, 1H, 4-H), 5.13 (s, 2H, 18-H);
(cmꢁ1) ¼ 3403, 2962, 1661, 1595, 1563, 1525, 1496, 1437, 1309, 1242,
1217, 1154, 845, 752, 736, 693: HR-MS (ESI): m/z calculated for
13C-NMR (75 MHz, CD2Cl2):
d
[ppm] ¼ 139.1 (C-2), 136.3 (C-10),
12

€
R.H.E. Schirmacher, D. Rosch and F. Thomas
Tetrahedron 83 (2021) 131985
C33H29FN2O þ Hþ: 489.2337 [MþH]þ; observed 489.2338.
J ¼ 8.85 Hz, 7-H, 7-H, 70-H, 70-H), 8.15 (d, 4H, J ¼ 8.85 Hz, 6-H, 6-H,
60-H, 60-H), 7.56 (s, 2H, 2-H, 3-H); 13C-NMR (75 MHz, DMSO-d6):
4.34. General procedure for the synthesis of di-to tetra-substituted
furans or thiophenes
d
[ppm] ¼ 153.0 (C-1, C-4), 135.7 (C-8, C-80), 125.1 (C-7, C-7, C-70, C-
70), 125.0 (C-6, C-6, C-60, C-60), 113.6 (C-5, C-50), 100.0 (C-2, C-3); FT-
IR (solid): ṽ (cmꢁ1) ¼ 3117, 1594, 1504, 1485, 1327, 1287, 1105, 1035,
930, 851, 792, 750, 690; HR-MS (EI): m/z calculated for C16H10N2O5:
310.0584 [M]þ; observed 310.0582.
The 1,4-diketone (2 mmol) was dissolved in 4e10 mL 1,1,1,3,3,3-
hexafluoroisopropanol at ambient temperature. Hydrochloric acid
(15 mol-%) for furans or Lawessons’s reagent (3.5 mmol) for thio-
phenes was added slowly and the mixture was stirred for the
indicated time under reflux conditions. The reaction mixture was
allowed to cool to room temperature and the solvent was removed.
The residue was dissolved in an appropriate solvent and the
insoluble solids were removed by filtration. The organic phase was
dried over MgSO4 and the solvent was removed under reduced
pressure. The residue was purified with an appropriate method
(column chromatography or recrystallization).
4.39. 2-Methyl-5-phenylfuran (32)
The reaction was refluxed for 6 h and worked-up according to
the general procedure. For purification column chromatography (n-
pentane, Rf ¼ 0.82) was performed. Slightly yellow oil, 128 mg, 81%
yield. 1H-NMR (300 MHz, CD2Cl2):
d
[ppm] ¼ 7.62 (d, 2H,
J ¼ 7.38 Hz, 7-H, 70-H), 7.36 (t, 2H, J ¼ 7.77 Hz, 8-H, 80-H), 7.22 (t, 1H,
J ¼ 7.95 Hz, 9-H), 6.57 (d, 1H, J ¼ 3.20 Hz, 3-H), 6.08 (d, 1H,
J ¼ 3.20 Hz, 2-H), 2.37 (s, 3H, 5-H); 13C-NMR (75 MHz, CD2Cl2):
4.35. 2,5-bis(4-Cyanophenyl)furan (28)
d
[ppm] ¼ 152.1 (C-6), 131.1 (C-4), 128.6 (C-8, C-80), 126.7 (C-9),
123.1 (C-7, C-70), 107.6 (C-2), 105.9 (C-3), 100.0 (C-1), 13.4 (C-5); FT-
IR (solid): ṽ (cmꢁ1) ¼ 2918,1667,1595,1546,1488,1446,1205,1065,
1021, 784, 756, 589, 661; HR-MS (EI): m/z calculated for C11H10O:
158.0732 [M]þ; observed 158.0728.
The reaction was refluxed for 2 h and worked-up according to
the general procedure. For purification the crude product was
recrystallized from THF. Yellow solid, 238 mg, 88% yield. m.p.:
292.1 ꢀC; 1H-NMR (300 MHz, CD2Cl2):
d
[ppm] ¼ 7.86 (d, 4H,
J ¼ 8.7 Hz, 6-H, 6-H, 60-H, 60-H), 7.72 (d, 4H, J ¼ 8.7 Hz, 7-H, 7-H, 70-
4.40. 2-Methyl-5-(4-(methylthio)phenyl)furan (33)
H, 70-H), 6.99 (s, 2H, 2-H, 3-H); 13C-NMR (75 MHz, CD2Cl2):
d
[ppm] ¼ 152.8 (C-1, C-4), 133.8 (C-5, C-50), 132.7 (7-C, 7-C, 70-C, 70-
The reaction was refluxed for 2 h and worked-up according to
the general procedure. For purification column chromatography (n-
hexane/EtOAc, 10:1, Rf ¼ 0.74) was performed. Yellow solid, 177 mg,
C), 124.1 (6-C, 6-C, 60-C, 60-C), 118.7 (9-C, 90-C), 110.9 (8-C, 80-C),
110.7 (2-C, 3-C); FT-IR (solid): ṽ (cmꢁ1) ¼ 3352, 2222, 1605, 842,
792, 664; HR-MS (ESI): m/z calculated for C18H10N2O þ Naþ:
293.0685 [MþNa]þ; observed 293.0678.
87% yield. m.p.: 81.8 ꢀC; 1H-NMR (300 MHz, CD2Cl2):
d
[ppm] ¼ 7.55
(d, 2H, J ¼ 8.55 Hz, 6-H, 60-H), 7.24 (d, 2H, J ¼ 8.55 Hz, 5-H, 50-H),
6.52 (d, 1H, J ¼ 3.18 Hz, 2-H), 6.07 (d, 1H, J ¼ 3.18 Hz, 3-H), 2.49 (s,
3H, 10-H), 2.35 (s, 3H, 9-H); 13C-NMR (75 MHz, CD2Cl2):
4.36. 2,5-Diphenylfuran (29)
d
[ppm] ¼ 152.0 (C-1), 151. 8 (C-4), 136.9 (C-8), 128.1 (C-5), 126.6 (C-
The reaction was refluxed for 3 h and worked-up according to
the general procedure. For purification column chromatography (n-
hexane/EtOAc, 10:1, Rf ¼ 0.85) was performed. White solid, 176 mg,
6, C-60), 123.6 (C-7, C-70), 107.7 (C-3), 105.6 (C-2), 15.6 (C-9), 13.4 (C-
10); FT-IR (solid): ṽ (cmꢁ1) ¼ 2912, 2402, 1689, 1553, 1492, 1433,
1073, 1020, 974, 793, 771; HR-MS (EI): m/z calculated for C12H12OS:
204.0609 [M]þ; observed 204.0599.
80% yield. m.p.: 91 ꢀC; 1H-NMR (300 MHz, CD2Cl2):
d
[ppm] ¼ 7.79
(d, 4H, J ¼ 7.29 Hz, 6-H, 60-H), 7.45 (t, 4H, J ¼ 7.29 Hz, 7-H, 70-H), 7.31
(7, 2H, J ¼ 7.29 Hz, 8-H, 80-H), 6.80 (s, 2H, 2-H, 3-H); 13C-NMR
4.41. 2-Methyl-5-(4-(methylsulfonyl)phenyl)furan (34)
(75 MHz, CD2Cl2):
d
[ppm] ¼ 155.3 (C-1, C-4),130.7 (C-5, C-50), 128.7
(C-7, C-70), 127.4 (C-8, C-80), 123.6 (C-6, C-60), 107.3 (C-2, C-3); FT-IR
(solid): ṽ (cmꢁ1) ¼ 3039,1610,1488,1480,1260,1021, 928, 794, 754,
689, 671. HR-MS (EI): m/z calculated for C16H12O: 220.0888 [M]þ;
observed 220.0890.
The reaction was refluxed for 4 h and worked-up according to
the general procedure. For purification column chromatography (n-
hexane/EtOAc, 4:1, Rf ¼ 0.74) was performed. White solid, 194 mg,
82% yield. m.p. (decomposition): 140 ꢀC; 1H-NMR (300 MHz,
CD2Cl2):
d
[ppm] ¼ 7.89 (d, 2H, J ¼ 8.61 Hz, 6-H, 60-H), 7.79 (d, 2H,
4.37. 2,5-bis(4-Bromophenyl)furan (30)
J ¼ 8.61 Hz, 7-H, 70-H), 6.78 (d, 1H, J ¼ 3.29 Hz, 2-H), 6.15 (dd, 1H,
J ¼ 3.29 Hz, J ¼ 0.87 Hz, 3-H), 3.04 (s, 3H, 9-H), 2.39 (s, 3H, 10-H);
The reaction was refluxed for 2 h and worked-up according to
the general procedure. For purification the crude product was
recrystallized from THF. Colorless needles, 342 mg, 91% yield. m.p.:
13C-NMR (75 MHz, CD2Cl2):
d
[ppm] ¼ 154.2 (C-5),150.3 (C-4),138.0
(C-8), 135.8 (C-1), 127.9 (C-6, C-60), 123.4 (C-7, C-70), 109.4 (C-2),
108.4 (C-3), 44.5 (C-9), 13.5 (C-10); FT-IR (solid): ṽ (cmꢁ1) ¼ 2919,
1590, 1300, 1279, 1143, 1089, 1026, 835, 796, 775; HR-MS (ESI): m/z
calculated for C12H12O3S þ Hþ: 237.0580 [MþH]þ; observed
237.0582.
205.9 ꢀC; 1H-NMR (300 MHz, DMSO-d6):
d
[ppm] ¼ 7.79 (d, 4H,
J ¼ 8.58 Hz, 7-H, 7-H, 70-H, 70-H), 7.65 (d, 4H, J ¼ 8.58 Hz, 6-H, 6-H,
60-H, 60-H), 7.17 (s, 2H, 2-H, 3-H); 13C-NMR (75 MHz, DMSO-d6):
d
[ppm] ¼ 152.4 (C-1, C-4), 132.3 (C-6, C-6, C-60, C-60), 129.6 (C-5, C-
50), 126.0 (C-7, C-7, C-70, C-70), 121.1 (C-8, C-80), 109.7 (C-2, C-3); FT-
IR (solid): ṽ (cmꢁ1) ¼ 1471, 1406, 1106, 1072, 1020, 1004, 924, 824,
790, 715, 669; HR-MS (EI): m/z calculated for C16H10Br2O: 375.9098
[M]þ; observed 375.9104.
4.42. 2,3,5-Triphenylfuran (35)
The reaction was refluxed for 4 h and worked-up according to
the general procedure. For purification column chromatography (n-
hexane/EtOAc, 20:1, Rf ¼ 0.79) was performed. Colorless crystals,
207 mg, 70% yield. m.p.: 95 ꢀC; 1H-NMR (300 MHz, CD2Cl2):
4.38. 2,5-bis(4-Nitrophenyl)furan (31)
d
[ppm] ¼ 7.79 (d, 2H, J ¼ 7.71 Hz, 14-H, 140-H), 7.62 (d, 2H,
The reaction was refluxed for 2 h and worked-up according to
the general procedure. For purification the crude product was
recrystallized from THF. Orange solid, 264 mg, 85% yield. m.p.:
J ¼ 7.17 Hz, 6-H, 60-H), 7.51e7.23 (m, 11H, 7-H, 70H, 8-H, 10-H, 100-H,
11-H, 110-H, 12-H, 15-H, 150-H, 16-H), 6.87 (s, 1H, 2-H); 13C-NMR
(75 MHz, CD2Cl2):
d
[ppm] ¼ 152.5 (C-13), 147.9 (C-1), 134.2 (C-9),
270.4 ꢀC; 1H-NMR (300 MHz, DMSO-d6):
d
[ppm] ¼ 8.35 (d, 4H,
131.1 (C-13), 130.4 (C-5), 128.8 (C-10, C-100), 128.7 (C-15, C-150),
13

€
R.H.E. Schirmacher, D. Rosch and F. Thomas
Tetrahedron 83 (2021) 131985
128.6 (C-7, C-70), 127.4 (C-11, C-110), 127.6 (C-16), 127.6 (C-8), 127.3
(C-12), 126.1 (C-6, C-60), 124.6 (C-3), 123.7 (C-14, C-140), 109.5 (C-2);
FT-IR (solid): ṽ (cmꢁ1) ¼ 2922, 2360, 1487, 1143, 950, 804, 766, 753,
687, 568; HR-MS (EI): m/z calculated for C22H16O: 296.1201 [M]þ;
observed 296.1202.
4.46. 2,5-bis(4-Bromophenyl)thiophene (39)
1,4-bis(4-Bromo-phenyl)butane-1,4-dione (402.3 mg, 1.0 mmol,
1 equiv.) and Lawesson’s Reagent (636.2 mg, 1.5 mmol, 3 equiv.)
were dissolved in 1,1,1,3,3,3-hexafluoroisopropanol (6 mL) in an
atmosphere of argon. The reaction mixture was refluxed for 18 h.
The solvent was evaporated and the yellow residue was purified
with column chromatography (n-hexane/EtOAc 25:1, Rf ¼ 0.55).
White solid, 328.5 mg 83% yield. m.p.: 206.5 ꢀC; 1H-NMR
4.43. Ethyl 5-(4-bromophenyl)-2-phenylfuran-3-carboxylate (36)
The reaction was refluxed for 4 h and worked-up according to
the general procedure. For purification column chromatography (n-
hexane/EtOAc, 3:1, Rf ¼ 0.88) was performed. Colorless liquid,
(300 MHz, CD2Cl2):
d
[ppm] ¼ 7.52 (s, 8H, 7-H, 70-H, 8-H, 80-H), 7.32
(s, 2H, 3-H, 4-H); 13C-NMR (75 MHz, CD2Cl2):
d
[ppm] ¼ 142.59 (C-
2, C-5), 133.1 (C-6, C-60), 132.0 (C-8, C-80), 127.0 (C-7, C-70), 124.6 (C-
3, C-4), 121.4 (C-9, C-90); FT-IR (solid): ṽ (cmꢁ1) ¼ 3076, 1446, 1400,
1118, 934, 825, 794; HR-MS (EI): m/z calculated for C16H10Br2S:
391.8870 [M]þ; observed 391.8867.
315 mg, 85% yield. 1H-NMR (300 MHz, CD2Cl2):
d
[ppm] ¼ 8.06 (d,
2H, J ¼ 8.34 Hz, 13-H, 130-H), 7.64 (d, 2H, J ¼ 8.58 Hz, 6-H, 60-H), 7.57
(d, 2H, J ¼ 8.58 Hz, 7-H, 70-H), 7.52e7.39 (m, 3H, 14-H, 140-H, 15-H),
7.13 (s,1H, 2-H), 4.31 (q, 2H, J ¼ 7.11 Hz,10-H),1.35 (t, 3H, J ¼ 7.11 Hz,
11-H); 13C-NMR (75 MHz, CD2Cl2):
d
[ppm] ¼ 163.1 (C-9), 156.5 (C-
4.47. 2,5-bis(4-Nitrophenyl)thiophene (40)
12), 151.3 (C-5), 132.0 (C-7, C-70), 129.6 (C-1), 129.4 (C-15), 128.8 (C-
4), 128.3 (C-13, C-130), 128.1 (C-14, C-140), 125.4 (C-6, C-60), 121.8 (C-
8), 116.1 (C-3), 108.5 (C-2), 60.7 (C-10), 14.0 (C-11); FT-IR (solid): ṽ
(cmꢁ1) ¼ 2973, 2360, 1271, 1479, 1267, 1238, 1157, 1094, 1071, 825,
813, 776, 753, 683; HR-MS (EI): m/z calculated for C19H16BrO3:
371.0277 [M]þ; observed 371.0280.
1,4-bis(4-Nitrophenyl)-butane-1,4-dione (330 mg, 1.0 mmol, 1
equiv.) and Lawesson’s Reagent (622.6 mg, 1.5 mmol, 3 equiv.) were
dissolved in 1,1,1,3,3,3-hexafluoroisopropanol (6 mL) in an atmo-
sphere of argon. The reaction mixture was refluxed for 8 h. The
solvent was evaporated and the yellow residue was refluxed in
saturated sodium carbonate solution (20 mL) for 14 h. The sus-
pension was then extracted with dichloromethane (3 ꢂ 30 mL). The
combined organic layers were washed with saturated sodium car-
bonate solution (30 mL) and brine (30 mL). After drying over
magnesium sulfate and evaporation of the solvent the product was
obtained as a highly hygroscopic orange solid. 270 mg, 82% yield.
m.p. (decomposition): 257.0 ꢀC; 1H-NMR (300 MHz, CD2Cl2):
4.44. 5-(4-Fluorophenyl)-2-isopropyl-N,4-diphenylfuran-3-
carboxamide (37)
The reaction was refluxed for 14 h and worked-up according to
the general procedure. For purification column chromatography (n-
hexane/EtOAc, 4:1, Rf ¼ 0.62) was performed. Brown solid, 219 mg,
55% yield. m.p.: 160 ꢀC; 1H-NMR (300 MHz, CD2Cl2):
d
[ppm] ¼ 8.28 (d, 4H, J ¼ 8.89 Hz, 8-H, 80-H), 7.83 (d, 4H,
J ¼ 8.91 Hz, 7-H, 70-H), 7.57 (s, 2H, 3-H, 4-H); 13C NMR could not be
d
[ppm] ¼ 7.38e7.21 (m, 8H, 11-H, 110-H, 12-H, 15-H, 150-H, 16-H,
measured because the product was not soluble in common organic
160-H, 17-H), 7.21e7.12 (m, 2H, 10-H, 100-H), 6.89 (m, 2H, 6-H, 60-H),
solvents (CD2Cl2, DMSO-d6, acetone-d6); FT-IR (solid):
ṽ
6.72 (m, 2H, 7-H, 70-H), 2.43 (sept, 1H, J ¼ 6.78 Hz, 18-H), 1.01 (d, 6H,
(cmꢁ1) ¼ 1587, 1506, 1335, 1278, 1107, 846, 796, 746, 682; HR-MS
(EI): m/z calculated for C16H10N2O4S: 326.0361 [M]þ; observed
326.0358.
J
d
¼
6.78 Hz, 19-H, 190-H); 13C-NMR (75 MHz, CD2Cl2):
[ppm] ¼ 186.04 (C-4), 168.82 (C-13), 163.38 (C-8), 160.10 (C-1),
135.09 (C-14), 134.79 (C-9), 132.06 (C-6, C-60), 130.77 (C-11, C-110),
130.02 (C-15), 128.65 (C-16, C-160), 128.10 (C-10, C-100), 127.40 (C-
15, C-150), 127.33 (C-12), 127.10 (C-17), 116.55 (C-2), 114.60 (C-7, C-
70), 105.05 (C-3), 30.88 (C-18), 18.95 (C-19, C-190); 19F-NMR
4.48. 2-Methyl-5-(4-(methylthio)phenyl)thiophene (41)
1-(4-(Methylthio)phenyl)pentane-1,4-dione
(223.7
mg,
(282 MHz, CD2Cl2):
d
[ppm]
¼
ꢁ114.49; FT-IR (solid):
ṽ
(cmꢁ1) ¼ 2965, 1592, 1504, 1489, 1222, 1156, 1074, 845, 740, 704,
687; HR-MS (ESI): m/z calculated for C26H22FNO2þHþ: 400.1707
[MþH]þ; observed 400.1699.
1.0 mmol, 1 equiv.) and Lawesson’s Reagent (638.2 mg, 1.5 mmol, 3
equiv.) were dissolved in 1,1,1,3,3,3-hexafluoroisopropanol (6 mL)
in an atmosphere of argon. The reaction mixture was refluxed for
20 h. The solvent was evaporated and the yellow residue was pu-
rified with column chromatography (n-hexane/EtOAc 25:1,
Rf ¼ 0.65). Light yellow solid,161.0 mg, 73% yield. m.p.: 117.7 ꢀC; 1H-
4.45. 2,5-Diphenylthiophene (38)
NMR (300 MHz, CD2Cl2):
d
[ppm] ¼ 7.47 (d, 2 H, J ¼ 8.37, 7-H, 70-H),
1,4-Diphenylbutane-1,4-dione (200.2 mg, 0.84 mmol, 1 equiv.)
and Lawesson’s Reagent (564.5 mg, 1.26 mmol, 3 equiv.) were dis-
solved in 1,1,1,3,3,3-hexafluoroisopropanol (6 mL) in an atmosphere
of argon. The reaction mixture was refluxed for 18 h. The solvent
was evaporated and the yellow residue was purified with column
chromatography (n-hexane/EtOAc 25:1, Rf ¼ 0.6). The 1H-NMR
spectrum revealed a mixture of the product and the corresponding
furan in a ratio of 4:1. 139.0 mg, 70% yield. After recrystallization
from hexane the product was obtained as white crystals. 29.5 mg,
15% yield. A furan impurification of 2% was detected by 1H-NMR
spectroscopy. m.p.: 151.7 ꢀC; 1H-NMR (300 MHz, CD2Cl2):
7.23 (d, 2 H, J ¼ 8.34 Hz, 8-H, 80-H), 7.09 (d, 2H, J ¼ 3.51 Hz, 4-H),
6.73 (d, 2 H, J ¼ 3.48 Hz, 3-H), 2.49 (s, 6 H, 11-H, 12-H); 13C-NMR
(75 MHz, CD2Cl2):
d
[ppm] ¼ 141.9 (C-9), 140.0 (C-5), 137.9 (C-2),
132.1 (C-6), 127.3 (C8), 126.8 (C-4), 126.2 (C-7), 123.2 (C-3), 16.2 (C-
11), 15.7 (C-12); FT-IR (solid): ṽ (cmꢁ1) ¼ 2915, 1497, 1404, 1095,
944, 815, 796; HR-MS (EI): m/z calculated for C12H12S2: 220.0380
[M]þ; observed 220.0379.
4.49. 2,3,5-Triphenylthiophene (42)
1,2,4-Triphenylbutane-1,4-dione (317.2 mg, 1.0 mmol, 1 equiv.)
and Lawesson’s Reagent (609.4 mg, 1.5 mmol, 3 equiv.) were dis-
solved in 1,1,1,3,3,3-hexafluoroisopropanol (9 mL) in an atmosphere
of argon. The reaction mixture was refluxed for 14 h. The solvent
was evaporated and the yellow residue purified with column
chromatography (n-hexane/EtOAc 25:1, Rf ¼ 0.7). The 1H-NMR
spectrum showed a mixture of the product and the corresponding
d
[ppm] ¼ 7.66 (d, 4H, J ¼ 7.26 Hz, 7-H, 70-H), 7.41 (t, 4H, J ¼ 7.26 Hz,
8-H, 80-H), 7.37e7.25 (m, 4H, 3-H, 4-H, 9-H, 90-H); 13C-NMR
(75 MHz, CD2Cl2):
d
[ppm] ¼ 143.5 (C-2, C-5),134.2 (C-6, C-60),128.9
(C-8, C-80), 127.6 (C-9, C-90), 125.5 (C-7, C-70), 124.1 (C-3, C-4); FT-IR
(solid): ṽ (cmꢁ1) ¼ 2158, 1453, 939, 902, 803, 746, 682; HR-MS (EI):
m/z calculated for C16H12S: 236.0660 [M]þ; observed 236.0660.
14

€
R.H.E. Schirmacher, D. Rosch and F. Thomas
Tetrahedron 83 (2021) 131985
furan in a ratio of 1:1. Recrystallization from n-hexane had no effect
on the purity. The mixture was obtained as slightly yellow crystals,
300.1 mg, 91% yield. HR-MS (EI): m/z calculated for C22H16S:
312.0973 [M]þ; observed 312.0974.
methyl tert-butyl ether. The combined organic phases were evap-
orated and the resulting yellowish solid was recrystallized from
EtOAc. Pale yellow solid, 661 mg, 90% yield. m.p.: 152 ꢀC; 1H-NMR
(300 MHz, DMSO-d6):
d
[ppm] ¼ 7.37e7.25 (m, 8H, 7-H, 7’-H, 8-H,
80-H), 7.18e7.04 (m, 3H, 15-H, 150-H, 16-H), 6.59 (d, 2H, J ¼ 6.78 Hz,
14-H, 140-H), 6.30 (s, 2H, 3-H, 4-H), 5.29 (2, 2H, 12-H), 3.69 (s, 4H,
10-H, 100-H), 2.96 (s br, 4H, 11-H, 110-H); 13C-NMR (75 MHz, DMSO-
4.50. 4,4’-(1-Benzyl-1H-pyrrole-2,5-diyl)dibenzoic acid (43)
A mixture of 4,4’-(1-benzyl-1H-pyrrole-2,5-diyl)dibenzonitrile
(718 mg, 2 mmol, 1 equiv) and KOH (898 mg, 16 mmol, 8 equiv) was
refluxed in EtOH/H2O (15 mL, 2:1) for 3 days. Ethanol was removed
under reduced pressure and the resulting suspension was filtered.
The filtrate was acidified to pH 2 with concentrated hydrochloric
acid. The resulting precipitate was isolated by filtration, washed
with cold water and dried under reduced pressure. Light yellow
solid, 746 mg, 96% yield. m.p.: 273 ꢀC; 1H-NMR (300 MHz, DMSO-
d6):
d
[ppm] ¼ 143.00 (C-9, C-90), 139.3 (C-13),136.2 (C-2, C-5), 131.1
(C-6, C-60), 128.3 (C-15, C-150), 128.1 (C-8, C-80), 127.1 (C-7, C-70),
126.7 (C-16), 125.2 (C-14, C-140), 109.5 (C-3, C-4), 48.0 (C-12), 45.3
(C-10, C-100); FT-IR (solid): ṽ (cmꢁ1) ¼ 3024, 2849, 1570, 1496,
1438, 1416, 1382, 1360, 1321, 1049, 1016, 968, 819, 769, 729, 694;
HR-MS (ESI): m/z calculated for C25H25N3þHþ: 368.2121 [MþH]þ;
observed 368.2118.
d6):
d
[ppm] ¼ 12.91 (s, 2H, CO2H), 7.92 (d, 4H, J ¼ 8.55 Hz, 8-H, 80-
Declaration of competing interest
H), 7.56 (d, 4H J ¼ 8.55 Hz, 7-H, 70-H), 7.13e7.01 (m, 3H, 14-H, 140-H,
15-H), 6.56e6.47 (m, 4H, 3-H, 4-H, 13-H, 130-H), 5.38 (s, 2H, 11-H);
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
13C-NMR (75 MHz, DMSO-d6):
d
[ppm] ¼ 167.5 (C-10, C-100), 138.9
(C-13), 137.4 (C-2, C-5), 137.4 (C-6, C-60), 130.1 (C-8, C-8‘), 129.5 (C-9,
C-9‘), 128.8 (C-14, C-14‘), 128.6 (C-7, C-7‘), 127.4 (C-15), 125.8 (C-13,
C-13‘), 112.1 (C-3, C-4), 49.2 (C-11); FT-IR (solid):
ṽ
Acknowledgements
(cmꢁ1) ¼ 3130e2020, 2969, 1698, 1604, 1422, 1278, 915, 866, 776,
701; HR-MS (ESI): m/z calculated for C25H19NO4þHþ: 398.1387
[MþH]þ; observed 398.1385.
R.H.E.S. and F.B.T. are grateful for funding from the FCI (Fonds
der Chemischen Industrie) and infastructre of the Center for Bio-
structural Imaging of Neurodegeneration. Furthermore, we thank
€
€
4.51. 4,4’-(1-Benzyl-1H-pyrrole-2,5-diyl)dibenzamide (44)
Prof. Dr. Ulf Diederichsen (Georg-August Universitat Gottingen,
Germany) for general scientific support.
A mixture of 4,4’-(1-benzyl-1H-pyrrole-2,5-diyl)dibenzonitrile
(718 mg, 2 mmol, 1 equiv) and sodium perborate (1.7 g, 11.1 mmol,
5.5 equiv) was dissolved in MeOH/H2O (120 mL, 5:1) and equili-
brated for 2 days at 60 ꢀC. After cooling to room temperature a
crystalline solid was formed and was filtered off along with boric
acid and unreacted sodium perborate. The filter cake was washed
thoroughly with water to remove water soluble salts and, after-
wards, with dichloromethane to remove traces of unreacted start-
ing material. The remaining solid was dissolved in a mixture of THF
and Et2O, washed with brine and dried over Na2SO4. The solvent
was removed under reduced pressure and the product was ob-
tained as light yellow crystals. 506 mg, 64% yield. m.p.: 242 ꢀC; 1H-
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.131985.
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16