General Transition Metal-Free Synthesis of NH-Pyrroles from Secondary Alcohols and 2-Aminoalcohols

Article abstract of DOI:10.1021/acs.joc.8b03215

A novel, transition metal-free and one-pot methodology to synthesize various substituted NH-pyrroles from readily available building blocks such as secondary alcohols and 2-aminoalcohols is described. The process is based on the venerable Oppenauer-Woodward oxidation, which uses benzophenone as an inexpensive reagent to achieve oxidation of secondary alcohols under mild condition to ketones, further in situ condensation with aminoalcohol, and oxidative cyclization to the target pyrrole ring. The reaction occurs under basic conditions, and features a broad substrate scope combined with very good tolerance for sensitive functional groups. This method can be used to synthesize various substituted pyrroles useful as a starting material for broad applications.

Full text of DOI:10.1021/acs.joc.8b03215

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Article
General Transition Metal-free Synthesis of NH-
Pyrroles from Secondary Alcohols and 2-Aminoalcohols
Besir Krasniqi, Kayle Geerts, and Wim Dehaen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03215 • Publication Date (Web): 06 Feb 2019
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General Transition Metal-free Synthesis of NH-Pyrroles from
Secondary Alcohols and 2-Aminoalcohols
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Besir Krasniqi, Kayle Geerts and Wim Dehaen *
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Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, 3000
Leuven, Belgium.
ABSTRACT: A novel, transition-metal
free and one pot methodology to synthesize
various substituted NH-pyrroles from
readily available building blocks such as
secondary alcohols and 2-aminoalcohols is
described. The process is based on the
venerable Oppenauer–Woodward oxidation which uses benzophenone as an inexpensive reagent to achieve
oxidation of secondary alcohols under mild condition to ketones, further in situ condensation with aminoalcohol
and oxidative cyclization to the target pyrrole ring. The reaction occurs under basic conditions, and features a broad
substrate scope combined with very good tolerance for sensitive functional-groups. This method can be used to
synthesize various substituted pyrroles useful as a starting material for broad applications.
INTRODUCTION
low, while other methods have issues with
availability of starting materials, regiospecificity,
multistep synthetic operation, compatibility etc.
Therefore, the direct synthesis of pyrroles using
readily available starting materials like alcohols
or ketones seems to be the preferred choice. In
1980 Trofimov et al. described a simple method
to synthesize pyrroles from alkyl or cyclic oximes
and acetylene, as well other alkynes as
inexpensive starting materials. This method is
effective, but it suffers from several drawbacks
such as selectivity due to formation of substantial
The synthesis of functionalized pyrroles over the
past decade has received considerable attention.
These heterocycles are crucial starting materials
for the synthesis of dyes, porphyrins, and many
other functional materials.
1
Pyrroles are
important motifs in some modern drugs with
antibacterial, 2 antifungal 3 and anti-inflammatory
4
properties.
Drugs like Atorvastatin (lipid-
lowering agent), Ketorolac (nonsteroidal anti-
inflammatory drug) and Sunitinib (anti-cancer)
are some medicinally important derivatives of
pyrroles. 5 Due to the importance of these pyrrole
derivatives, it is necessary to develop sustainable
methodologies that preferably are transition metal
free, one-pot, and one step. Well known classical
amounts of N-vinyl pyrrole as a side product, 9a
a
modern version of Trofimov is also well known.
9b
In recent years’ various strategies have been
developed, one of them being dehydrogenation of
secondary alcohols to ketones in situ and then
condensation/coupling with β-amino alcohols. In
this regard, a very sophisticated and attractive
6
7
methods like the Hantzsch, Knorr, and Paal–
8
Knorr
reactions are available for pyrrole
synthesis but there are some limitations e.g. the
Knorr method is limited in scope, usually works
only with activated ketones and the yields are
catalytic dehydrogenative method was reported
10a
by Milstein (Scheme 1, top).
This method is
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called acceptorless dehydrogenation, it uses
Oppenauer oxidation can be considered the
opposite of the
pincer ruthenium catalysts and potassium tert-
butoxide to dehydrogenate the secondary alcohol
to a ketone accompanied with hydrogen and
water liberation. Then in the presence of β-amino
alcohol, condensation occurs into imino-alcohol,
and the next step involves subsequent
dehydrogenation of alcohol from imino-alcohol
to aldehyde or ketone in situ, which then leads to
the desired pyrrole formation under the basic
Scheme 1. Synthesis of pyrroles from ketones or secondary
alcohols and β-amino alcohols using transition metal catalyst
(top), transition metal free pyrrole synthesis using
benzophenone as an oxidant (bottom).
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conditions.
Methods
using
acceptorless
dehydrogenation of alcohols as well as borrowing
hydrogen methodology 11a for pyrrole synthesis
were reported very recently from Michlik and
11b
Kempe.
These methods use iridium complex
PN5P-Ir and Ir@SiCN nanoparticles as a catalyst
system to obtain 2,5- and 2,3,5-substituted
12
pyrroles in very high yield. Moreover, in the
same line methodology Saito and co-workers 13
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and Beller research group
were able to
17
Meerwein–Ponndorf–Verley
reaction,
synthesize various pyrroles starting from
enolizable ketones, diols and primary amines or
ammonia. Despite these advances in pyrrole
synthesis using very advanced transition metal
catalyst systems, the following challenging issues
still remain: development of environmentally
benign synthetic strategies, access to various
substituted pyrroles without using expensive
transition metals and ligands which in many cases
are not commercially available and need to be
synthesized in multi-step procedures. Another
important issue is the possible contamination of
drug products with heavy metals. Therefore,
depending on the position of the equilibrium,
which is controlled by the oxidation potential of
the carbonyl compounds involved. Usually,
ketones or aldehydes with higher oxidation
potential are employed for this purpose. The
product can be obtained by removing the reduced
alcohol from the solution.
RESULT AND DISCUSION
Based on these facts mentioned above we
hypothesized that by using sodium tert-butoxide
and benzophenone as a hydride acceptor, it is
possible to oxidize secondary alcohols to ketones
and then in the presence of amino alcohol
condense to an imino-alcohol. The reaction
equilibrium in this case can shift to the right,
because the ketone is converted to the imine. The
oxidation process proceeds in the same way for
the alcohol functional group on the iminoalcohol
resulting in the formation of a carbonyl
compound which under basic conditions can be
cyclized to the pyrrole ring (Scheme 2). Thus, we
screened the reaction with sodium tert-butoxide
as a base which deprotonates and coordinates to
based on new regulations such as USP <232> and
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USP <233>
such procedures for drug
development are not recommended. Herein, we
report a new method for pyrrole synthesis based
on the venerable Oppenauer–Woodward
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oxidation.
The mechanism proposed by
Milstein and others in general can be affected by
the Oppenauer oxidation. This method is used
very rarely to oxidise secondary alcohols to
ketones and even less for the transformation of
primary alcohols to aldehydes, because aldol
condensation and Tischtschenko reactions cause
the formation of undesired side products. The
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the reacting alcohol enabling hydride transfer to
carbonyl compound, we have observed that
dimethoxy-2-phenylacetophenone 4d where to
the α carbon are attached two very strong electron
donating groups. This affects the reaction and the
yield drops by 10%.
Scheme 2. Plausible mechanism of pyrrole synthesis via
Oppenauer–Woodward oxidation of alcohols and selective
C-C, C-N bond formation.
Table 1. Screening of carbonyl oxidants of various oxidation
potentials. a
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Oxidation
Yield of 3a [%] c
Entry
1
Oxidant
potential [mV] b
167
199
4a
4b
41
43
2
3
460
4c
trace
4
5
-
4d
4e
33
72
126
2,5-disubstituted pyrrole forms in fair to good
yield (Table 1, top). From the literature we know
that the reaction equilibrium is controlled by the
oxidation potential of the carbonyl compound, 18
therefore we screened various ketones from
higher to lower oxidation potential (Table 1,
bottom). To optimize the reaction’s conditions, as
a model we have chosen 1-phenylethanol 1a,
NaOtBu as a base, 2-amino-1-butanol 2a, and
benzophenone 4e which was found from
preliminary screening to be the best hydride
acceptor (Table 1, Entry 5). All carbonyl
compounds that we have selected are non
enolizable ketones. From screening we found that
the oxidation potential of the ketone is very
important. If the oxidation potential is too high,
like that of benzoin methyl ether 4b, the
performance of the reaction drops drastically.
The reason behind this could be that: 1) the
oxidant forms a stable imine with β-amino
alcohol, because of the presence of a very strong
electron donating group at the α carbon in 4b, 2)
the oxidation of alcohol from β-amino alcohol 2a
to aldehyde takes place before the secondary
alcohol 1a gets oxidized and then undergoes self-
condensation, 3) the primary alcohol from β-
amino alcohol 2a is over oxidized to carboxylic
acid. A similar behavior was observed with 2,2-
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4f
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a Reaction condition: 1-phenylethanol (1.0 equiv, 2.456 mmol),
2-amino-1-butanol (1.1 equiv, 2.70 mmol), NaOtBu (1.1 equiv,
2.70 mmol), carbonyl oxidant (3.0 equiv), dry toluene 9 ml, 110
°C, ~18 h. b Details for oxidation potentials of compounds listed
c
above can be found in Ref.18. Isolated yield after column
chromatography.
Moreover, to validate this we have screened a
reaction with 9,10-phenanthrenequinone 4c
which has a very high oxidation potential and
according to the GC and NMR analysis we found
out that pyrrole was formed just in trace amount.
The same reaction was repeated with 4c at various
temperatures, starting from 20, then proceeding
to 40, 60, and finally 100 °C in order to
investigate if the higher oxidation potential can be
combined with lower temperature. However, in
all cases we have not observed any improvement.
From screening experiments, benzophenone 4e in
excess (6.0 equiv) was found to be optimal,
NaOtBu was the best base (1.1 equiv) and the
optimal temperature was found to be 110 °C. The
desired solvents for this reaction are non-polar
with a high boiling point except THF which
performs as good as non-polar solvents, however
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for the direct purification of the crude mixture by
column chromatography using non-polar solvents
is more convenient.
Next, we have investigated the scope with a wide
range of secondary alcohols. For this purpose, we
set-up an experiment using secondary alcohol
(1.0 equiv) phenylalaninol 2b (1.1 equiv),
NaOtBu (1.1 equiv), benzophenone 4e (6.0
equiv), and toluene as a solvent under reflux (110
°C) for approximately 18 h. These pyrroles were
isolated in yields of up to 80% and under these
conditions, various substituted aromatic and
aliphatic secondary alcohols are tolerated (Table
2). Substituted phenyl-ethanols 3b, 3d and 3e in
most cases convert into 2,5-di-substituted
pyrroles in very good yield, 77-80%, however 1-
naphthylethanol 3c gives a moderate yield of
40%. Aliphatic alcohols are tolerated and
transformed in their representative pyrroles 3g-i
in good yield (56-63%). According to NMR data
of the isolated compound 3f we have observed the
formation of a mixture of two isomers in the case
of 2-heptanol (entry 5) which 3f was the major
isomer in a yield of 56% together with a minor
product, the 4-methyl-5-butylpyrrole isomer,
formed in 10% yield.
Table 2. Secondary alcohol scope of the pyrrole synthesis a.
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Secondary
alcohol
Isolated
Entry
1
Product
Yield [%] b
3b
3c
77
40
2
3
4
3d
3e
80
80
Table 3. β-Amino alcohol scope of the pyrrole synthesis a
5
6
3f
66
63
3g
β-amino
alcohol
Isolated
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Entry
1
Product
3h
3i
65
56
yield [%] b
90
47
3k
2
3l
9
3j
86
3m
3
4
93
74
a
Reaction condition: secondary alcohol (1.0 equiv),
3n
3o
phenylalaninol (1.1 equiv), NaOtBu (1.1 equiv), benzophenone
(6.0 equiv), dry toluene 9 ml, 110 °C, ~18 h. b Isolated yield after
column chromatography.
5
n.r
a
More details regarding the optimization process
can be found in the supporting information. It is
interesting to note that when we started from
acetophenone rather than 1-phenylethanol under
otherwise identical conditions, the yields of 3a
were consistently lower (45 compared to 80%).
Reaction condition: 1-phenylethanol (1.0 equiv), β-amino
alcohol (1.1 equiv), NaOtBu (1.1 equiv), benzophenone (6.0
b
equiv), dry toluene 9 ml, 110 °C, ~18 h. Isolated yield after
column chromatography.
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Interestingly, 3j was isolated in very good yield
used 2-amino-1,2-diphenylethanol 2e as a
(86%) compared to other cyclic alcohols.
Furthermore, we studied the reactivity of
different β-amino alcohols. Aliphatic branched β-
amino alcohols (entry 1, and 3, table 3) react
better and give very high yields (90% and 93%)
of their pyrrole derivatives 3k, 3m, compared to
non-branched β-amino alcohols, like alaninol
(entry 2) and 2-phenylglycinol (entry 4) and their
pyrroles (3l, 47%) and (3n, 74%). However, in
the case of 1-amino-2-indanol (entry 5) we have
not observed any formation of product 3o.
In order to extend the scope of our method for
pyrrole synthesis we performed a reaction with
ethanolamine 2c to be able to synthetize 2-
phenylpyrrole 3p. Despite the fact that the yield
is low, around 28% (considering that they are
unstable and get quickly oxidized in the acidic
environment), this type of α-unsubstituted
pyrroles are very valuable starting materials for
the synthesis of BODIPYs, porphyrins, and other
functionalized advanced materials [Eq. (1)]. An
improvement was observed in the case of 1,2,3,4-
tetrahydro-1-naphthol 1b, for which fused
pyrrole 3q was obtained in an acceptable yield of
54%.
substrate [Eq. (3)]. In case where 2-amino-1,2-
diphenylethanol 2e was used as a substrate and 1-
phenylethanol 1a we have observed a better yield
(3t, 31%) compared to 1,2,3,4-tetrahydro-1-
naphthol 1b and the corresponding pyrrole 3u
(18%), this perhaps for several reasons:
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1) condensation of 1,2,3,4-tetrahydro-1-naphthol
1b with 2-amino-1,2-diphenylethanol 2e is more
sterically hindered, 2) because of competitive
oxidation, many side reactions take place like self
-condensation of 2-amino-1,2-diphenylethanol 2e
which can result in pyrazine formation.
Finally, to check the synthetic utility of the
method the reaction was carried out on a 3 gram
scale of 1a and we obtained 3a without affecting
the yield (~79%).
CONCLUSION
In summary, we have developed a novel,
transition metal-free, and one pot methodology
for synthesizing substituted pyrroles from
secondary alcohols and amino alcohols to
produce differently substituted pyrroles. The
oxidation process occurs selectively for
secondary alcohols which under basic conditions
and in presence of aminoalcohol leads to pyrrole
formation. The reaction operates under mild
oxidation conditions and it has a broad scope,
working best for 2,5-disubstituted pyrroles. 2-
Monosubstituted, 2,4-disubstituted and 2,3,5-
trisubstituted pyrroles were also prepared by this
method in low to fair yields, that however may
still be competitive with the yield offered by other
methods like the Trofimov reaction. Sensitive
functional groups are tolerated under these
reaction circumstances, which makes it very
convenient to apply for the synthesis of
functionalized pyrroles. The reaction can be easy
scaled up to more than 3 grams in the case of 3a
with a ~79% yield.
The same reaction conditions were applied to 1-
amino-2-propanol 2d in order to obtain 2,4-
disubstituted pyrroles [Eq. (2)]. As expected for
aminoalcohols where the alcohol function group
is in secondary position, a competitive reaction
takes place, where we have observed a low yield
for both pyrroles 3r (22%) and 3s (15%).
Furthermore, we have studied if we can prepare
heavily substituted pyrroles using the same
conditions and secondary alcohols, therefore we
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phenylethanol (24.56 mmol), 2.40 g 2-amino-1-
butanol (1.1 equiv, 27.0 mmol), 2.6 g NaOtBu
(1.1 equiv, 27.0 mmol), 26.8 g benzophenone (6.0
equiv, 147 mmol) and 90 ml dry toluene. The
reaction mixture was purged with argon and
refluxed (110 °C, oil bath) overnight (~18 h).
After the reaction mixture has been cooled to
room temperature, it was added directly to a silica
column and chromatographed using petroleum
ether (PE) 65:35 dichloromethane (DCM) as an
eluent. Yield: 3.34 g, 79% as colorless solid
(turns pink after contact with air).
EXPERIMENTAL SECTION
General Considerations
NMR spectra were recorded on a Bruker 400
Avance (400 MHz) or a Bruker 600 Avance II+
(600 MHz), and chemical shifts (δ) are reported
part per million (ppm) referenced to
tetramethylsilane (1H). Melting points were
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determined using
a
Reichert Thermovar
apparatus. For column chromatography 70-230
mesh silica 60 (E. M. Merck) was used as the
stationary phase. Chemicals received from
commercial sources were used without further
purification. Reaction dry solvents were used as
received from commercial sources. TLC were
carried out on Kieselgel 60 F254 plates (Merck)
and stained with iodine or visualized with UV-
lamp 254 nm. Exact mass spectra were acquired
with a quadrupole orthogonal acceleration time-
of-flight mass spectrometer (Synapt G2 HDMS,
Waters, Milford, MA). Samples were infused at 3
uL/min and spectra were obtained in positive (or:
negative) ionization mode with a resolution of
15000 (FWHM) using leucine enkephalin as lock
mass.
2-Benzyl-5-phenyl-1H-pyrrole
(3b):
1-
phenylethanol (300 mg, 1.0 equiv, 2.456 mmol),
phenylalaninol (241 mg, 1.1 equiv, 2.70 mmol),
NaOtBu (260 mg, 1.1 equiv, 2.70 mmol),
benzophenone (2.68 g, 6.0 equiv, 14.73 mmol),
dry toluene 9 ml, 110 °C, reaction time is
overnight (~18 h). The product was purified using
column chromatography and as the eluent was
used petroleum ether (PE) 65:35 dichloromethane
(DCM) affording (3b) (439 mg, 77% yield) as
slightly pink solid. m.p. 85 °C (m.p. from
1
literature 85.3–89.5 °C). H NMR (400 MHz,
CDCl3, δ): 8.00 (s, br, 1H), 7.45 – 7.18 (m, 9H),
7.13 (t, J = 7.3 Hz, 1H), 6.43 (m, 1H), 6.04 (m,
1H), 4.01 (s, 2H). 13C{1H} NMR (100 MHz,
CDCl3, δ): 139.3, 132.8, 132.0, 131.5, 128.8,
128.7, 128.7, 126.5, 125.8, 123.5, 108.6, 106.1,
34.2. HRMS (ESI-quadrupole) m/z: [M+H]+
Calcd for C17H15N1H 234.1277; found 234.1276.
The analytical data for 3b are consistent with the
literature 19. (m.p, NMR)
General procedure for the preparation of
pyrroles
To a screw-capped reaction tube was added
secondary alcohol, amino-alcohol, solvent,
oxidant and base. The pressure tube was closed
with a semi permeable membrane, purged with
argon for 10 minutes and heated with stirring for
the desired amount of time. The crude reaction
mixture was cooled to room temperature and then
directly purified by column chromatography
(silica gel) using petroleum ether and
dichloromethane as an eluent system (Note: some
pyrroles were twice chromatographed. The
column was cooled down to prevent from
overheating, to increase performance and was
protected from the light).
CAS Registry Number: 905971-72-4.
2-Benzyl-5-(naphthalen-1-yl)-1H-pyrrole (3c):
1-(1-Naphthyl)ethanol (300 mg, 1.0 equiv, 1.742
mmol), phenylalaninol (290 mg, 1.1 equiv, 1.916
mmol), NaOtBu (184 mg, 1.1 equiv, 1.916
mmol), benzophenone (1.90 g, 6.0 equiv, 10.45
mmol), dry toluene 9 ml, 110 °C, reaction time is
overnight (~18 h). The product was purified using
column chromatography and as the eluent was
used petroleum ether (PE) 65:35 dichloromethane
(DCM) affording (3c) (200 mg, 40% yield) as
Large scale synthesis of 2-ethyl-5-
phenylpyrrole
1
slightly brown oil. H NMR (400 MHz, CDCl3,
To a round bottom flask (250 ml) equipped with
a condenser and stirring bar was added 3 g 1-
δ): 8.39 – 8.22 (m, 1H), 7.99 (s, br, 1H), 7.91 –
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7.65 (m, 2H), 7.59 – 7.37 (m, 4H), 7.36 – 7.14 (m,
128.6, 126.5, 126.0, 124.9, 114.2, 108.4, 104.9,
55.3, 34.2. HRMS (ESI-quadrupole) m/z:
[M+H]+ Calcd for C18H17N1O1H 264.1382; found
264.1378. The analytical data for 3e are
consistent with literature. 11b (NMR)
5H), 6.42 (m, 1H), 6.15 (m, 1H), 4.07 (s, 2H).
13C{1H} NMR (100 MHz, CDCl3, δ): 139.3,
134.0, 131.6, 131.2, 129.8, 128.7, 128.7, 128.4,
127.1, 126.5, 126.2, 125.8, 125.8, 125.7, 125.4,
109.7, 107.9, 34.3. HRMS (ESI-quadrupole) m/z:
[M+H]+ Calcd for C21H17N1H 284.1433; found
284.1432. The compound has a CAS number but
it is not reported in the literature.
CAS Registry Number: 1422518-37-3
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2-Benzyl-5-pentyl-1H-pyrrole (3f): 2-Heptanol
(300 mg, 1.0 equiv, 2.58 mmol), phenylalaninol
(429 mg, 1.1 equiv, 2.84 mmol), NaOtBu (273
mg, 1.1 equiv, 2.84 mmol), benzophenone (2.82
g, 6.0 equiv, 15.49 mmol), dry toluene 9 ml, 110
°C, reaction time is overnight (~18 h). The
CAS Registry Number: 1858242-20-2
2-Benzyl-5-(4-chlorophenyl)-1H-pyrrole (3d): 1-
(4-Chlorophenyl)ethanol (300 mg, 1.0 equiv,
1.916 mmol), phenylalaninol (319 mg, 1.1 equiv,
2.107 mmol), NaOtBu (203 mg, 1.1 equiv, 2.107
mmol), benzophenone (2.049 g, 6.0 equiv, 11.49
mmol), dry toluene 9 ml, 110 °C, reaction time is
overnight (~18 h). The product was purified using
column chromatography and as the eluent was
used petroleum ether (PE) 65:35 dichloromethane
(DCM) affording (3d) (439 mg, 80% yield) as
product
was
purified
using
column
chromatography and as the eluent was used
petroleum ether (PE) 65:35 dichloromethane
(DCM) affording (3f) (390 mg, 66% yield) as
1
colorless oil. H NMR (400 MHz, CDCl3, δ):
7.47 (s, br, 1H), 7.34 – 7.25 (m, 2H), 7.21 (m,
3H), 5.85 (m, 1H), 5.79 (m, 1H), 3.93 (s, 2H),
2.54 – 2.45 (m, 2H), 1.55 (m, 2H), 1.30 (m, 4H),
1
13
slightly light pink solid m.p. 120 °C. H NMR
0.89 (m, 3H). C{1H} NMR (100 MHz, CDCl3,
(400 MHz, CDCl3, δ): 7.97 (s, br, 1H), 7.47 – 7.09
(m, 9H), 6.41 (m, 1H), 6.04 (m, 1H), 4.01 (s, 2H).
13C{1H} NMR (100 MHz, CDCl3, δ): 139.1,
132.5, 131.3, 131.2, 130.4, 128.9, 128.7, 128.6,
126.6, 124.6, 108.8, 106.6, 34.2. HRMS (ESI-
δ): 139.8, 132.4, 128.9, 128.7, 128.6, 128.5,
126.3, 106.4, 104.6, 77.2, 77.0, 76.8, 34.2, 31.6,
29.3, 27.7, 25.6, 22.4, 14.0. HRMS (ESI-
quadrupole) m/z: [M+H]+ Calcd for C16H21N1H
228.1746; found 228.1748.
quadrupole)
m/z:
[M+H]+
Calcd
for
2-Benzyl-5-isopropyl-1H-pyrrole (3g): 3-Methyl-
2-butanol (300 mg, 1.0 equiv, 3.40 mmol),
phenylalaninol (566 mg, 1.1 equiv, 3.74 mmol),
NaOtBu (360 mg, 1.1 equiv, 3.74 mmol),
benzophenone (3.72 g, 6.0 equiv, 20.42 mmol),
dry toluene 9 ml, 110 °C, reaction time is
overnight (~18 h). The product was purified using
column chromatography and as the eluent was
used petroleum ether (PE) 65:35 dichloromethane
(DCM) affording (3g) (429 mg, 63% yield) as
C17H14Cl1N1H 268.0887; found 268.0885. The
analytical data for 3d are consistent with
literature. 11b (NMR)
CAS Registry Number: 1422518-38-4
2-Benzyl-5-(4-methoxyphenyl)-1H-pyrrole (3e):
1-(4-Methoxyphenyl)ethanol (300 mg, 1.0 equiv,
1.971 mmol), phenylalaninol (328 mg, 1.1 equiv,
2.168 mmol), NaOtBu (208 mg, 1.1 equiv, 2.168
mmol), benzophenone (2.155 g, 6.0 equiv, 11.83
mmol), dry toluene 9 ml, 110 °C, reaction time is
overnight (~18 h). The product was purified using
column chromatography and as the eluent was
used petroleum ether (PE) 95:5 ethyl acetate
(EtOAc) affording (3e) (439 mg, 80% yield) as
off-white solid. m.p. 101 °C. 1H NMR (400 MHz,
CDCl3, δ): 7.91 (s, br, 1H), 7.45 – 7.13 (m, 7H),
6.86 (d, J = 8.7 Hz, 2H), 6.30 (m, 1H), 6.01 (m,
1H), 4.00 (s, 2H), 3.79 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3, δ): 158.0, 139.4, 131.5, 131.2,
1
colorless oil. H NMR (400 MHz, CDCl3, δ):
7.52 (s, br, 1H), 7.30 (t, 2H), 7.22 (t, 3H), 5.84
(m, 1H), 5.81 (m, 1H), 3.94 (s, 2H), 2.83 (sept,
1H), 1.20 (d, J = 6.9 Hz, 6H). 13C{1H} NMR (100
MHz, CDCl3, δ): 139.8, 138.4, 128.9, 128.6,
128.5, 126.3, 106.2, 102.7, 34.2, 27.0, 22.6.
HRMS (ESI-quadrupole) m/z: [M+H]+ Calcd for
C14H17N1H 200.1433; found 200.1436. The
analytical data for 3g are consistent with
literature. 11b (NMR)
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CAS Registry Number: 1422518-36-2
2-Benzyl-4,5-dihydro-1H-benzo[g]indole (3j):
1,2,3,4-tetrahydro-1-naphthol (300 mg, 1.0
equiv, 2.024 mmol), phenylalaninol (337 mg, 1.1
equiv, 2.227 mmol), NaOtBu (214 mg, 1.1 equiv,
2.227 mmol), benzophenone (2.21 g, 6.0 equiv,
12.15 mmol), dry toluene 9 ml, 110 °C, reaction
time is overnight (~18 h). The product was
purified using column chromatography and as the
eluent was used petroleum ether (PE) 65:35
dichloromethane (DCM) affording (3j) (451 mg,
2-Benzyl-4,5,6,7,8,9-hexahydro-1H-
cycloocta[b]pyrrole (3h): cyclooctanol (300 mg,
1.0 equiv, 2.340 mmol), phenylalaninol (389 mg,
1.1 equiv, 2.57 mmol), NaOtBu (247 mg, 1.1
equiv, 2.57 mmol), benzophenone (2.56 g, 6.0
equiv, 14.04 mmol), dry toluene 9 ml, 110 °C,
reaction time is overnight (~18 h). The product
was purified using column chromatography and
as the eluent was used petroleum ether (PE) 65:35
dichloromethane (DCM) affording (3h) ( 367 mg,
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1
86% yield) as colorless crystals m.p. 85 °C. H
NMR (400 MHz, CDCl3, δ): 7.88 (s, 1H), 7.28
(m, 5H), 7.13 (m, 2H), 6.99 (m, 2H), 5.87 (s, 1H),
4.00 (s, 2H), 2.90 (t, J = 7.6 Hz, 2H), 2.69 (t, J =
7.6 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3,
δ): 139.3, 134.4, 131.5, 129.3, 128.7, 128.6,
128.2, 127.1, 126.5, 126.3, 124.5, 120.5, 117.7,
106.8, 34.4, 30.0, 21.8. HRMS (ESI-quadrupole)
m/z: [M+H]+ Calcd for C19H17N1H 260.1433;
found 260.1418.
1
65% yield) as slightly brown oil. H NMR (600
MHz, CDCl3, δ): 7.31 – 7.24 (m, 3H), 7.21 (d, J
= 7.8 Hz, 3H), 5.68 (d, J = 2.2 Hz, 1H), 3.90 (s,
2H), 2.62 – 2.57 (m, 2H), 2.55 – 2.51 (m, 2H),
1.63 – 1.56 (m, 4H), 1.43 (m, 4H). 13C{1H} NMR
(151 MHz, CDCl3, δ): 128.6, 128.5, 127.6, 127.1,
126.2, 119.0, 107.6, 34.2, 30.6, 29.6, 26.0, 25.6,
25.5, 25.0. HRMS (ESI-quadrupole) m/z:
[M+H]+ Calcd for C17H21N1H 240.1746; found
240.1750. The analytical data for 3h are
consistent with literature. 11b (NMR)
2-Isopropyl-5-phenyl-1H-pyrrole
(3k):
1-
phenylethanol (300 mg, 1.0 equiv, 2.456 mmol),
2-amino-3-methyl-1-butanol (279 mg, 1.1 equiv,
2.70 mmol), NaOtBu (260 mg, 1.1 equiv, 2.70
mmol), benzophenone (2.68 g, 6.0 equiv, 14.73
mmol), dry toluene 9 ml, 110 °C, reaction time is
overnight (~18 h). The product was purified using
column chromatography and as the eluent was
used petroleum ether (PE) 65:35 dichloromethane
(DCM) affording (3k) (411 mg, 90% yield) as
CAS Registry Number: 1422518-52-2
2-Benzyl-4,5,6,7-tetrahydro-1H-indole
(3i):
cyclohexanol (300 mg, 1.0 equiv, 3 mmol),
phenylalaninol (498 mg, 1.1 equiv, 3.29 mmol),
NaOtBu (317 mg, 1.1 equiv, 3.29 mmol),
benzophenone (3.27 g, 6.0 equiv, 17.97 mmol),
dry toluene 9 ml, 110 °C, reaction time is
overnight (~18 h). The product was purified using
column chromatography and as the eluent was
used petroleum ether (PE) 65:35 dichloromethane
(DCM) affording (3i) (357 mg, 56% yield) as
1
colorless crystals. m.p. 44 °C. H NMR (400
MHz, CDCl3, δ): 8.11 (s, br, 1H), 7.43 (d, J = 7.9
Hz, 2H), 7.33 (t, J = 7.7 Hz, 2H), 7.16 (t, J = 7.3
Hz, 1H), 6.41 (m, 1H), 5.98 (m, 1H), 2.97 (m,
1H), 1.30 (d, J = 6.9 Hz, 6H). 13C{1H} NMR (100
MHz, CDCl3, δ): 140.3, 133.0, 130.4, 128.8,
125.6, 123.4, 105.8, 104.9, 27.2, 22.6. HRMS
(ESI-quadrupole) m/z: [M+H]+ Calcd for
C13H15N1H 186.1277; found 186.1272. The
analytical data for 3k are consistent with
literature. 11b (NMR)
1
slightly brown oil. H NMR (600 MHz, CDCl3,
δ): 7.30 (m, 2H), 7.27 – 7.19 (m, 3H), 5.70 (d, J
= 2.1 Hz, 1H), 3.91 (s, 2H), 2.47 (m, 4H), 1.77
(m, 2H), 1.72 (m, 2H). 13C{1H} NMR (151 MHz,
CDCl3, δ): 139.7, 128.8, 128.5, 126.3, 126.1,
116.8, 105.5, 34.3, 23.8, 23.4, 22.8, 22.7. HRMS
(ESI-quadrupole) m/z: [M+H]+ Calcd for
C15H17N1H 212.1433; found 212.1437. The
analytical data for 3i are consistent with
literature. 12 (NMR)
CAS Registry Number: 13713-07-0
2-Methyl-5-phenyl-1H-pyrrole (3l): 300 mg 1-
phenylethanol (1.0 equiv, 2.456 mmol), 203 mg
alaninol (1.1 equiv, 2.70 mmol), 260 mg NaOtBu
(1.1 equiv, 2.70 mmol), 2.68 g benzophenone (6.0
CAS Registry Number: 233585-17-6
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equiv, 14.73 mmol), dry toluene 9 ml, 110 °C,
column chromatography and as the eluent was
used petroleum ether (PE) 65:35 dichloromethane
(DCM) affording (3n) (398 mg, 74% yield) as
colorless crystals. m.p. 141 °C (m.p. from
reaction time is overnight (~18 h). The product
was purified using column chromatography and
as the eluent was used petroleum ether (PE) 65:35
dichloromethane (DCM) affording (3l) (182 mg,
47% yield) as colorless crystals. m.p. 98 °C (m.p.
1
literature 143 °C). H NMR (400 MHz, CDCl3,
δ): 8.57 (s, br, 1H), 7.53 (d, J = 7.7 Hz, 4H), 7.39
(m, 4H), 7.23 (m, 2H), 6.58 (d, J = 2.6 Hz, 2H).
13C{1H} NMR (100 MHz, CDCl3, δ): 133.1,
132.4, 128.9, 126.3, 123.7, 107.9. HRMS (ESI-
quadrupole) m/z: [M+H]+ Calcd for C16H13N1H
1
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from literature 98-100 °C). H NMR (400 MHz,
CDCl3, δ): 8.09 (s, br, 1H), 7.42 (d, J = 7.8 Hz,
2H), 7.33 (m, 2H), 7.15 (m, 1H), 6.39 (m, 1H),
5.95 (m, 1H), 2.33 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3, δ): 132.9, 130.7, 129.0, 128.8,
125.6, 123.3, 107.9, 106.1, 13.1. HRMS (ESI-
quadrupole) m/z: [M+H]+ Calcd for C11H11N1H
158.0964; found 158.0965. The analytical data
for 3l are consistent with literature. 20 (m.p, NMR)
220.1120; found 220.1126. The analytical data
21
for 3n are consistent with literature.
(m.p,
NMR)
CAS Registry Number: 838-40-4
2-Ethyl-5-phenyl-1H-pyrrole
(3a):
1-
CAS Registry Number: 3042-21-5
phenylethanol (300 mg, 1.0 equiv, 2.456 mmol),
2-amino-1-butanol (241 mg, 1.1 equiv, 2.70
mmol), NaOtBu (260 mg, 1.1 equiv, 2.70 mmol),
benzophenone (2.68 g, 6.0 equiv, 14.73 mmol),
dry toluene 9 ml, 110 °C, reaction time is
overnight (~18 h). The product was purified using
column chromatography and as the eluent was
used petroleum ether (PE) 65:35 dichloromethane
(DCM) affording (3a) (337 mg, 80% yield) as
colorless crystals. m.p. 50 °C (m.p. from
2-(sec-Butyl)-5-phenyl-1H-pyrrole (3m): 1-
phenylethanol (300 mg, 1.0 equiv, 2.456 mmol),
L-isoleucinol (317 mg, 1.1 equiv, 2.70 mmol),
NaOtBu (260 mg, 1.1 equiv, 2.70 mmol),
benzophenone (2.68 g, 6.0 equiv, 14.73 mmol),
dry toluene 9 ml, 110 °C, reaction time is
overnight (~18 h). The product was purified using
column chromatography and as the eluent was
used petroleum ether (PE) 65:35 dichloromethane
(DCM) affording (3m) (457 mg, 93% yield) as
colorless oil. 1H NMR (400 MHz, CDCl3, δ): 8.08
(s, br, 1H), 7.43 (d, J = 7.9 Hz, 2H), 7.33 (t, J =
7.7 Hz, 2H), 7.15 (t, J = 7.3 Hz, 1H), 6.42 (m,
1H), 5.97 (m, 1H), 2.71 (m, 1H), 1.78 – 1.47 (m,
2H), 1.28 (d, J = 7.0 Hz, 3H), 0.92 (t, J = 7.4 Hz,
3H). 13C{1H} NMR (100 MHz, CDCl3, δ): 139.1,
133.0, 130.2, 128.7, 125.6, 123.3, 105.8, 105.6,
34.4, 30.2, 20.0, 11.8. HRMS (ESI-quadrupole)
m/z: [M+H]+ Calcd for C14H17N1H 200.1433;
found 200.1425. The analytical data for 3h are
consistent with literature. 11b (NMR)
1
literature 47.0-48.5 °C). H NMR (400 MHz,
CDCl3, δ): 8.09 (s, br, 1H), 7.42 (d, J = 7.7 Hz,
2H), 7.32 (m, 2H), 7.15 (m, 1H), 6.41 (m, 1H),
5.98 (m, 1H), 2.67 (m, 2H), 1.28 (t, J = 7.6 Hz,
3H). 13C{1H} NMR (100 MHz, CDCl3, δ): 135.6,
132.9, 130.5, 128.8, 125.6, 123.3, 106.2, 105.9,
20.9, 13.5. These analytical data for 3a are
consistent with literature. 22 (m.p, NMR)
CAS Registry Number: 13713-06-9
2-Phenyl-1H-pyrrole (3p): 1-phenylethanol (300
mg, 1.0 equiv, 2.456 mmol), ethanolamine (165
mg, 1.1 equiv, 2.70 mmol), NaOtBu (260 mg, 1.1
equiv, 2.70 mmol), benzophenone (2.68 g, 6.0
equiv, 14.73 mmol), dry toluene 9 ml, 110 °C,
reaction time is overnight (~18 h). The product
was purified using column chromatography and
as the eluent was used petroleum ether (PE) 65:35
dichloromethane (DCM) affording (3p) (98.2 mg,
28% yield) as colorless crystals. m.p. 124 °C
(m.p. from literature 126-128 °C). 1H NMR (600
CAS Registry Number: 1422518-32-8
2,5-Diphenyl-1H-pyrrole (3n): 1-phenylethanol
(300 mg, 1.0 equiv, 2.456 mmol), 2-
phenylglycinol (371 mg, 1.1 equiv, 2.70 mmol),
NaOtBu (260 mg, 1.1 equiv, 2.70 mmol),
benzophenone (2.68 g, 6.0 equiv, 14.73 mmol),
dry toluene 9 ml, 110 °C, reaction time is
overnight (~18 h). The product was purified using
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MHz, CDCl3, δ): 8.42 (s, br, 1H), 7.47 (d, J = 7.5
(t, J = 7.7 Hz, 2H), 7.18 (t, J = 7.3 Hz, 1H), 6.62
(s, br, 1H), 6.36 (s, br, 1H), 2.15 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3, δ): 132.0, 128.8, 126.0,
123.6, 116.7, 107.4, 11.9. HRMS (ESI-
quadrupole) m/z: [M+H]+ Calcd for C11H11N1H
Hz, 2H), 7.36 (t, J = 7.7 Hz, 2H), 7.20 (t, J = 7.3
Hz, 1H), 6.86 (s, br, 1H), 6.53 (s, br, 1H), 6.30 (s,
br, 1H). 13C{1H} NMR (151 MHz, CDCl3, δ):
132.8, 132.1, 128.9, 126.2, 123.8, 118.8, 110.1,
105.9. HRMS (ESI-quadrupole) m/z: [M+H]+
Calcd for C10H9N1H 144.0807; found 144.0811.
The analytical data for 3p are consistent with
literature. 23 (m.p, NMR)
158.0964; found 158.0959. The analytical data
24
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for 3r are consistent with literature.
(m.p,
NMR)
CAS Registry Number: 20055-04-3
CAS Registry Number: 3042-22-6
3-Methyl-4,5-dihydro-1H-benzo[g]indole (3s):
1,2,3,4-tetrahydro-1-naphthol (300 mg, 1.0
equiv, 2.024 mmol), 1-amino-2-propanol (167
mg, 1.1 equiv, 2.227 mmol), NaOtBu (214 mg,
1.1 equiv, 2.227 mmol), benzophenone (2.213 g,
6.0 equiv, 12.15 mmol), dry toluene 9 ml, 110 °C,
reaction time is overnight (~18 h). The product
was purified using column chromatography and
as the eluent was used petroleum ether (PE) 65:35
dichloromethane (DCM) affording (3s) (56.3 mg,
15% yield) as slightly green crystals. m.p. 100 °C.
1H NMR (400 MHz, CDCl3, δ): 8.06 (s, br, 1H),
7.15 (m, 3H), 7.03 (t, J = 7.3 Hz, 1H), 6.55 (s,
1H), 2.93 (t, J = 7.6 Hz, 2H), 2.65 (t, J = 7.6 Hz,
2H), 2.07 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3, δ): 134.7, 128.2, 126.4, 124.8, 118.0,
117.4, 116.1, 29.9, 19.9, 9.8. HRMS (ESI-
quadrupole) m/z: [M+H]+ Calcd for C13H13N1H
184.1120; found 184.1124. The analytical data
for 3q are consistent with literature. 26 (NMR)
4,5-Dihydro-1H-benzo[g]indole (3q): 1,2,3,4-
Tetrahydro-1-naphthol (300 mg, 1.0 equiv, 2.024
mmol), ethanolamine (136 mg, 1.1 equiv, 2.227
mmol), NaOtBu (214 mg, 1.1 equiv, 2.227
mmol), benzophenone (2.213 g, 6.0 equiv, 12.15
mmol), dry toluene 9 ml, 110 °C, reaction time is
overnight (~18 h). The product was purified using
column chromatography and as the eluent was
used petroleum ether (PE) 65:35 dichloromethane
(DCM) affording (3q) (187 mg, 54% yield) as
slightly green crystals. m.p. 104 °C (m.p. from
1
literature 109-110 °C). H NMR (400 MHz,
CDCl3, δ): 8.28 (s, br, 1H), 7.23 – 7.11 (m, 3H),
7.06 (m, 1H), 6.76 (m, 1H), 6.12 (m, 1H), 2.93 (t,
J = 7.6 Hz, 2H), 2.75 (t, J = 7.6 Hz, 2H). 13C{1H}
NMR (100 MHz, CDCl3, δ): 134.8, 129.3, 128.3,
127.7, 126.4, 125.0, 120.1, 118.1, 108.1, 30.0,
21.8. HRMS (ESI-quadrupole) m/z: [M+H]+
Calcd for C12H11N1H 170.0964; found 170.0961.
The analytical data for 3q are consistent with
literature. 23 (m.p, NMR)
CAS Registry Number: 172907-65-2
2,3,5-Triphenyl-1H-pyrrole (3t): 1-phenylethanol
(300 mg, 1.0 equiv, 2.456 mmol), 2-amino-1,2-
diphenylethanol (576 mg, 1.1 equiv, 2.70 mmol),
NaOtBu (260 mg, 1.1 equiv, 2.70 mmol),
benzophenone (2.68 g, 6.0 equiv, 14.73 mmol),
dry toluene 9 ml, 110 °C, reaction time is
overnight (~18 h). The product was purified using
column chromatography and as the eluent was
used petroleum ether (PE) 65:35 dichloromethane
(DCM) affording (3t) (228.5 mg, 31% yield) as
off white crystals. m.p. 127 °C (m.p. from
CAS Registry Number: 4995-14-6
4-Methyl-2-phenyl-1H-pyrrole
(3r):
1-
phenylethanol (300 mg, 1.0 equiv, 2.456 mmol),
203 mg 1-amino-2-propanol (1.1 equiv, 2.70
mmol), NaOtBu (260 mg, 1.1 equiv, 2.70 mmol),
benzophenone (2.68 g, 6.0 equiv, 14.73 mmol),
dry toluene 9 ml, 110 °C, reaction time is
overnight (~18 h). The product was purified using
column chromatography and as the eluent was
used petroleum ether (PE) 65:35 dichloromethane
(DCM) affording (3r) (85.3 mg, 22% yield) as
colorless crystals. m.p. 150 °C (m.p. from
1
literature 133-135 °C). H NMR (400 MHz,
CDCl3, δ): 8.40 (s, br, 1H), 7.54 (d, J = 7.7 Hz,
2H), 7.39 (m, 6H), 7.36 – 7.15 (m, 7H), 6.70 (s,
br, 1H). 13C{1H} NMR (100 MHz, CDCl3, δ):
1
literature 152 °C). H NMR (400 MHz, CDCl3,
δ): 8.15 (s, br, 1H), 7.44 (d, J = 7.5 Hz, 2H), 7.34
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136.3, 133.0, 132.2, 132.2, 129.3, 128.9, 128.7,
Notes: The authors declare no conflict of interest.
128.4, 128.3, 127.4, 126.9, 126.5, 125.9, 123.8,
123.7, 108.5. HRMS (ESI-quadrupole) m/z:
[M+H]+ Calcd for C22H17N1H 296.1433; found
296.1438. The analytical data for 3t are consistent
with literature. 25 (m.p, NMR)
AUTHOR CONTRIBUTION
B.K. carried out the design, synthesis and data
analysis of the experiments, K.G. the synthesis of
pyrroles from ketones, W.D. designed the
experiments and co-wrote the manuscript.
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CAS Registry Number: 3274-61-1
2,3-Diphenyl-4,5-dihydro-1H-benzo[g]indole
(3u): 1,2,3,4-tetrahydro-1-naphthol (300 mg, 1.0
equiv,
2.024
mmol),
2-amino-1,2-
diphenylethanol (475 mg, 1.1 equiv, 2.227
mmol), NaOtBu (214 mg, 1.1 equiv, 2.227
mmol), benzophenone (2.213 g, 6.0 equiv, 12.15
mmol), dry toluene 9 ml, 110 °C, reaction time is
overnight (~18 h). The product was purified using
column chromatography and as the eluent was
used petroleum ether (PE) 65:35 dichloromethane
(DCM) affording (3u) (118.2 mg, 18% yield) as
ACKNOWLEDGMENTS
B.K. acknowledges Erasmus Mundus Western
Balkan Action 2 and KU Leuven for the doctoral
fellowship. KU Leuven is thanked for financial
support (IDO/12/020). Mass spectrometry was
made possible by the support of the Hercules
Foundation of the Flemish Government (grant:
20100225-7).
1
off white crystals. m.p. 156 °C. H NMR (400
MHz, CDCl3) δ 8.37 (s, br, 1H), 7.42 – 7.15 (m,
13H), 7.09 (t, J = 7.0 Hz, 1H), 2.96 (t, J = 7.5 Hz,
2H), 2.76 (t, J = 7.5 Hz, 2H). 13C{1H} NMR (100
MHz, CDCl3, δ): 135.5, 133.0, 129.8, 128.6,
128.2, 127.0, 126.5, 126.0, 125.4, 121.2, 121.1,
121.0, 118.3, 29.9, 20.7. HRMS (ESI-
quadrupole) m/z: [M+H]+ Calcd for C24H19N1H
322.1590; found 322.1570.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of
charge on the ACS Publications website at DOI:
xxxx
Screening procedure
Copies of 1H and 13C{1H} NMR spectra
Biofilm
Agents:
Design,
Synthesis,
AUTHOR INFORMATION
Pharmacokinetics and Antibacterial Activities.
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*E-mail: wim.dehaen@kuleuven.be
Wim Dehaen
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