Clauson-kaas-type synthesis of pyrrolyl-phenols, from the hydrochlorides of aminophenols, in the presence of nicotinamide

Article abstract of DOI:10.1080/00397911.2012.753460

A facile Clauson-Kaas-type pyrrolyl-phenol synthesis has been achieved in the presence of nicotinamide, which is inexpensive and nontoxic. The starting material is aminophenol hydrochloride. This is advantageous in certain cases because it is the only isolatable form of the corresponding aminophenol.

Full text of DOI:10.1080/00397911.2012.753460

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Clauson–Kaas-Type Synthesis of Pyrrolyl-
phenols, from the Hydrochlorides of
Aminophenols, in the Presence of
Nicotinamide
Maria Chatzopoulou a , Eleni Kotsampasakou a & Vassilis J.
Demopoulos a
a Department of Pharmaceutical Chemistry, School of Pharmacy ,
Aristotle University of Thessaloniki , Thessaloniki , Greece
Accepted author version posted online: 31 May 2013.Published
online: 25 Jul 2013.
To cite this article: Maria Chatzopoulou , Eleni Kotsampasakou & Vassilis J. Demopoulos
(2013) Clauson–Kaas-Type Synthesis of Pyrrolyl-phenols, from the Hydrochlorides of
Aminophenols, in the Presence of Nicotinamide, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 43:21, 2949-2954, DOI:
10.1080/00397911.2012.753460
To link to this article: http://dx.doi.org/10.1080/00397911.2012.753460
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Synthetic Communications1, 43: 2949–2954, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.753460
CLAUSON–KAAS-TYPE SYNTHESIS OF PYRROLYL-
PHENOLS, FROM THE HYDROCHLORIDES
OF AMINOPHENOLS, IN THE PRESENCE
OF NICOTINAMIDE
Maria Chatzopoulou, Eleni Kotsampasakou, and
Vassilis J. Demopoulos
Department of Pharmaceutical Chemistry, School of Pharmacy,
Aristotle University of Thessaloniki, Thessaloniki, Greece
GRAPHICAL ABSTRACT
Abstract A facile Clauson–Kaas-type pyrrolyl-phenol synthesis has been achieved in the
presence of nicotinamide, which is inexpensive and nontoxic. The starting material is
aminophenol hydrochloride. This is advantageous in certain cases because it is the only
isolatable form of the corresponding aminophenol.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource: Full
experimental and spectral details.]
Keywords Aminophenol hydrochloride; Clauson–Kaas; nicotinamide; pyrrolyl-phenol
INTRODUCTION
A number of N-substituted pyrrolyl-derivatives have been shown to possess
(sub)micromolar aldose reductase enzyme inhibitory activities and are useful in
the prevention of long-term diabetic complications.[1] In the context of scaffold
morphing in this class of compounds, we targeted 3-(1H-pyrrol-1-yl)phenol (1) as
an appropriate starting material for further chemical elaborations. The preparation
Received November 5, 2012.
Address correspondence to Vassilis J. Demopoulos, Department of Pharmaceutical Chemistry,
School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece. E-mail: vdem@
pharm.auth.gr
2949

2950
M. CHATZOPOULOU, E. KOTSAMPASAKOU, AND V. J. DEMOPOULOS
of 1 has been previously reported[2] by means of a Clauson–Kaas condensation of
3-aminophenol (1a) with 2,5-dimethoxytetrahydrofurane in acetic acid, albeit in
poor yield (23%). Thus, in the present work we explored alternate catalyses and reac-
tions’ solvents for this Clauson–Kaas condensation to obtain 1. Furthermore, we
investigated the applicability of the developed new methodology (vide infra) for
the preparation of the related pyrrolyl-phenols 2–5.
RESULTS AND DISCUSSION
After its initial introduction in the early nineties,[3] 4-chloropyridine hydro-
chloride has gained extensive usage[4] in catalyzing the Clausson–Kaas pyrrole
syntheses with aryl- and heteroarylamines. Alternatively, 4-chloropyridine and the
hydrochloride of an arylamine could be utilized.[1a] However, an attempt to
implement either one of these methodologies for the preparation of 1 led to disap-
pointing results (Table 1, entries 1 and 2). At this point, we postulated that during
the performed reactions a substantial portion of the 3-aminophenol (1a) is in its free
base (i.e., nonprotonated) form and will be prone to oxidative decomposition[5] in
the refluxing milieu of 1,4-dioxane.
4-Chloropyridine has a pKa value of 3.83,[6] close to the pKa of the conjugated
acid of 3-aminophenol, which is 4.3.[7] These pKa values are mentioned here only for
comparison’s sake, as they refer to an aqueous medium and room temperature.
However, we sought a catalyst that has both a lower pKa than 4-chloropyridine
and exhibits antioxidant properties as well. Nicotinamide was selected as a candidate
catalyst for investigation, because it has a pKa of 3.43[8] and, in addition, it could act
as a chemical antioxidant.[9] We found out that the condensation of 3-aminophenol
hydrochloride (1a ꢀ HCl) with 2,5-dimethoxytetrahydrofuran in the presence of an
equimolar amount of nicotinamide in refluxing 1,4-dioxane, is a clean reaction fur-
nishing 1 in good yield (Table 1, entry 3).
A number of solvents and solvent systems were also investigated (Table 2).
From the results, acetonitrile (entry 11) was shown to be a less toxic[10] alternate
solvent to 1,4-dioxane.
Table 1. Clauson–Kaas-type reactions of the aminophenol 1a/1a ꢀ HCl
Entry
Starting aminophenol
Catalyst
Yielda (%)
1
2
3
1a
1a ꢀ HCl
4-Chloropyridine ꢀ HCl
4-Chloropyridine
Nicotinamide
27
9
1a ꢀ HCl
75
aIsolated product 1 after refluxing for 4 h.

SYNTHESIS OF PYRROLYL-PHENOLS
2951
Table 2. Clauson–Kaas-type reactions of the aminophenol 1a ꢀ HCl, in the presence of nicotinamide, in
various solvents and solvent systems
Entry
Reaction medium
Yielda (%)
1
2
H2O
18
Trace
41
2-Methyltetrahydrofuran
3
2-Methyltetrahydrofuran=H2O, 14=86 (v=v), solubility[11]
2-Methyltetrahydrofuran=H2O, 89.4=10.6 (v=v), azeotrope[11]
2-Methyltetrahydrofuran=H2O, 50=50 (v=v)
Isopropanol
4
44
44
5
6
20
31
7
2-Methyltetrahydrofuran=isopropanol, 50=50 (v=v)
2-Methyltetrahydrofuran=isopropanol, 72=18 (v=v), azeotrope[11]
Cyclopentylmethyl ether
Cyclopentylmethyl ether=H2O, 83.7=16.3 (v=v), azeotrope[12]
Acetonitrile
8
19
9
23b
38
10
11
60
aIsolated product 1 after refluxing for 9 h.
bSimilar yield after 24 h refluxing.
Table 3. Clauson–Kaas-type reactions of aminophenols 2a ꢀ HCl–5a ꢀ HCl with 2,5-dimethoxytetrahydro-
furan in the presence of nicotinamide
Entry
Starting aminophenol
Yielda (%)
Reported yield (%)
1
2
3
4
2a ꢀ HCl
3a ꢀ HCl
4a ꢀ HCl
5a ꢀ HCl
67
63
75
77
75,[13],b 61[14],b
57,[15],c 62[16],c
—
86[1a], d
aIsolated products 2–5 after refluxing for 9 h.
bFrom 2a in refluxing acetic acid.
cFrom 3a in refluxing acetic acid.
dIn the presence of 4-chloropyridine.

2952
M. CHATZOPOULOU, E. KOTSAMPASAKOU, AND V. J. DEMOPOULOS
Having in hand this novel methodology, we proceeded to assess its applica-
bility for the formation of the pyrrole ring with the aminophenol hydrochlorides
2a ꢀ HCl–5a ꢀ HCl (Table 3). In all cases the yield of products was quite good, and
for the known 2, 3, and 5 it was comparable or higher than the reported
Clauson–Kaas-type pyrrole ring formation with 2,5-dimethoxytetrahydrofuran
and aminophenols (Table 3, entries 1, 2, and 4).
A special note should be made to the preparation of the amine salt 4a ꢀ HCl,
which was achieved by a gradual addition of the hydrogen donor cyclohexene, in
the catalytic reduction of 2-fluoro-4-nitrophenol with Pd=C. Under these conditions,
the defluorinating[17] side reaction was minimal.
In summary, we have developed a high-yielding Clauson–Kaas pyrrole syn-
thesis in the presence of nicotinamide, which is inexpensive and nontoxic (actually
it is a vitamin, enzyme cofactor). Another important aspect is that the starting
material is an aminophenol hydrochloride, which is advantageous in certain cases
because it is the only isolatable form of the corresponding aminophenol (e.g.,
4-amino-2,6-difluorophenol[1a]).
EXPERIMENTAL
All reagents were purchased from Sigma-Aldrich and used without further
purification. Infrared (IR) spectra were taken with a Perkin-Elmer Fourier transform
(FT)–IR System Spectrum BX. NMR spectra were recorded at 300 MHz (1H NMR)
and 75.5 MHz (13C NMR) on a Bruker AM 300 using tetramethylsilane (TMS) as
the internal standard. Elemental analyses were performed at Galbraith Laboratories,
Inc., Knoxville, TN. Melting points are uncorrected and were determined in open
glass capillaries using a Mel-Temp II apparatus. Flash column chromatography
was carried out with Merck silica gel 60 (230–400 mesh ASTM). Thin-layer chroma-
tography (TLC) was run with Fluka silica gel=TLC cards. All solvents used for
column chromatography were routinely distilled prior to use. Petroleum ether refers
to the fraction with bp 40–60 ꢁC.
Preparation of 4-Amino-2-fluorophenol Hydrochloride (4a ꢀ HCl)
Cyclohexene (123 mg, 1.5 mmol) and 10% Pd=C (50 mg) were added to a sol-
ution of 2-fluoro-4-nitrophenol (157 mg, 1.0 mmol) in EtOH (18.8 mL), and the
resulting mixture was stirred and refluxed under a nitrogen atmosphere for 1 h. Then,
cyclohexene (41 mg, 0.5 mmol) was added, and refluxing was continued for 1 h. This
process was repeated two more times, resulting in a total added cyclohexene of
226 mg (3.0 mmol) and a total reaction time of 4 h. Afterward, the resulted mixture
was cooled (ice bath), acidified with concentrated HCl solution, filtered through a
Whatman paper, and the filtrate was concentrated under reduced pressure. The solid
residue was recrystallized from EtOH=Et2O to yield 106 mg (65%) of 4a ꢀ HCl; mp
242–245 ꢁC; IR (KBr): 3273 (OH), 2906 (þNH) cmꢂ1 1H NMR (MeOH-d4): d
;
5.03 (br s, 4H, OH & þNH), 7.03–7.13 (m, 2H, 5-H & 6-H), 7.15–7.27 (m, 1H,
3-H); 13C NMR (MeOH-d4): d 111.3 (d, J ¼ 22.7 Hz, 3-C), 118.3 (d, J ¼ 3.6 Hz,
6-C), 119.1 (d, J ¼ 3.6 Hz, 5-C), 121.6 (d, J ¼ 8.4 Hz, 4-C), 145.8 (d, J ¼ 12.5 Hz,

SYNTHESIS OF PYRROLYL-PHENOLS
2953
1-C), 151.2 (d, J ¼ 244.4 Hz, 2-C); Anal. calcd. for C6H7ClFNO: C, 44.06; H, 4.31;
N, 8.56. Found: C, 43.75; H, 4.45; N, 8.20.
Preparation of 2-Fluoro-4-(1H-pyrrol-1-yl)phenol (4)
A mixture of 4-amino-2-fluorophenol hydrochloride (4a ꢀ HCl) (164 mg,
1.0 mmol), 2,5-dimethoxytetrahydrofurane (213 mg, 1.61 mmol), and nicotinamide
(192 mg, 1.57 mmol) in 1,4-dioxane (17 mL) was stirred and refluxed under a nitro-
gen atmosphere for 4 h. The resulting mixture was cooled to room temperature
and concentrated under reduced pressure. The residue was gradually extracted in
CH2Cl2 (5 ꢃ 15 mL) with the aid of ultrasound irradiation (5 min) during the process
of each extraction. The combined organic extracts were concentrated under reduced
pressure, and the residue was subject to flash chromatography with a mixture of pet-
roleum ether=ethyl acetate 9:1 to yield 133 mg (75%) of 4. An analytical sample was
prepared by recrystallization from CH2Cl2=petroleum ether; mp 89 ꢁC; IR 3392
1
(OH) cmꢂ1; H NMR (CDCl3): d 5.19 (br s, 1H, OH), 6.31–6.42 (m, 2H, pyrrolyl
3-H & 4-H), 6.96–7.19 (m, 5H, phenyl H and pyrrolyl 2-H & 5-H); 13C NMR
(CDCl3): d 108.9 (d, J ¼ 21.5 Hz, phenyl 3-C), 110.4 (s, pyrrolyl 3-C & 4-C), 117.1
(d, J ¼ 3.4 Hz, phenyl 6-C), 117.8 (d, J ¼ 2.7 Hz, 5-C), 119.6 (s, pyrrolyl 2-C &
5-C), 134.4 (d, J ¼ 8.5, phenyl 4-C), 141.4 (d, J ¼ 14.3 Hz, phenyl 1-C), 150.9 (d,
J ¼ 238.6 Hz, phenyl 2-C). Anal. Calcd. for C10H8FNO: C, 67.79; H, 4.55; N,
7.91. Found: C, 67.61; H, 4.49; N, 7.46.
Supporting Information
1
Full experimental details (1–3 and 5) and H and 13C NMR spectra (4a ꢀ HCl
and 4) can be found via the Supplementary Content section of this article’s Web page.
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