A Study of the Electrophilic Aroylation of 1-Aryl-1H-pyrroles: An Improved Preparation of an Active and Selective Aldose Reductase Inhibitor

Full text of DOI:10.1080/00304948.2019.1577109

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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A Study of the Electrophilic Aroylation of 1-Aryl-1H-
pyrroles: An Improved Preparation of an Active
and Selective Aldose Reductase Inhibitor
Nikolaos Kontonikas, Panagiota Kotsampasakou, Nikolaos Sakalis & Vassilis
J. Demopoulos
To cite this article: Nikolaos Kontonikas, Panagiota Kotsampasakou, Nikolaos Sakalis & Vassilis
J. Demopoulos (2019) A Study of the Electrophilic Aroylation of 1-Aryl-1H-pyrroles: An Improved
Preparation of an Active and Selective Aldose Reductase Inhibitor, Organic Preparations and
Procedures International, 51:2, 147-152, DOI: 10.1080/00304948.2019.1577109
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2019
Organic Preparations and Procedures International, 51:147–152,
# 2019 Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2019.1577109
A Study of the Electrophilic Aroylation of 1-Aryl-
1H-pyrroles: An Improved Preparation of an
Active and Selective Aldose Reductase Inhibitor
Nikolaos Kontonikas, Panagiota Kotsampasakou,
Nikolaos Sakalis, and Vassilis J. Demopoulos
Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle
University of Thessaloniki, 54124 Thessaloniki, Greece
The aroyl-1-aryl-1H-pyrrole moiety is an important scaffold present in a number of bio-
logically active compounds.1–5 Based on such precedent, we were prompted to study
the electrophilic benzoylation of 1-phenyl-1H-pyrrole (1). We sought to develop an
appropriate methodology for the selective preparation of 1-aryl-1H-pyrrolyl derivatives
with aroyl substituents at the underexplored pyrrolyl C-a position. The new method-
ology described herein was applied to prepare the known active and selective aldose
reductase inhibitor (ARI) ([1,1’-biphenyl]-4-yl)[1-(3,5-difluoro-4-hydroxyphenyl)-1H-
pyrrol-2-yl]methanone (2).2 We have previously prepared compound 2, however in low
yield and not selectively.2 Thus, in the present work we improve our own methodology.
Initially, the AlCl3 catalyzed reaction of 1 with benzoyl chloride was investigated
by varying the ratio of reactants2,5 and by adding nitromethane6 (Table 1, entries 1–3).
In all cases, the main product was the C-b substituted pyrrolyl derivative 3. We noted,
however, that the addition of nitromethane resulted in the formation of small amounts
of the C-a isomer 4. Subsequently, the AlCl3 was replaced with the weaker Lewis acids
Et2AlCl7 or BF3ꢀOEt2 (Table 1, entries 4 and 5). In the first case, the reaction was
1,8
clean and both isomers were formed in good yields, with the higher yield that of the C-
b isomer 3. On the other hand, BF3ꢀOEt2 proved to be an ineffective catalyst; only
traces of products were formed, and a substantial amount of the pyrrolyl starting mater-
ial remained unreacted even after seven days. Finally, the reaction of 1 with benzoyl
chloride was studied in the presence of DBN,9 Zn,10 or I-,11 without any added Lewis
acid catalyst. With the first two methods, no reaction was observed; but the use of I-
resulted in the selective formation of the C-a isomer 4. We found out that the best yield
was obtained with the combination of CH3CN as the solvent and KI as the catalyst
(Table 1, entry 6). All compounds were isolated by flash column chromatography, and
the solids were further recrystallized. Structural identification was based on spectro-
scopic methods (IR, NMR and HRMS).
The data show that the most selective procedure for C-a substitution is the one
with CH3CN and KI. Thus, we went on to investigate selective preparation of the
Received December 13, 2017; in final form October 21, 2018.
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
147

148
Demopoulos et al.
Table 1
Conditions and Yields for the Electrophilic Aroylation Reactions
1-Aryl-1H-
pyrrole
(1 mmol)
Aroyl
chloride
(equivalents)
Catalyst(s)
(equivalents),
solvent (mL)
Time(h),
conditions
Producta
(yield%)
Entry
1
1
1
1
R ¼ H (2.24)
R ¼ H (2.24)
R ¼ H (2.24)
AlCl3 (2.4),
ClCH2CH2Cl
(29.5)
AlCl3 (1.2),
ClCH2CH2Cl
(14.5)
AlCl3 (1.2) and
CH3NO2 (1.2),
ClCH2CH2Cl
(14.5)
48, room temp.
24, room temp.
24, room temp.
4 (0)
3 (39)
2
3
4 (0)
3 (72)
4 (10.5)
3 (72)
4
5
1
1
R ¼ H (2)
R ¼ H (3)
Et2AlCl (1.4),
ClCH2CH2Cl (4)
BF3.Et2O (3),
ClCH2CH2Cl
(10.5)
2, ice bath
4 (41)
3 (57)
4 (5)
168, room temp.
3 (3)
[1 (25)]
4 (40)
3 (16)
2 (61)
6 (24)
6
7
1
5
R ¼ H (1.2)
R ¼ Ph (2.4)
KI (0.6),
CH3CN (1)
KI (1.2)
24, reflux
24, reflux
CH3CN (2)
aYields are for isolated products.
Scheme 1
ARI 2. Under the above conditions 2 could be synthesized in good yield (61%, Table 1,
entry 7), much higher than that reported previously (34%).2 In that preparation, the
electrophilic aroylation of 5 was catalyzed by AlCl3. It is hoped that the ready availabil-
ity of 2 will stimulate further research.
To summarize, we have developed an effective synthetic procedure for preparing
potentially bioactive 2-aroyl-1-aryl-1H-pyrrole derivatives.

Aroylation of 1-Aryl-1H-pyrroles
149
Experimental Section
All reagents were purchased from Sigma–Aldrich and used without further purification.
Melting points are uncorrected and were determined in open glass capillaries using a
Mel-Temp II apparatus. IR spectra were taken with a Perkin-Elmer FT-IR System
Spectrum BX. NMR spectra were recorded on an Agilent 500/54 (DD2) spectrometer
1
(500 MHz for H NMR, 125 MHz for 13C NMR) using tetramethylsilane (TMS) as the
internal standard. Mass spectra were obtained on a hybrid LTQ Orbitrap Discovery
mass spectrometer (Thermo Scientific, Bremen, Germany), which was equipped with an
electrospray ionization (ESI) MAX2 source. Flash column chromatography was carried
out with Merck silica gel 60 (230–400 Mesh ASTM). TLC was run with Merck 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.
General Procedure for the Electrophilic Benzoylation of 1 in the Presence of a
Lewis Acid Catalyst (Table 1, entries 1–5)
To a stirred cold (ice bath) solution of benzoyl chloride in 1,2-dichloroethane under a
nitrogen atmosphere, the catalyst was added and stirring was continued at the same tem-
perature for 10 min. After this period, 1 was added and stirring was continued for the
specified time and temperature conditions. The reaction mixture was then poured into
ice/water (150 mL), stirred overnight, the two phases were separated and the aqueous
fraction extracted with CH2Cl2 (3x50 mL). The combined organic phases were washed
with 5% aqueous NaHCO3 solution (1x100 mL), brine (1x100 mL), dried over anhyd-
rous Na2SO4 and concentrated under reduced pressure. The residue was subjected to
flash chromatography with a mixture of petroleum ether/ethyl acetate 18:1 as
the eluent.
General Procedure for the Electrophilic Aroylation of 1-Aryl-1H-pyrrole 1 or 5 in
the Presence of KI (Table 1, entries 6 and 7)
To a stirred mixture of 1-aryl-1H-pyrrole 1 or 5 and KI in anhydrous CH3CN (3Å
molecular sieves) under a nitrogen atmosphere, the appropriate aroyl chloride was
added and the resulted mixture was heated at 82 ꢁC for the specified time. The reaction
mixture was then poured, with the aid of 5 mL CH3CN, into a 1% aqueous Na2S2O3
solution (100 mL). The resulting mixture was stirred overnight at room temperature
under a nitrogen atmosphere.
Entry 6: The mixture was then extracted with CH2Cl2 (3x50 mL), the combined
extracts were washed with 5% aqueous NaHCO3 solution (1x50 mL), brine (1x50 mL),
dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue
was subjected to flash chromatography with a mixture of petroleum ether/ethyl acetate
18:1 as the eluent.
Entry 7: The mixture was then acidified, to pHꢂ2, with 5% aqueous HCl solution
and extracted with 9:1 CHCl3/EtOH (3x50 mL). The acidification step was necessary in
order to free any present phenolic salts before the extraction. The combined extracts
were evaporated under reduced pressure, the residue was dissolved in 1,4-dioxane
(27 mL), treated with 5% aqueous NaOH solution (27 mL) and the resulting mixture
was stirred overnight at room temperature under a nitrogen atmosphere. The reaction

150
Demopoulos et al.
mixture was then concentrated to half of its volume under reduced pressure, H2O
(50 mL) was added, cooled (ice bath), acidified with concentrated aqueous HCl solu-
tion, extracted with CH2Cl2 (3x50 mL) while cold, and the organic extracts were con-
centrated under reduced pressure. The residue was dissolved in a mixture of ethyl
acetate (70 mL) and petroleum ether (70 mL), and this was washed consecutively with a
phosphate buffer (Na2HPO4-KH2PO4) pH 8 (6x50 mL), 5% aqueous HCl solution
(1x50 mL), brine (1x50 mL), dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The residue was subjected to flash chromatography with a mixture of
petroleum ether/ethyl acetate 18:1 as the eluent.
Phenyl(1-phenyl-1H-pyrrol-2-yl)methanone (4). An analytical sample was prepared by
recrystallization from 95% aqueous ethanol; Rf¼0.65, petroleum ether/ethyl acetate 8:2;
mp 68-69 ꢁC; lit.12 116 ꢁC; lit.13,14 95-96; lit.15 brown oil; IR (KBr): 1628 (C ¼ O)
1
cmꢃ1, consistent with the reported13 IR data; H NMR (CDCl3): d 6.34 (dd, J ¼ 2.7,
3.9 Hz, 1H, pyrrolyl 4-H), 6.89 (dd, J ¼ 1.6, 3.9 Hz, 1H, pyrrolyl 3-H), 7.12 (dd,
J ¼ 1.8, 2.4 Hz, 1H, pyrrolyl 5-H), 7.31–7.35 (m, 2H, phenyl 3-H and 5-H), 7.35–7.39
(m, 1H, phenyl 4-H), 7.40-7.48 (m, 4H, phenyl 2-H & 6-H and benzoyl 3-H and 5-H),
7.55 (t, J ¼ 7.4 Hz, 1H, benzoyl 4-H), 7.87–7.91 (m, 2H, benzoyl 2-H & 6-H), consist-
ent with the reported13–15 1H NMR data; 13C NMR (CDCl3): d 109.5, 123,5, 125.5,
127.5, 128.1, 128.9, 129.5, 131.0, 131.1, 131.9, 139.0, 140.6, 184.8, consistent with the
reported13–15 13C NMR data; HRMS m/z calc. for C17H13NO: 247.0997(248.1075 for
M þ H)þ; Found: 248.1085 (ESIþ).
Phenyl(1-phenyl-1H-pyrrol-3-yl)methanone (3). Viscous oil; Rf¼0.49, petroleum
ether/ethyl acetate 8:2; IR (neat): 1633 (C ¼ O) cmꢃ1, consistent with the reported4 IR
1
data; H NMR (CDCl3): d 6.88 (s, 1H, pyrrolyl 4-H), 7.11 (d, J ¼ 2.1 Hz, 1H, pyrrolyl
5-H), 7.34 (t, J ¼ 7.2 Hz, 1H, phenyl 4-H), 7.42 (d, J ¼ 7.5 Hz, 2H, phenyl 3-H and 5-
H), 7.46 (d, J ¼ 7.2 Hz, 2H, phenyl 2-H & 6-H), 7.49 (d, J ¼ 7.4 Hz, 2H, benzoyl 3-H
and 5-H), 7.55 (t, J ¼ 7.4 Hz, 1H, benzoyl 4-H), 7.61 (s, 1H, pyrrolyl 2-H), 7.88 (d,
J ¼ 7.7 Hz, 2H, benzoyl 2-H and 6-H), consistent with the reported3,4 1H NMR data;
13C NMR (CDCl3): d 112.4. 121.1, 121.2, 126.1, 126.2, 127.1, 128.2, 128.9, 129.8,
131.5, 139.7, 139.8, 190.7, consistent with the reported3 13C NMR data; HRMS m/z
calc. for C17H13NO: 247.0997(248.1075 for M þ H)þ; Found: 248.1082 (ESIþ).
([1,1’-Biphenyl]-4-yl)[1-(3,5-difluoro-4-hydroxyphenyl)-1H-pyrrol-2-yl]methanone (2).
An analytical sample was prepared by recrystallization from CH2Cl2/petroleum ether;
Rf¼0.33, petroleum ether/ethyl acetate 8:2; mp 210-213 ꢁC; lit.2 214–216 ꢁC; IR (nujol):
1
3137 (OH), 1592 (C ¼ O) cmꢃ1, consistent with the reported2 IR data; H NMR (CDCl3
þ DMSO-d6, the addition of DMSO-d6 was necessary in order to dissolve the compound):
d 6.03 (br s, 1H, O-H), 6.25 (dd, J ¼ 2.8, 3.8 Hz, 1H, pyrrolyl 4-H), 6.74-6.86 (m, 3H,
pyrrolyl 3-H and phenyl 2-H and 6-H), 6.96-6.99 (m, 1H, pyrrolyl 5-H), 7.31 (t,
J ¼ 7.4 Hz, 1H, biphenyl 4’-H), 7.39 (t, J ¼ 7.6 Hz, 2H, biphenyl 3’-H and 5’-H), 7.56 (d,
J ¼ 7.3 Hz, 2H, biphenyl 2’-H and 6’-H), 7.60 (d, J ¼ 8.3 Hz, 2H, biphenyl 3-H and 5-H),
7.86 (d, J ¼ 8.3 Hz, 2H, biphenyl 2-H and 6-H), consistent with the reported2 1H NMR
data; 13C NMR (CDCl3 þ DMSO-d6, the addition of DMSO-d6 was necessary in order to
dissolve the compound): d 109.7(dd, J ¼ 7.5, 17.4 Hz), 123.2, 126.7, 126.8, 127.1, 127.2,
128.0, 128.9, 129.9, 130.0, 131.1 (t, J ¼ 10.0 Hz), 133.9 (t, J ¼ 15.8 Hz), 137.5, 139.9,
144.7, 152.0 (dd, J ¼ 8.1, 243.7 Hz), 184.1; HRMS m/z calc. for C23H15F2NO2: 375.1071
(374.0993 for M-H)-; Found: 374.0997 (ESI-).

Aroylation of 1-Aryl-1H-pyrroles
151
([1,1’-Biphenyl]-4-yl)[1-(3,5-difluoro-4-hydroxyphenyl)-1H-pyrrol-3-yl]methanone (6).
An analytical sample was prepared by recrystallization from CH2Cl2/petroleum ether;
Rf¼0.18, petroleum ether/ethyl acetate 8:2; mp 202–204 ꢁC; lit.2 205–207 ꢁC; IR (nujol):
1
3154 (OH), 1617 (C ¼ O) cmꢃ1, consistent with the reported2 IR data; H NMR (CDCl3
þ DMSO-d6, the addition of DMSO-d6 was necessary in order to dissolve the compound):
d 6.12 (br s, 1H, O-H), 6.73 (dd, J ¼ 1.6, 2.8 Hz, 1H, pyrrolyl 4-H), 6.86-6.92 6.92 (m,
3H, pyrrolyl 5-H and phenyl 2-H and 6-H), 7.27 (t, J ¼ 6.9 Hz, 1H, biphenyl 4’-H), 7.36
(t, J ¼ 7.6 Hz, 2H, biphenyl 3’-H and 5’-H), 7.42 (t, J ¼ 1.7 Hz, 1H, pyrrolyl 5-H), 7.51-
7.54 (m, 2H, biphenyl 2’-H and 6’-H), 7.59 (d, J ¼ 8.1 Hz, 2H, biphenyl 3-H and 5-H),
7.82 (d, J ¼ 8.2 Hz, 2H, biphenyl 2-H and 6-H), consistent with the reported2 1H NMR
data; 13C NMR (CDCl3 þ DMSO-d6, the addition of DMSO-d6 was necessary in order to
dissolve the compound): d 105.3 (dd, J ¼ 8.3, 17.8 Hz), 112.3, 125.8, 125.85, 126.1,
126.9, 127.1, 127.9, 128.8, 129.5, 130.5 (t, J ¼ 11.0 Hz), 133.5 (t, J ¼ 16.1 Hz), 138.2,
140.0, 144.5, 152.7 (dd, J ¼ 8.4, 244.9 Hz), 189.9; HRMS m/z calc. for C23H15F2NO2:
375.1071 (374.0993 for M-H)-; Found: 374.0999 (ESI-).
Acknowledgments
Many thanks to Dr. Evagelos Gikas (Department of Pharmaceutical Chemistry, Faculty
of Pharmacy, National and Kapodistrian University of Athens) for the mass spec-
tral data.
ORCID
Vassilis J. Demopoulos
http://orcid.org/0000-0002-6957-2467
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