Synthesis and reactivity of new 1-pentafluorophenyl-1H-pyrrole derivatives

Article abstract of DOI:10.3390/80700536

We present 1-pentafluorophenyl-1H-pyrrole and some of its electrophilic substitution reactions: formylation and acetylations. The 2-substituted products formed in these reactions are selectively and in high yield converted into 3-substituted products by treatment with trifluoromethanesulfonic acid. A general synthesis of 3-acylpyrroles was developed by the trifluoromethanesulfonic acid-mediated rearrangement of the corresponding 2-acylpyrroles.

Full text of DOI:10.3390/80700536

Molecules 2003, 8, 536-540
molecules
ISSN 1420-3049
http://www.mdpi.org
Synthesis and Reactivity of New 1-Pentafluorophenyl-1H-
pyrrole Derivatives
Katarína Hrnčariková and Daniel Végh*
Department of Organic Chemistry, Slovak University of Technology, Radlinského Street 9, SK-812 37
Tel. (+421) 259325127, Fax. (+421) 252968560
* Author to whom correspondence should be addressed; e-mail: dvegh@chelin.chtf.stuba.sk
Received: 13 June 2003 / Accepted: 26 June 2003 / Published 15 July 2003
Abstract: We present 1-pentafluorophenyl-1H-pyrrole and some of its electrophilic
substitution reactions: formylation and acetylations. The 2-substituted products formed in
these reactions are selectively and in high yield converted into 3-substituted products by
treatment with trifluoromethanesulfonic acid. A general synthesis of 3-acylpyrroles was
developed by the trifluoromethanesulfonic acid–mediated rearrangement of the
corresponding 2-acylpyrroles.
Keywords: Conducting materials, supramolecular synthons, pyrroles.
Introduction
Pyrrole itself and substituted pyrroles are important starting materials for the synthesis of naturally-
occuring porphynoid compounds and other porphyrins, potential chemotherapeutic agents and
conducting polymers [1]. Polypyrrole films are currently being explored in aplications such as
biosensors, adressable gene-ships and interactive conduits for neuronal tissue engineering [2]. Control
of molecular architecture of electronic functionalities to the backbone or to the side chains of the
conjugated polymers have got very various properties. The pentafluorophenyl group is known for face-
to-face stacking interactions between phenyl and pentafluorophenyl group as common non-covalent
interactions. With this supramolecular synthon it should be possible to design molecules that have high
probability of packing in the desired crystalline arrangement [3].

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537
Results and Discussion
In 1993 Chen and Li described pentafluorophenylation of pyrrole by a photo-induced electron-
transfer cation-diradical coupling process. By this route they prepared 2- and 3- pentafluorophenyl
substituted pyrroles [4]. Henrie II and Yeager [5] and Biemans et al. [6] were interested in the reaction
of hexafluorobenzene with the sodium salt of pyrrole. They prepared several substituted products but
failed to prepare the monosubstituted product 1-pentafluorophenyl-1H-pyrrole (1). The synthesis of
this compound starts of pentafluoroaniline and provides compound 1 by cyclization with
2,5-dimethoxytetrahydrofuran by a slightly modified Clauson-Kass procedure [7a] (yield 78%) or by
P2O5 initiated cyclization [7b] (yield 64%).
These reactions are suitable for a multi-gram preparation of 1-pentafluorophenyl-1H-pyrrole. The
product is a stable colorless crystalline compound; it can easily be purified by steam distillation or by
vacuum sublimation. Electrophilic substitution reactions of compound 1 such as Vilsmeyer-Haack
formylation and acylations with aliphatic acid anhydrides lead in very good yields predominantly to 2-
substituted products (2a-c) [8] with no more than 5% of the corresponding 3-substituted products (3a-
c) (Scheme 1).
Scheme 1: Preparation and some reactions of compound 1
X
X
F
NH2
N
N
F
N
F
F
F
F
F
F
F
F
F
F
F
F
F
F
+
X
MeO
O
OMe
+
CH3COOH or P2O5
F
F
F
F
1
2a-c
3a-c
X= a: -CHO, b: -COCH3, c: -COCH2CH3
CF3SO3H
ClCH2CH2Cl
3-Substituted products were prepared in near quantitative yields by isomerisation of 2-substituted
products using trifluoromethanesulfonic acid [9]. Only one example of isomerisation of
carboxaldehyde group [9] has been reported in the literature. We used this method for isomerisation of
a keto group in near quantitative yield. The acid-promoted conversion of 2-substituted into 3-
substituted pyrroles has preparative significance. Such compounds, heretofore prepared by multi-step
sequences can now often be obtained in one step from the readily available 2-substituted pyrroles. All
19F-NMR spectra displayed two triplets and one doublet in a 2:1:2 ratio which characterize the
pentafluorophenyl group.

Molecules 2003, 8
538
Conclusions
In this paper we have described a straightforward and efficient preparation of new
1-pentafluorophenyl-1H-pyrrole derivatives, all of which are important precursors for preparation of
new oligo- and polypyrrole derivatives with optoelectronical properties. Our objective has been to
produce well-defined polypyrroles containing electroactive functionalities, such as those giving rise to
self-compensated materials and well-organized self-assembled structures.
Experimental
General
1H-, 13C- and 19F NMR spectra were obtained using a Varian VXR 300 NMR and were recorded at
300, 75.4 and 282.2 MHz respectively. Chemical shifts are reported in parts per million downfield
using the CDCl3 peak (7.27 ppm, 1H; 77.4 ppm, 13C) or trifluoroacetic acid (-78.5 ppm, 19F) as internal
references. Coupling constants are recorded in Hz. MS measurements were made with an MS 902-S
mass spectrophotometer. Melting points were measured on a Kofler block and are uncorrected.
Analytical TLC was performed on precoated 0.25 mm silica gel 60F-254 plates (E. Merck), developed
with toluene and visualized with UV irradiation.
Synthesis of 1-Pentafluorophenyl-1H-Pyrrole (1).
A solution of the pentafluoroaniline (3.0 g, 16.4 mmol) and 2,5-dimethoxytetrahydrofuran (2.6 g,
19.7 mmol) in acetic acid (30 mL) is first refluxed for 3 hours, then the solvent is removed under
reduced pressure, and the oily residue is taken up with diethyl ether. The organics were washed
sequentially with water and saturated sodium bicarbonate solution. Purification by steam distillation or
vacuum sublimation gives pure pyrrole 1 (2.98 g, 78% yield), m.p. 58-60oC; Rf 0.67; 1H-NMR δ: 6.78
(t, 2H, J=2.0), 6.41 (d, 2H, J=2.1); 13C-NMR δ: 110.9, 116.7, 122.4, 136.5, 139.9, 140.7; 19F-NMR δ:
-145.3 (d, 2F, J=15.6), -152.7 (t, 1F, J=23.1), -157.5 (t, 2F, J=20.3); HRMS (CI) for C10H4F5N (MH+,
100): 233.
Synthesis of 1-Pentafluorophenyl-1H-Pyrrole-2-Carbaldehyde (2a).
Phosphorus oxychloride (0.35 g, 2.26 mmol) was added dropwise to cooled N,N-dimethyl-
formamide (0.17 g, 2.26 mmol). The mixture was brought to room temperature and a solution of 1-
pentafluorophenyl-1H-pyrrole (1) (0.44 g, 1.89 mmol) in 1,2-dichloroethane (10 mL) is added in small
portions over 15 min. After 7 hours warming at 80oC the reaction mixture was cooled and poured into
ice. The solution was neutralized with saturated aqueous sodium carbonate and extracted with diethyl
ether (3x20 mL). The combined organic layers were dried over calcium chloride. Removal of the
solvent in vacuo gave the crude product, which was then purified by chromatography on a silica gel

Molecules 2003, 8
539
column (eluent = toluene) to yield 2a as a colorless crystalline solid (0.38 g, 76% yield); m.p. 77-79oC;
1
13
Rf 0.49; H-NMR δ: 9.59 (s, 1H), 7.19 (d, 1H, J=3.9), 6.99 (s, 1H), 6.55 (t, 1H, J= 3.5); C-NMR δ:
112.4, 125.0, 131.6, 136.0, 139.5, 141.9, 142.1, 145.4, 178.7; 19F-NMR δ: -143.44 (d, 2F, J=17.7),
-149.82 (t, 1F, J=22.8), -158.22 (dd, 2F, J=17.7); HRMS (CI) for C11H4F5NO (MH+, 100): 261
Synthesis of Compounds 2b,c.
A mixture of 1-pentafluorophenyl-1H-pyrrole (1) (1.0 g, 4.29 mmol), Mg(ClO4)2·2H2O (0.1 g) and
the appropriate anhydride (10 mL) was heated for 4 hours at 80oC. After cooling it was poured onto
ice. The solution was neutralized with saturated aqueous sodium carbonate solution and extracted with
diethyl ether (3x20 mL). The combined organic layers were dried over calcium chloride. Removal of
the solvent in vacuo afforded the crude products, which were then purified by chromatography on a
silica gel column (eluent = toluene) to yield 2b or 2c as colorless crystalline solids.
Analytical and Spectral Data: 1-(1-Pentafluorophenyl-1H-pyrrole-2-yl)-ethanone (2b): 0.83 g (70%
yield); m.p: 45-48oC; Rf 0.45; 1H-NMR δ: 7.20 (d, 1H, J=2.3), 6.87 (s, 1H), 6.45 (t, 1H, J=3.5), 2.44 (s,
13
19
3H); C-NMR δ: 26.11, 111.3, 120.6, 130.6, 132.1, 135.8, 139.6, 142.2, 145.4, 187.7; F-NMR δ: -
143.63 (d, 2F, J=17.4), -150.60 (t, 1F, J=22.8), -158.62 (dd, 2F, J=17.4); HRMS (CI) for C12H6F5NO
(MH+, 100): 275.
1-(1-Pentafluorophenyl-1H-pyrrole-2-yl)-propan-1-one (2c): 0.89 g (72% yield); m.p. 75-77oC; Rf
0.55; 1H-NMR δ: 7.17 (d, 1H, J=2.4), 6.87 (s, 1H), 6.45 (t, 1H, J=3.5), 2.87 (q, 1H, J= 7.5), 1.13 (t, 3H,
J=7.5); 13C-NMR δ: 8.3, 31.8, 111.2, 119.5, 130.3, 131.7, 135.9, 139.3, 142.1, 145.6, 191.2; 19F-NMR
δ: -69.76 (d, 2F, J=17.4), -76.81 (t, 1F, J=22.8), -84.70 (dd, 2F, J=17.7); HRMS (CI) for C13H8F5NO
(MH+, 100): 289.
Synthesis of Compounds 3a-c.
Triflic acid (1.8 ml, 20 mmol) was added to a solution of 2a-c (5 mmol) in dichloroethane (10 mL).
The reaction mixture was refluxed for 3 hours and then evaporated to dryness under reduced pressure.
The residue was dissolved in diethyl ether and the solution was washed twice with a saturated aqueous
solution of sodium carbonate. The organic layer was separated, dried over magnesium sulphate and the
solvent was removed under reduced pressure. Vacuum sublimation gives the compounds 3a, 3b or 3c,
respectively, in nearly quantitative yields.
Analytical and Spectral Data: 1-Pentafluorophenyl-1H-pyrrole-3-carbaldehyde (3a): m.p. 53-56oC; Rf
0.38; 1H-NMR δ: 9.89 (s, 1H), 7.49 (t, 1H, J=1.8), 6.86-6.91 (m, 2H); 13C-NMR δ: 109.6, 125.0, 128.6,
130.3, 136.6, 139.7, 140.6, 142.6, 144.0, 185.2; 19F-NMR δ: -65.91 (d, 2F, J=18.0), -70.97 (t, 1F,
J=23.1), -77.54 (t, 2F, J=18.0); HRMS (CI) for C11H4F5NO (MH+, 100): 261.

Molecules 2003, 8
540
1
1-(1-Pentafluorophenyl-1H-pyrrole-3-yl)-ethanone (3b): m.p. 114-115oC; Rf 0.33; H-NMR δ: 7.45
13
(t, 1H, J=1.8), 6.82-6.85 (m, 2H), 2.46 (s, 3H); C-NMR δ: 27.4, 110.9, 124.1, 127.0, 128.2, 136.7,
139.7, 140.8, 142.1, 144.0, 193.0; 19F-NMR δ: -65.97 (d, 2F, J=18.0), -71.43 (t, 1F, J=23.1), -77.81 (t,
2F, J=18.0); HRMS (CI) for C12H6F5NO (MH+, 100): 275.
1
1-(1-Pentafluorophenyl-1H-pyrrole-3-yl)-propan-1-one (3c): m.p. 102-104oC; Rf 0.52; H-NMR δ:
13
7.46 (t, 1H, J=1.8), 6.83-6.85 (m, 2H), 2.82 (q, 2H, J=7.2), 1.21 (t, 3H, J= 7.5); C-NMR δ: 196.2,
19
144.0, 143.8, 142.4, 140.7, 127.6, 126.4, 123.9, 110.8, 32.9, 8.4; F-NMR δ: -65.99 (d, 2F, J=18.6),
-71.58 (t, 1F, J=23.1), -77.85 (t, 2F, J=18.0); HRMS (CI) for C13H8F5NO (MH+, 100): 289.
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Sample Availability: Available from the authors.
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