Preparation of α-free pyrroles with perfluorinated groups at β-positions

Article abstract of DOI:10.1055/s-2001-18437

Ethyl pyrrole-2-carboxylates bearing trifluoromethyl and/or pentafluorophenyl groups at β-positions were converted to the corresponding α-free pyrroles in good yields by reduction with LiAlH₄, oxidation with MnO₂ and decarbonylation

Full text of DOI:10.1055/s-2001-18437

PAPER
2255
Preparation of -Free Pyrroles with Perfluorinated Groups at -Positions
P
reparationof -F
i
ree
P
yr
d
r
oles
w
ithPe
e
rfluorinate
m
G
roupsat -Posit
i
a
Advanced Instrumentation Center for Chemical Analysis, Ehime University, Bunkyo-cho 2-5, Matsuyama 790-8577, Japan
Fax +81(89)9279670; E-mail: uno@dpc.ehime-u.ac.jp
b
Department of Chemistry, Faculty of Science, Ehime University, Bunkyo-cho 2-5, Matsuyama 790-8577, Japan
Received 26 July 2001; revised 4 September 2001
ing three methods: Wittig reaction with (S)-hexyl trifluo-
rothioacetate followed by oxidation with mCPBA (1a, 1c,
and 1e);10 condensation of pentafluorobenzyl tolyl sulfone
with aldehydes followed by dehydration with MsCl and
Et3N (1b, 1d, and 1f); condensation of benzyl tolyl sul-
fone with pentafluorobenzaldehyde followed by dehydra-
tion with MsCl and Et3N (1g).
Abstract: Ethyl pyrrole-2-carboxylates bearing trifluoromethyl
and/or pentafluorophenyl groups at -positions were converted to
the corresponding -free pyrroles in good yields by reduction with
LiAlH4, oxidation with MnO2 and decarbonylation with Pd/C.
Key words: trifluoromethyl, pentafluorophenyl, vinylsulfone, Bar-
ton–Zard pyrrole synthesis -free pyrrole
-Free pyrroles are very important precursors for the syn-
thesis of a variety of porphyrinoid dyes and polypyrroles.1
In order to modulate electronic properties of these func-
tional materials such pyrroles bearing various kinds of
electronic properties at -positions are required. -Free
pyrroles having strongly electron-withdrawing groups
such as alkoxycarbonyl, cyano, acyl and nitro groups at
the -position were successfully prepared by van Leus-
en’s method based on the reaction of , -unsaturated car-
bonyl compounds with tosylmethyl isocyanide.2,3 Simple
alkyl- aryl- and alkoxy-substituted -free pyrroles were
also prepared either by condensation of -tosyl vinyl iso-
cyanide with carbonyl compounds4 or by heating the cor-
responding pyrrole-2-carboxylic acid esters in strongly
alkaline media.5 The latter pyrrole-2-carboxylic acid es-
ters were in turn easily prepared by Barton–Zard pyrrole
synthesis6 or by the Hinsberg-type condensation of imin-
odiacetic acid esters.7 Cycloaddition8 of azomethine
ylides with acetylenes and bromination9 of N-triisopropyl-
silyl-protected pyrrole are convenient methods for prepa-
ration of symmetrically -substituted -free pyrroles.
However, these methods could not be applied for prepara-
tion of -free pyrroles bearing perfluorinated groups such
as trifluoromethyl and pentafluorophenyl groups due to
lability of these functional groups in strongly alkaline me-
dia and the insufficient electron-withdrawing nature com-
pared with nitro, sulfonyl and carbonyl groups. Bulkiness
of these perfluoroalkylated groups sometimes hampered
the desired pyrrole formation reactions.10 In this paper, we
would like to report a facile route to -unsubstituted pyr-
roles having trifluoromethyl and/or pentafluorophenyl
groups at -positions.
R1
R2
R2
3
4
CNCH2CO2Et
R1
SO2R
t-BuOK
EtO2C
LiAlH4
N
1
H
40—82%
2
R1
R1
R2
4
R2
3
MnO2
44—93%
(2 steps)
OHC
HOH2C
N
N
H
H
4
3
Pd/C
R1
R2
R
25—89%
a
Ph
Ph
CF3
C6H13
b
c
C6F5 p-CH3C6H4
C6H13
2,6-Cl2C6H3- C6F5 p-CH3C6H4
R1
R2
4
3
2,6-Cl2C6H3- CF3
d
e
f
N
H
C6F5
C6F5
C6F5
CF3
C6F5 p-CH3C6H4
Ph p-CH3C6H4
C6H13
5
g
Scheme Preparation of -free pyrroles bearing perflourinated
groups
Condensation of the , -unsaturated sulfones 1 with ethyl
isocyanoacetate was achieved by t-BuOK in THF in good
yields (Table 1). In this conversion, a poorer result was
obtained by using DBU instead of t-BuOK, probably due
to the less electrophilic nature of , -unsaturated sulfones
bearing perfluorinated groups compared to the carbonyl
and cyano groups.10 In the case of 1g, a fluorine atom at
the para position of the pentafluorophenyl group was par-
tially replaced by an ethoxy group, which would be
formed by decomposition of ethyl isocyanoacetate. A
mixture of pentafluorophenyl derivative 2g and 4-ethoxy-
2,3,5,6-tetrafluorophenyl derivative 2g’ was obtained in
Our method is based on the modified Barton–Zard pyrrole
synthesis11 followed by palladium-catalyzed decarbonyla-
tion of pyrrole-2-carbaldehyde12 (Scheme). The starting
, -unsaturated sulfones 1 were prepared by the follow-
Synthesis 2001, No. 15, 12 11 2001. Article Identifier:
1437-210X,E;2001,0,15,2255,2258,ftx,en;F06301SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
70% yield. In other -pentafluorophenylethenyl and
-

2256
H. Uno et al.
PAPER
(pentafluorophenyl)ethenyl sulfones such as 1e, 1f, 1b The pyrrole 5a was subject to the porphyrin synthesis.
and 1d, no such substitution was observed. These results However, the reaction of 5a with benzaldehyde in the
were rationalized as follows. In the case of 1g, para posi- presence of p-TSA followed by oxidation with DDQ gave
tion of the pentafluorophenyl group would be highly sus- an intractable mixture, although porphyrins were obtained
ceptible toward the nucleophilic attack due to conjugation in 10–26% yields by the sequential treatment of 2a and 2c
with the -sulfonyl group, while the same position of 1b with LiAlH4, p-TSA, and DDQ.13
and 1d would be less electrophilic due to the lack of such
conjugation with the -sulfonyl group. In the cases of 1e
Melting points are uncorrected. NMR spectra were obtained with a
and 1f, additional electron-withdrawing groups would
help the Michael addition of an anion of isocyanoacetate
to the highly electrophilic olefinic carbon giving the de-
sired pyrrole derivatives.
JEOL GSX-270 or JNM-400 spectrometer at ambient temperature
by using CDCl3 as a solvent and tetramethylsilane and CFCl3 as in-
ternal standards for 1H, 13C and 19F. Coupling constants (J) values
are reported in Hz. Mass spectra were measured with a Hitachi
M80B spectrometer under the EI and CI conditions: (EI: 20 eV; CI:
70 eV, isobutane as the CI gas; high boiling perfluorokerosine as a
standard) or with JEOL JMS-LX2000 under FAB conditions (ni-
trobenzyl alcohol as matrix). IR spectra were recorded on a
Table 1 Preparation and oxidation potentials of -free pyrroles 5
Yield/%
Eox of 5
1a
2
4
5
/eVb
1.05
1.01
1.36
1.26
1.51
1.31
–
RIBA FF 72C. Column chromatography and TLC analyses were
carried out using C-200 (Wakogel) and Kieselgel 60 F254 (Merk),
respectively. Et2O and THF were freshly distilled from sodium ben-
zophenone ketyl. CH2Cl2 was distilled from CaH2 under an inert at-
mosphere. Methanesulfonyl chloride and mesitylene were used
after distillation. Other commercially available materials were used
without further purification. Sulfones and pyrroles with a trifluo-
romethyl group (1a, 1c, 1e, 2a, 2c and 2e) were prepared according
to the reported procedure.12 General or typical procedures used in
this paper are as follows.
a
b
c
d
e
f
c
40
73
60
82
51
65
70d
93
49
93
44
72
62
–
89
41
52
25
37
40
–
51
c
58
c
82
57
Preparation of Sulfones 1b, 1d, 1f, and 1g; Typical Procedure
for 1f
g
To a stirred solution of 2,3,4,5,6-pentafluorobenzyl tolyl sulfone
(3.36 g, 10 mmol) in anhyd THF (20 mL) was added n-BuLi (1.5 M,
8 mL, 12 mmol) over 5 min at 0 °C and the mixture was stirred for
10 min. Pentafluorobenzaldehyde (1.48 mL, 12 mmol) was added at
the same temperature. After 45 min, saturated aq NH4Cl solution
(100 mL) was added and the mixture was extracted with Et2O
(3 30 mL). The ethereal organic phase was washed with brine (50
mL), dried over MgSO4 and concentrated to leave 5.55 g (over-
weighed) of a crude -hydroxy sulfone as a mixture of diastere-
omers. The crude material was dissolved in anhyd CH2Cl2 and
MsCl (0.93 mL, 12 mmol) and then Et3N (4.18 mL, 30 mmol) were
successively added at 0 °C. After removal of the cooling bath, the
mixture was stirred for 1 h. The reaction was quenched with sat.
NaHCO3 (20 mL) and extracted with CHCl3. The organic extract
was washed with brine, dried over Na2SO4 and concentrated. The
residue was purified by chromatography on silica gel (15% EtOAc–
hexane) to give 4.23 g (82%) of 1,2-bis(pentafluorophenyl)ethenyl
tolyl sulfone (1f) as colorless crystals; mp 147 °C.
a The yield was calculated from the sulfone.
b Cyclic voltammetry was performed in a solution of 0.1 molL–1
TBAP in anhydrous MeCN at 25 °C using a platinum working elec-
trode. Peak potentials were recorded toward Fc/Fc+.
c See ref 10
.
d 4-Ethoxy-2,3,5,6-tetrafluorophenyl derivative 2g’ contaminated.
The ratio was 2g:2g’ = 3:2.
Treatment of 2 with one molar equivalent of LiAlH4 at 0
°C gave the corresponding 2-hydroxymethylpyrroles 3 in
quantitative yields. Higher temperature or use of a large
excess amount of LiAlH4 led to partial replacement of a
fluorine atom by a hydrogen atom or ethoxy group. Al-
though the 2-hydroxymethylpyrroles 3 were fairly stable
and could be isolated by column chromatography, these
compounds were directly oxidized with MnO2 without
purification and pyrrole-2-carbaldehydes 4 were obtained
in good yields from 2. Decarbonylation of 4 was achieved
by refluxing with activated palladium on charcoal in mes-
itylene. The targeted -free pyrroles 5 were obtained in
good to moderate yields. All -free pyrroles 5 obtained
are very stable and they did not color in the air for several
weeks. Oxidation potentials of 5 were measured in a solu-
tion of 0.1 molL–1 TBAP in anhydrous MeCN at 25 °C us-
ing a platinum working electrode. In all cases, the
oxidation potentials are much higher than that of 3,4-di-
ethylpyrrole (0.48 V), and the peak potentials toward Fc/
Fc+ are listed in Table 1. All cyclic voltammograms of 5
are reversible and no oxidative polymerization is ob-
served.
IR (KBr ): 1523, 1496, 1332, 1157, 991 cm–1.
1H NMR (400 MHz): H = 2.46 (3 H, s), 7.30 (2 H, m), 7.63 (2 H,
m), 8.08 (1 H, d J = 1.0).
19F NMR (376 MHz): F = –136.4 (2 F, m), –137.4 (2 F, m), –
149.0 (2 F, m), –160.0 (2 F, m), –160.3 (2 F, m).
13C NMR (100 MHz):
= 21.7, 105.6 (td, J = 18, 4), 107.4 (td,
C
J = 17, 4), 128.7, 130.1, 130.5, 134.2, 137.4 (dm, J = 251), 137.7
(dm, J = 251), 138.3, 142.4 (dm, J = 260), 142.5 (dm, J = 259),
144.1 (dm, J = 254), 144.2 (dm, J = 254), 146.0.
MS–[FAB]– m/z: 515, 359, 137.
1-Pentafluorophenyl-2-phenylethenyl tolyl sulfone (1b)
Colorless crystals; mp 139 °C.
IR (KBr): 1519, 1498, 1315, 1157, 991cm–1.
1H NMR (270 MHz): H = 2.44 (3 H, s), 7.12 (2 H, m), 7.2–7.45 (5
H, m), 7.63 (2 H, m), 8.26 (1 H, s).
Synthesis 2001, No. 15, 2255–2258 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Preparation of -Free Pyrroles with Perfluorinated Groups at -Positions
2257
19F NMR (254 MHz): F = –136.4 (2 F, m), –150.3 (1 F, m), –160.5
(2 F, m).
2-(2,6-Dichlorophenyl)-1-(pentafluorophenyl)ethenyl tolyl
sulfone (1d)
Colorless crystals; mp 164 °C.
IR (KBr): 1520, 1495, 1323, 1159, 989 cm–1.
1H NMR (270 MHz): H = 2.45 (3 H, s), 7.1–7.4 (5 H, m), 7.71 (2
H, m), 8.18 (1 H, s).
13C NMR (62.8 MHz):
J = 1), 128.5, 129.1, 129.3, 129.8, 131.2, 131.8, 135.2, 137.6 (dm,
J = 253), 142.3 (dm, J = 243), 144.3, 144.7 (dm, J = 252), 145.1.
= 21.7, 107.0 (td, J = 18, 4), 128.0 (d,
C
EIMS–[FAB]– m/z: 424, 359, 285, 268, 250, 219, 139.
Table 2 Selected Spectroscopic Data for Pyrroles
Com-
pound
Mp (°C)
NMR/ in ppm
IR/cm–1
EI-MS
-H
7.08
7.19
7.22
19F
C2a
C3a
C4a
C5a
NH and
C=O
m/z
2b
2d
2f
166
154
161
–140.3, –156.4, 120.2
–163.2
129.7
124.8
113.9
110.2
110.9
111.5
122.5
123.2
123.3
3278, 1673 381, 335
3282, 1683 449, 414, 386
3317, 1697 471, 425
–141.1, –156.2, 121.5
–163.1
–141.0, –141.8, 122.4
–154.9, –155.0
–162.1, –163.3
b
b
c
2g
–
–
–139.1, –156.1, 121.8
–163.8
111.5
128.1
128.0
120.8
120.7
–
381, 335
407, 361
b
b
b
c
2g’
4a
–
–
–141.2, –159.0
–55.8
–
112.5
–
106–108
124
7.46
7.31
130.1
135.0 (1)
136.7
116.0 (37) 125.4 (5)
109.8 126.7
3224, 1660 238, 211d
4b
–140.2, –155.7, 130.0
–162.6
3245, 1641 337, 318, 289
4c
157–159
141
7.59
7.39
–58.6
129.8
128.5 (2)
129.3
116.5 (37) 125.5 (5)
111.6 126. 3
3290, 1666 310, 308, 272d
3234, 1660 405, 370
4d
–141.4, –155.5, 129.7
–162.6
4e
4f
74
7.59
7.44
–58.4, –138.4,
–151.7, –161.4
130.9
115.3 e
118.1
117.7 (37) 125.3 (4)
3248, 1666 329, 309, 212
3330, 1666 427, 407
171
–140.5, –141.9, 130.4
–152.2, –154.2,
112.0
126.9
–160.8, –161.6
5a
5b
oil
6.79, 7.09 –55.1
118.2
123.4 (2)
135.2
112.8 (36) 119.6 (5)
106.3 119.9
3423
3463
211, 115
309, 289
124
6.97, 7.04 –140.7, –157.7, 117.0
–163.5
5c
93–94
141
6.73, 7.25 –58.0
119.4
117.3 (2)
119.3
114.0 (36) 118.7 (5)
108.9 128.0
3479
3469
281, 279, 245
377, 343, 308
5d
6.97, 7.07 –142.2, –157.9, 128.8
–163.7
5e
5f
172
171
6.89, 7.27 –57.7, –140.1,
–155.6, –163.4
120.5
105.4d
108.6
115.0 (37) 119.8 (5)
3481
3429
301, 282
399, 330f
7.11
–142.6, –156.8, 120.2
–162.9
–
–
a The carbon numbering is not based on the nomenclature, but on Scheme 1. Numerals in the parentheses are the coupling constants (Hz)
with fluorine atoms.
b These compounds were obtained as a mixture and some signals could not be assigned due to complexity.
c Not measured.
d Under CI conditions (isobutane as the CI gas).
e Multiplet signal.
f Under FAB– conditions.
Synthesis 2001, No. 15, 2255–2258 ISSN 0039-7881 © Thieme Stuttgart · New York

2258
H. Uno et al.
PAPER
19F NMR (254 MHz): F = –134.5 (2 F, m), –150.3 (1 F, m), –161.2
(2 F, m).
Preparation of a-Free Pyrrole 5; General Procedure
Pd(OH)2 on charcoal (10%, 200 mg) was suspended in mesitylene
(10 mL) and the palladium was activated by five cycles of evacua-
tion and flush with hydrogen. The suspension was stirred for 30 min
at r.t. After the atmosphere was changed to argon, cyclohexene (6
mL) was added. Pyrrole-2-carbaldehyde (4, 1 mmol) in mesitylene
(10–25 mL) was added at r.t. The mixture was heated to reflux for
24 h. After cooling, the mixture was filtered through a Celite pad,
which was washed with CHCl3 (30 mL). The organic solvent was
removed in vacuo to give crude 5. The residue was chromato-
graphed on silica gel (CHCl3). Selected spectoscopic data of 4 are
tabulated in Table 2.
13C NMR (62.8 MHz):
= 22.2, 105.7 (td, J = 18 and 4), 128.3,
C
128.5, 129.9, 130.1, 130.8, 133.9, 135.3, 136.3, 137.3 (dm,
J = 256), 141.9, 142.1 (dm, J = 258), 144.8 (dm, J = 255), 145.4.
EIMS m/z: 493, 457, 336, 301, 267, 248, 139.
2-Pentafluorophenyl-1-phenylethenyl tolyl sulfone (1g)
Colorless crystals; mp 158 °C.
IR (KBr): 1523, 1498, 1317, 1151 cm–1.
1H NMR (270 MHz): H = 2.38 (3 H, s), 7.03 (2 H, m), 7.18 (4 H,
m), 7.28 (1 H, m), 7.51 (2 H, m), and 7.74 (1 H, m),
19F NMR (254 MHz): F = –137.1 (2 F, m), –152.3 (1 F, m), –161.7
(2 F, m).
References
(1) The Porphyrin Handbook; Kadash, M. K.; Smith, K. M.;
Guilard, R., Eds.; Academic Press: San Diego, 1999.
(2) (a) Donohoe, T. J.; Harji, R. R.; Cousins, R. P. C. Chem.
Commun. 1999, 141. (b) Dikstra, H. P.; ten Have, R.; van
Leusen, A. N. J. Org. Chem. 1998, 63, 5332. (c) ten Have,
R.; Leusink, F. R.; van Leusen, A. N. Synthesis 1996, 871.
(d) Magnus, P.; Gallagher, T.; Schultz, J.; Or, Y.-S.;
Ananthanarayan, T. P. J. Am. Chem. Soc. 1987, 109, 2706.
(3) (a) Ono, N.; Muratani, E.; Ogawa, T. J. Heterocycl. Chem.
1991, 28, 2053. (b) Also see: van Leusen, D.; Flentge, E.;
van Leusen, A. M. Tetrahedron. 1991, 47, 4639.
(4) van Leusen, D.; van Echten, E.; van Leusen, A. M. J. Org.
Chem. 1992, 57, 2245.
(5) Murashima, T.; Shiga, D.; Nishi, K.; Uno, H.; Ono, N. J.
Chem. Soc., Perkin Trans. 1 2000, 2671.
(6) Barton, D. H. R.; Zard, S. Z. J. Chem. Soc., Chem. Commun.
1985, 1098.
(7) (a) Merz, A.; Schropp, R.; Lex, J. Angew. Chem. Int. Ed.
Engl. 1993, 32, 291. (b) Also see: Merz, A.; Meyer, T.
Synthesis 1999, 94.
(8) Liu, J.-H.; Chan, H.-W.; Wong, H. N. C. J. Org. Chem.
2000, 65, 3274.
(9) Sugiura, K.; Ushiroda, K.; Johnson, M. T.; Miller, J. S.;
Sakata, Y. J. Mater. Chem. 2000, 10, 2507.
(10) Uno, H.; Tanaka, M.; Inoue, T.; Ono, N. Synthesis 1999,
471.
(11) (a) Arnord, D. P.; Burgess-Dean, L.; Hubbard, J.; Rahman,
M. A. Aust. J. Chem. 1994, 47, 969. (b) Uno, H.; Sakamoto,
K.; Tominaga, T.; Ono, N. Bull. Chem. Soc. Jpn. 1994, 67,
1441.
(12) (a) Anderson, H. J.; Loader, C. E. Synthesis 1985, 353.
(b) Demopoulos, B. J.; Anderson, H. J.; Loader, C. E.; Faber,
K. Can. J. Chem. 1983, 61, 2415.
13C NMR (62.8 MHz): C = 21.6, 108.9 (td, J = 18 and 4), 122.6 (d,
J = 2), 128.3, 128.7, 129.6, 129.7, 130.2, 134.8, 137.5 (dm,
J = 255), 141.5 (dm, J = 256), 143.9 (dm, J = 252), 144.8, 151.1,
one carbon signal is hidden.
EIMS m/z: 424, 269, 256, 219, 139.
Reaction of 1 with Ethyl Isocyanoacetate; General Procedure
To a solution of sulfone (1, 1 mmol) and ethyl isocyanoacetate (0.12
mL, 1.1 mmol) in anhyd THF (5 mL) was added a 1.0 M solution of
t-BuOK (1 mL, 1 mmol) at 0 °C. After the mixture was stirred over-
night at r.t., an aq HCl solution (1 M, 5 mL) was added and the mix-
ture was extracted with EtOAc (4 10 mL). The organic phase was
washed with saturated aq NaHCO3 (2 10 mL), H2O (3 10 mL)
and brine (10 mL), dried over Na2SO4 and concentrated. The resi-
due was chromatographed on silica gel (10% EtOAc–hexane). Se-
lected spectoscopic data of 2 are tabulated in Table 2.
Preparation of Pyrrolecarbaldehyde 4; General Procedure
To a stirred solution of ethyl pyrrole-2-carboxylate (4, 1 mmol) in
anhyd THF (5 mL) was added LiAlH4 (38 mg, 1 mmol) at 0 °C. Af-
ter 1 h at 0 °C, H2O (1 mL) was added and the mixture was filtered
through a Celite pad, which was washed with EtOAc (30 mL). The
organic phase was washed with H2O (2 10 mL) and brine (10
mL), dried over Na2SO4 and concentrated. The residue was dis-
solved in anhyd CH2Cl2 (30 mL) and MnO2 (435 mg, 5 mmol) was
added. The mixture was stirred in the dark for 12 h and then filtered
through a Celite pad, which was washed with CH2Cl2 (10 mL). The
combined organic solution was concentrated and the residue was
chromatographed on silica gel (CHCl3). Selected spectoscopic data
of 4 are tabulated in Table 2.
(13) Uno, H.; Inoue, T.; Fumoto, Y.; Shiro, M.; Ono, N. J. Am.
Chem. Soc. 2000, 122, 6773.
Synthesis 2001, No. 15, 2255–2258 ISSN 0039-7881 © Thieme Stuttgart · New York