Preparation of pyrrole-2-carboxylates with electron-withdrawing groups at the 4-position

Article abstract of DOI:10.1055/s-1999-3406

Reaction of α-trifluoromethyl, α-cyano, and α-ethoxycarbonyl alkenyl sulfones with ethyl isocyanoacetate in the presence of a base gave 4- substituted pyrrole-2-carboxylates in moderate to good yields.

Full text of DOI:10.1055/s-1999-3406

PAPER
471
Preparation of Pyrrole-2-carboxylates with Electron-Withdrawing Groups at
the 4-Position
Hidemitsu Uno,a* Masanori Tanaka,a Takashi Inoue,a Noboru Onob
a Advanced Instrumentation Center for Chemical Analysis, Ehime University, Bunkyo-cho 2Ð5, Matsuyama 790Ð8577, Japan
b Department of Chemistry, Faculty of Science, Ehime University, Bunkyo-cho 2Ð5, Matsuyama 790Ð8577, Japan
Fax +81(89)9279670; E-mail: uno@dpc.ehime-u.ac.jp
Received 17 July 1998; revised 24 August 1998
initially reported by Barton and Zard.2 In this pyrrole syn-
Abstract: Reaction of a-trifluoromethyl, a-cyano, and a-ethoxy-
thesis, nitroalkenes are commonly employed because the
carbonyl alkenyl sulfones with ethyl isocyanoacetate in the
nitro group can act both as a powerful stabilizer of the in-
presence of a base gave 4-substituted pyrrole-2-carboxylates in
termediate anion and as a good nucleofuge in the aroma-
tization forming a pyrrole ring. Vinyl sulfones can be
employed instead of the nitro compounds,3 although the
sulfonyl group is less effective as the anion stabilizer.
From a synthetic viewpoint, however, the sulfonyl com-
pounds are more desirable as they are more accessible
than the corresponding nitro compounds. When another
electron-withdrawing group is substituted, the sulfonyl
group would be sufficient to stabilize the anion. This is
found to be the case for a-trifluoromethyl, a-cyano, and
a-ethoxycarbonyl alkenyl sulfones. In this paper, we
would like to report a new and facile method for 4-tri-
fluoromethyl-, 4-ethoxycarbonyl-, and 4-cyano-substitut-
ed pyrroles 2 from the sulfones 1 (Eq 1).
moderate to good yields.
Key words: pyrrole-2-carboxylate, trifluoromethyl, BartonÐZard
reaction, alkenyl sulfones
Pyrroles having various redox potentials are increasingly
required in the synthesis of porphyrins and polypyrroles in
order to regulate their optical and electric properties. For
these purposes, synthetic methods for various b-substitut-
ed pyrroles have been investigated. We are continuously
interested in developing new and efficient synthetic meth-
ods of such pyrroles and have demonstrated the successful
preparations1 based on the condensation of electron-de-
ficient alkenes with isocyanomethylide anions, which was
Although a-toluenesulfonyl-substituted acryl derivatives
(1aÐ1f) were easily prepared by the Knoevenagel reac-
tion,4 preparation of vinyl sulfones with a perfluoroalkyl
group is rare probably due to the failure of condensation
of trifluoroethyl sulfones with aldehydes.5 A potent route
to a-trifluoromethyl a,b-unsaturated sulfones is oxidation
of the corresponding sulfides. One reported method6 for
such a sulfide is based on the Vilsmeier reaction of a tri-
fluoromethyl ketone (Scheme 1) and we started to prepare
1ga from trifluoroacetic acid. Thus, 1,1,1-trifluoro-3-phen-
ylacetone (3)7, prepared from trifluoroacetic acid and the
benzyl Grignard reagent in 77%, was treated with DMF
and phosphoryl chloride to give 3-chloro-4,4,4-trifluoro-
2-phenylbut-2-enal (4) as a mixture of stereoisomers.
Substitution of the chloride with phenylthiolate followed
by decarbonylation with in situ-generated KOH gave a-
trifluoromethyl vinyl sulfide (5), which was then success-
fully oxidized to give the sulfone 1ga (E/Z = 4:1) by an ex-
cess amount of m-chloroperbenzoic acid (mCPBA).
Although the overall yield is quite good, there is no com-
mon intermediate for the preparation of variously b-sub-
Scheme 1
Synthesis 1999, No. 3, 471–474 ISSN 0039-7881 © Thieme Stuttgart á New York

472
H. Uno et al.
PAPER
stituted sulfones in this route and we must start from the Condensation reaction of sulfones 1 with 2 equivalents of
first step of the Grignard reaction every time.
ethyl isocyanoacetate was carried out in THF at room
temperature for 3 h (Table 2). t-Butyliminotris(pyrrolidi-
no)phosphrane (BTPP)10 and 1,8-diazabicyclo[5.4.0]un-
dec-7-ene (DBU) can be employed with the similar
efficiency, though BTPP gave somewhat better yields
(runs 7Ð12). Although potasium t-butoxide was reported
to be the efficient base in the reaction of cyclohexenyl sul-
fone,3a no aimed pyrrole was obtained in the reaction of
1gb (run 13). In the cases of 1o and 1p, regioisomeric
mixtures were obtained (2o:7o = 5:6; 2p:7p = 1:2). Even
the corresponding sulfide 6o reacted with the isocyanoac-
etate to give 2o. Regiochemical determination was unam-
Recently, BŽguŽ et al. reported the preparation of a-triflu-
oromethyl vinyl sulfides based on the Wittig reaction with
S-alkyl trifluorothioacetate.8 This method is quite attrac-
tive for our purpose. Thus, a variety of sulfides were pre-
pared by this method and oxidized with mCPBA to the
corresponding sulfones (1gbÐ1o; Scheme 2 and Table 1).
Similarly, a-pentafluoroethyl sulfones 1qÐ1s were pre-
pared from S-hexyl pentafluorothiopropionate. As no 1p
could be obtained by using mCPBA probably due to the
decomposition of labile 1p during the reaction and purifi-
cation, dimethyldioxirane9 was used instead of mCPBA
and 1p was used immediately after short silica gel column
chromatography.
1
biguously done by H NMR analysis based on the long-
range coupling between the trifluoromethyl group and the
pyrrole a-proton in 2o, since the similar coupling was ob-
served in other 2 compounds. The reactions of pentafluo-
roethyl sulfones 1qÐ1s gave trifluoromethylated pyrrole 8
in low yields accompanied with a comparable amount of
diethyl 3-arylpyrrole-2,4-dicarboxylates (2aÐ2c) and pen-
tafluoroethyl derivatives could not be detected even in the
reaction mixture by 19F NMR analysis (runs 24Ð26).
Scheme 2
Table 1 Preparation of Sulfides 6 and Sulfones 1
Condi- Sulfide
Condi-
tionsa
Sulfone
A probable route to 8 and 2aÐ2c is illustrated in Scheme
3. The Michael addition of the isocyanoacetate anion to
the vinyl sulfones would give the sulfone-stabilized anion
9. In the cases of trifluoromethyl vinyl sulfones, the simi-
lar anions to 9 underwent the ring closure between the an-
ionic carbon and isocyano carbon, while the anion 9
would be then equilibrated with enolate 10 probably due
to interference toward the nucleophilic ring closure by the
tionsa
6
Yield/% E/Zb
1c
Yield/%
A
A
A
A
A
C
A
A
D
D
F
6gb
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
6s
62
79
89
43
66
16
30
73
63
83
44
49
51
<5/>95
14/86
17/83
<5/>95
10/90
<5/>95
<5/>95
<5/>95
<5/>95
11/89
<5/>95
<5/>95
13/87
B
B
B
B
B
B
B
B
B
E
B
B
B
1gb
1h
1i
76
60
95
57
35
44
87
93
83
89
77
83
87
1j
1kd
1l
1m
1n
1o
1p
1q
1r
F
F
1s
a
A: Phosphonium salt (1.1 equiv), CF3COS-n-C6H13, NaH,
HMDSA (cat), THF, r.t., overnight; B: mCPBA (3 equiv), CHCl3,
r.t., overnight; C: Phosphonium salt (1.1 equiv), CF3COS-n-
C6H13, NaH, HMDSA (cat), THF, reflux, 72 h; D: Phosphorane
(2 equiv), CF3COS-n-C6H13, CH2Cl2, r.t. overnight; E: Dimethyl-
dioxirane (3 equiv), acetone, r.t., overnight; F: Phosphonium salt
(1.1 equiv), CF3CF2COS-n-C6H13, NaH, HMDSA (cat), THF, r.t.,
overnight.
b
c
d
1
Stereosiomeric ratio was estimated by H NMR spectra of the
chromatographed or recrystallized material.
The corresponding (Z)-sulfides were employed as the starting ma-
terials and only the Z isomers of sulfones were obtained.
A stereoisomeric mixture of 6k (E/Z = 1/2) was used for the oxi-
dation.
Scheme 3
Synthesis 1999, No. 3, 471–474 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Preparation of Pyrrole-2-carboxylates with Electron-Withdrawing Groups at the 4-Position
473
Table 2 Preparation of Pyrroles 2
very bulky pentafluoroethyl group. The enolate 10 would
decompose to 2,2,3,3,3-pentafluoropropyl anion 11 and
a-isocyano a,b-unsaturated ester 12. The former would
lose a b-fluoride to provide 2,3,3,3-tetrafluoropropenyl
sulfone 13. The a,b-unsaturated ester 12 and sulfone 13
would then react with ethyl isocyanoacetate to afford the
observed products 8 and 2aÐ2c.
Run Sulf- Basea Prod- Yield Run Sulf- Basea Prod- Yield
one
ucts
%
one
ucts
%
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1ga
1ga
1gb
A
A
A
A
A
A
A
B
C
D
A
E
2a
2b
2c
2d
2e
2f
2g
2g
2g
2g
2g
2g
2g
2h
2i
81
87
98
94
95
88
20
70
42
56
57
79
0
17
18
19
20
21
1k
1l
1m
1n
1o
A
A
A
A
A
2k
2l
61
60
51
49
34
40
15
19
11
21
23
26
30
18
27
2m
2n
2o
7o
2o
2p
7p
8
2a
8
2b
8
Melting points are uncorrected. NMR spectra were obtained with a
JEOL GSX-270 or JMN-400 spectrometer at ambient temperature
by using CDCl3 as a solvent and TMS and CFCl3 as internal stan-
dards for 1H, 13C, and 19F. Mass spectra and HRMS were measured
with a Hitachi M80B-LCAPI spectrometer under the following ion-
izing conditions: EI (electron impact, 20 eV; 70 eV for HRMS; high
boiling perfluorokerosine as a standard) and CI (chemical ioniza-
tion, 70 eV, isobutane as CI gas). Column chromatography and
TLC analysis were carried out using C-200 (Wakogel) and Kiesel-
gel 60 F254 (Merk), respectively. Et2O and THF were freshly dis-
tilled from sodium benzophenone ketyl. CH2Cl2 was distilled from
CaH2 under an inert atmosphere. Other commercially available ma-
terials were used without further purification. General procedures
used in this paper are as follows. Satisfactory microanalyses (C,
±0.4; H, ±0.2; N, ±0.13) or HRMS were found for all compounds.
22
23
6o
1p
A
A
10 1bg
11 1gb
12 1gb
13 1gb
14 1h
15 1i
24
25
26
1q
1r
1s
A
A
A
F
A
A
A
40
47
40
2c
16 1j
2j
a
A: 4 equivs of DBU; B: 4 equivs of BTPP; C: 1.3 equivs of DBU;
D. 2.7 equivs of DBU; E 1.3 equivs of BTPP; F: 1.3 equivs of t-
BuOK.
Table 3 Selected Spectroscopic Data for Sulfones
Com-
pound
Mp
(¡C)
NMR/d in ppm
IR/cmÐ1
SO2
EI-MS
m/z
Vinylica
Rfb
C2a
C3a
Others
(E)-1a
(E)-1b 107
77Ð78
7.94
7.90
Ð
Ð
Ð
Ð
Ð
Ð
131.5
129.7
130.1
131.9
114.9
113.4
131.2 (33)
134.6 (34)
131.5 (30)
130.1 (30)
131.8 (30)
127.8 (30)
134.4 (31)
Ð
135.4 (31)
138.4 (32)
122.4 (31)
136.3 (33)
147.5 (34)
143.0
143.2
141.8
143.2
151.0
151.0
1316, 1150
1316, 1148
1314, 1148
1318, 1150
1328, 1160
1328, 1156
1328, 1153
Ð
1334, 1148
1332, 1158
1336, 1160
1332, 1158
1336, 1148
Ð
1342, 1155
1344, 1160
1334, 1154
1342, 1156
1336, 1149
1334, 1152
1334, 1152
1336, 1152
1722, 1622
1724, 1606
1722
1720, 1598
2216, 1594
2212, 1588
1267, 1172
Ð
(331, 285, 266)c
344, 280, 189
364, 209, 181
360, 203, 132
(284, 155, 128)c
297, 155, 142
312, 156, 125
Ð
(E)-1c
(E)-1d
(E)-1e
(E)-1f
(Z)-1ga
(E)-1ga
1gb
1h
1i
1j
138Ð140 7.89
88
123
7.89
8.21
153Ð155 8.17
40Ð70d 7.84 (1.6) Ð61.16 (1.6)
148.7 (3)
146.2 (6)
145.7 (6)
135.6 (6)
144.7 (6)
145.0 (6)
144.4 (5)
Ð
142.4 (5)
131.9 (m)
137.9 (6)
137.7 (5)
115.9 (69)
149.4 (9)
149.3 (8)
148.5 (9)
40Ð70d 8.43
Ð55.48
Ð61.23 (0.9)
Ð60.93
oil
7.92
7.84
7.84
7.76
8.08
8.25
7.75
7.55
1266, 1148
1268, 1192
1262, 1160
320, 171, 151
334, 184, 139
354, 205, 133
oil
oil
oil
Ð61.21
Ð60.45 (1.6)
Ð61.62 (1.6)
Ð55.46
Ð61.66
Ð61.45
1598, 1264, 1184 350, 202, 200
(Z)-1k
(E)-1k
1l
77e
1524, 1348, 1182 (366, 336, 316)c
Ð
Ð
Ð
oil
oil
oil
oil
oil
oil
oil
oil
1646, 1270, 1172 (389, 353, 269)c
1664, 1270, 1132 (411, 327, 192)c
1606, 1270, 1140 (327, 307, 178)c
1744, 1272, 1180 (317, 271, 215)c
2231, 1270, 1186 (270, 186)c
1m
1n
7.86 (1.5) Ð60.24
7.18 Ð63.06
6.84 (1.5) Ð63.10 (1.5)
7.39
7.68
7.81
1of
1pf
1qf
Ð82.90, Ð107.92 131.2 (22)
Ð82.90, Ð107.58 129.8 (23)
Ð82.99, Ð108.24 131.6 (22)
1212, 1192, 1060 370, 221, 105
1216, 1186, 1060 384, 234, 151
1216, 1194, 1062 404, 255, 133
1rf
1sf
a Numerals in the parentheses are the coupling constants (Hz) with CF3 fluorine atoms.
b Numerals in the parentheses are the coupling constants (Hz) with H5.
c Spectra were measured under CI conditions.
d E/Z (4/1) mixture.
e E/Z (1/2) mixture.
f The position numbering is not done by the IUPAC nomenclature rule but based on Eq 1.
Synthesis 1999, No. 3, 471–474 ISSN 0039-7881 © Thieme Stuttgart · New York

474
H. Uno et al.
PAPER
Table 4 Selected Spectroscopic Data for Pyrroles
Com- Mp
pound (¡C)
NMR/d in ppm
a-Ha Rfb
IR/cmÐ1
NH
EI-MS
m/z
C2a
C3a
C4a
C5a
C=O and Others
1688
2a
2b
2c
2d
2e
2f
2g
2h
2i
113Ð115
94
7.57
7.56
7.59
7.57
7.33
7.31
Ð
Ð
Ð
Ð
Ð
Ð
120.8
120.9
120.7
120.7
119.7
119.5
132.4
132.6
131.0
132.2
133.7
133.9
116.7
116.8
116.7
116.6
96.4
127.3
127.1
127.1
127.2
128.4
128.4
3288
287, 242, 196
301, 255, 205
321, 275, 230
317, 271, 226
321, 275, 230
254, 208, 139
3280, 3140 1704, 1674
3260, 3132 1706, 1674
3292
3268
3272
3296
3320, 3292 1680, 1298, 1110 297, 251, 154
3384
3300
117Ð120
105
153Ð154
159Ð161
107
1692
2228, 1692
2224, 1724
96.4
7.28 Ð56.05 121.2
7.27 Ð55.93 121.0
7.27 Ð56.00 121.2
7.25 Ð56.03 121.1
7.34 Ð56.00 121.4
7.23 Ð58.66 121.6
7.40 Ð58.52 123.0
7.28 Ð56.73 122.4
7.23 Ð57.75 122.8
7.31 Ð59.04 129.4
129.2 (3) 116.4 (36) 121.4 (6)
129.4 (3) 116.2 (36) 121.6 (5)
127.7 (3) 116.3 (35) 121.7 (5)
129.0 (3) 116.3 (35) 121.5 (5)
126.4 (3) 116.4 (36) 121.8 (5)
123.0 (3) 115.9 (37) 122.2 (5)
111.1 (br) 117.3 (37) 122.5 (5)
121.0 (3) 117.3 (35) 121.6 (6)
119.3 (3) 115.5 (38) 121.5 (5)
1686, 1298, 1114 283, 237, 140
130
128
1702, 1280, 1136 317, 271, 208
1702, 1290, 1118 313, 267, 170
2j
2k
2l
2m
2n
2o
2p
3o
3p
8
118Ð120
167
128Ð129
158Ð159
116
91Ð93
185Ð186
124Ð126
112Ð115
oil
3356, 3140 1702, 1520, 1348 328, 282, 237
3270
3280
3260
1691, 1300, 1117 (352, 316, 288)c
1700, 1298, 1120 373, 327, 230
1680, 1294, 1116 289, 243, 146
3368, 3172 1742, 1714, 1308 279, 234, 188
95.7 (2) 119.7 (39) 122.6 (br) 3236, 3134 2244, 1720, 1314 232, 204, 186
7.49 Ð54.56 123.3 (4) 116.5 (40) 117.5 (2) 126.5
7.45 Ð56.55 122.2 (5) 119.4 (39) 95.3 (3) 128.5
7.59 Ð53.19 125.0 (4) 115.2 (40) 124.0
3367, 3172 1741, 1712, 1308 (280, 260,212)c
3162, 3102 1712, 1631, 1306 (233, 187, 152)c
128.1
3380
1743, 1324, 1139 (356, 336)c
a Numerals in the parentheses are the coupling constants (Hz) with CF3 fluorine atoms.
b Numerals in the parentheses are the coupling constants (Hz) with H5.
c Spectra were measured under CI conditions.
Sulfide 6
EtOAc (3 × 30 mL). The organic phase was washed with H2O (3 ×
30 mL) and brine (30 mL), dried (Na2SO4) and concentrated. The
residue was chromatographed on silica gel (EtOAc/hexane). Select-
ed spectroscopic data are tabulated in Table 4.
To a suspension of phosphonium salt (20 mmol) and NaH (60% oil
dispersion, 20 mmol) in anhyd THF (100 mL) was added with stir-
ring
a catalytic amount (0.1 mL) of hexamethyldisilazane
(HMDSA) followed by S-ethyl perfluorothioacetate (20 mmol) at
r.t. After the mixture was stirred overnight, hexane (200 mL) was
added and the mixture was filtered through a short pad of silica gel,
which is washed with hexane (200 mL). The combined filtrate was
again filtered through a short pad of silica gel and then the solvent
was evaporated. The residual oil was purified by silica gel column
chromatography (EtOAc/hexane). In all cases except for 6k, the Z-
isomers of 6 were eluted first and obtained as oil in a pure form. The
last few fractions of 6 were gradually contaminated with the E-iso-
mers of 6. The yields combining all fractions of 6 and the isomeric
ratios calculated by the NMR are listed in Table 1. In the next step,
the pure Z-isomers of 6 were used in order to simplify the spectro-
scopic determination, although the oxidation of stereoisomeric mix-
tures of 6 could be carried out with similar efficiency. In the case of
6k, the stereoisomers did not separate even on TLC.
References
(1) Ito, S.; Murashima, T.; Ono, N. J. Chem. Soc., Perkin Trans.
1 1997, 3161, and the corresponding examples cited therein.
(2) Barton, D. H. R.; Zard, S. Z. J. Chem. Soc., Chem. Commun.
1985, 1098.
(3) (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.
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(4) Happer, D. A. R.; Steenson, B. E. Synthesis 1980, 806.
(5) The 2,2,2-trifluoro-1-phenylsulfonylethyl carbanion genera-
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however, failed to react with aldehydes probably due to the re-
versible nature of such aldol-type reaction especially in the
presence of an onium counter cation.
Oxidation of Sulfide with mCPBA
To a stirred solution of sulfide 5 or 6 (5 mmol) in CHCl3 (25 mL) was
added mCPBA (15 mmol) over 5 min at r.t. and the mixture was stirred
overnight. To the resulting suspension was added aq Na2S2O3 (1 M,
20 mL) and the solvent was removed in vacuo at r.t. The white pow-
dery m-chlorobenzoic acid was triturated with toluene/hexane (1:4,
30 mL), filtered, and washed with toluene/hexane (1:4, 2 × 10 mL).
The combined organic phase was washed with sat. NaHCO3 (5 ×
20 mL) and brine (20 mL), dried (MgSO4), and concentrated. The res-
idue was purified by chromatography on silica gel (EtOAc/hexane) or
recrystallization. Selected spectoscopic data are tabulated in Table 3.
(6) Alvernhe, G.; Langlois, B.; Laurent, A.; Le Drean, I.; Selmi,
A. Tetrahedron Lett. 1991, 32, 643.
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Reaction of 1 with Ethyl Isocyanoacetate
To a solution of sulfone (1, 3 mmol) and ethyl isocyanoacetate
(0.66 mL, 6 mmol) in anhyd THF (6 mL) was added DBU
(1.79 mL, 12 mmol) at r.t. After the mixture was stirred for 3 h, aq
HCl (1 M, 15 mL) was added and the mixture was extracted with
Schwesinger, R.; Hasenfratz, C.; Schlemper, H.; Walz, L.; Pe-
ters, E. -M.; Schnering, H. G. Angew. Chem., Int. Ed. Engl.
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Synthesis 1999, No. 3, 471–474 ISSN 0039-7881 © Thieme Stuttgart · New York