One-step synthesis of dialkyl 2-[(4-methylphenyl)sulfonyl]-1H-pyrrole-3,4- dicarboxylates by reaction of acetylenedicarboxylates with 'tosylmethyl isocyanide' (TsMIC) and triphenylphosphine

Article abstract of DOI:10.1002/hlca.200690095

The reactive 1:1 adducts in the reaction between Ph₃P and dialkyl acetylenedicarboxylates have been trapped with 'tosylmethyl isocyanide' (TsMIC; 1) to yield dialkyl 2-[(4-methylphenyl)sulfonyl]-1H-pyrrole-3,4- dicarboxylates 3 (Scheme 1). The

Full text of DOI:10.1002/hlca.200690095

Helvetica Chimica Acta – Vol. 89 (2006)
923
One-Step Synthesis of Dialkyl 2-[(4-Methylphenyl)sulfonyl]-1H-pyrrole-3,4-
dicarboxylates by Reaction of Acetylenedicarboxylates with ꢀTosylmethyl
Isocyanideꢁ (TsMIC) and Triphenylphosphine
by Abdolali Alizadeh*, Hassan Masrouri, Sadegh Rostamnia, and Farnaz Movahedi
Department of Chemistry, Tarbiat Modarres University, P.O. Box 14155-175, Tehran, Iran
(
phone: +92-21-88006631; fax: +98-21-88006544; e-mail: abdol_alizad@yahoo.com and
aalizadeh@modares.ac.ir)
The reactive 1:1 adducts in the reaction between Ph P and dialkyl acetylenedicarboxylates have
A
H
R
U
G
3
been trapped with ꢀtosylmethyl isocyanideꢁ (TsMIC; 1) to yield dialkyl 2-[(4-methylphenyl)sulfonyl]-
H-pyrrole-3,4-dicarboxylates 3 (Scheme 1). The structures of the highly functionalized compounds 3
1
1
13
were corroborated spectroscopically (IR, H-and C-NMR, and EI-MS) and by elemental analyses. A
plausible mechanism for this type of cyclization is proposed (Scheme 2).
1
. Introduction. – Isonitrile cyclization provides a useful alternative of the Knorr-
type cyclization for pyrrole synthesis. In 1972, van Leusen and co-workers reported a
pyrrole synthesis based on the reaction between ꢀtosylmethyl isocyanideꢁ (TsMIC;
1
1
) ) with electron-deficient alkenes [1]. Barton and Zard found that the base-catalyzed
reaction of nitroalkenes or b-nitroacetates with alkyl isocyanoacetate or TsMIC affords
pyrrole-2-carboxylates or 2-sulfonylpyrroles, respectively [2][3]. TsMIC (1) and its sub-
stituted derivatives are being extensively used in the synthesis of 3,4-di
,3,4-trisubstituted pyrroles, respectively. With these results in mind, we decided to pre-
pare 2,3,4-trisubstituted pyrroles from the reaction of 1 and dialkyl acetylenedicarbox-
ylates in the presence of Ph P.
A
H
R
U
G
2
AHCTREUNG
3
2
. Results and Discussion. – When TsMIC (1) and dialkyl acetylenedicarboxylates 2
were mixed in the presence of Ph3P in anhydrous CH Cl at ambient temperature, a
AHCTREUNG
2
2
smooth 1:1 addition took place to produce the highly functionalized dialkyl 2-[(4-
methylphenyl)sulfonyl]-1H-pyrrole-3,4-dicarboxylates 3 in 50–90% yield (Scheme 1).
1
13
The H-and C-NMR spectra of the crude reaction mixtures clearly indicated the for-
1
13
mation of the products. The structures of 3a–d were deduced by IR, H-and C-NMR,
+
MS, and elemental analysis. The mass spectra displayed the M signals, and fragmen-
tation always involved the loss of ester moieties.
1
The H-NMR spectrum of 3a exhibited three resonances at d(H) 2.36 (s, Me), 3.77
3
(
s, MeO), and 3.93 (s, MeO). The pyrrole H-atom resonated at d(H) 7.44 ( J=3.2 Hz,
HÀC(5)), the pyrrole NH was observed at d(H) 10.69 (br. s), and the aryl residues gave
1)
Systematic name: 1-[(isocyanomethyl)sulfonyl]-4-methylbenzene.
ꢂ 2006 Verlag Helvetica Chimica Acta AG, Zürich

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24
Helvetica Chimica Acta – Vol. 89 (2006)
Scheme 1
1
rise to characteristic signals in the aromatic region of the spectrum. The H-decoupled
1
3
C-NMR spectrum of 3a showed 13 distinct resonances, in agreement with the pyrrole
1
13
structure. The H-and C-NMR spectra of 3b–d were similar to those of 3a, except for
the ester resonances, which exhibited characteristic signals with appropriate chemical
shifts (see Exper. Part).
The mechanism of the reaction between TsMIC (1) and acetylene-1,2-dicarboxy-
lates in the presence of Ph P has not yet been fully established experimentally. A pos-
A
T
E
N
3
sible pathway is shown in Scheme 2.
On the basis of the well-established chemistry of trivalent-phosphorus nucleophiles
[
4–11], it is reasonable to assume that the pyrroles 3 in the above reaction result from
Scheme 2

Helvetica Chimica Acta – Vol. 89 (2006)
925
nucleophilic addition of Ph P to the acetylenic esters 2, followed by protonation of the
A
H
R
U
G
3
1
:1 adduct by TsMIC (1). Then, the positively charged ion 4 and the TsMIC anion 5
undergo a 1,3-dipolar cycloaddition to produce the betain 6. Alternatively, the posi-
tively charged ion 4 is attacked in a nucleophilic reaction by 5 to produce the ylide 7,
which, under the reaction conditions employed, may cyclize to the betain 6. Finally,
loss of Ph
A
T
E
N
P under formation of 8 and a [1,5]-H shift give rise to the observed pyrroles
3
3
.
In summary, we have established a simple one-pot procedure for the preparation of
trisubstituted pyrroles carrying a sulfonyl group in 2-position. The reaction can be per-
formed under neutral conditions, and the reagents can be mixed without any pre-acti-
vation or modification, in contrast to multistep approaches.
Experimental Part
General. Dimethyl-, diethyl- and di(tert-butyl) acetylene-1,2-dicarboxylate, and tert-butyl isocyanide
were obtained from Merck (Germany) and Fluka (Switzerland), and were used without further purifica-
tion. Diisopropyl acetylenedicarboxylate was prepared according to lit. procedures [12][13]. Column
chromatography (CC): Merck silica gel (230–240 mesh). Melting points (m.p.): Electrothermal 9100
À1
1
13
31
apparatus; uncorrected. IR Spectra: Shimadzu IR-460 spectrometer; in cm . H-, C-, and P-NMR
Spectra: Bruker DRX 500-AVANCE instrument, at 500.1, 125.7, and 202.4, MHz, resp., in CDCl3
soln.; d in ppm, J in Hz. EI-MS (70 eV): Finnigan MAT-8430 mass spectrometer; in m/z (rel. %).
Elemental analyses: Heraeus CHN-O-Rapid analyzer.
General Procedure for the Preparation of Compounds 2 (exemplified for 2a). To a magnetically stir-
red soln. of Ph3
A
H
R
U
G
wise a soln. of 2a (0.14 g, 1 mmol) in anh. CH Cl (3 ml) at r.t. over 10 min. The mixture was stirred for 48
2
2
h, the solvent was removed under reduced pressure, and the residue was separated by CC (SiO ; hexane/
2
AcOEt).
Dimethyl 2-[(4-Methylphenyl)sulfonyl]-1H-pyrrole-3,4-dicarboxylate (3a). Yield: 300 mg (90%).
Colorless crystals. M.p. 107–1088. IR (KBr): 3255 (NH); 1710 (COO); 1284, 1128 (SO ); 1210, 1166
2
1
(
ester CÀO). H-NMR (500 MHz, CDCl ): 2.36 (s, 3 H); 3.77 (s, 3 H); 3.93 (s, 3 H); 7.25 (d, J=8.0, 2
3
13
H); 7.44 (d, J=3.2, 1 H); 7.82 (d, J=8.0, 2 H); 10.96 (s, 1 H). C-NMR (125 MHz, CDCl ): 15.21;
3
5
1.84; 52.92; 116.43; 121.77; 127.19; 127.69; 128.63; 129.91; 137.68; 144.95; 162.89; 164.43. EI-MS: 337
+
(
9, M ), 306 (41), 274 (33), 242 (100), 183 (69), 139 (16), 107 (12), 91 (61), 65 (47), 39 (16). Anal. calc.
for C H NO S (337.34): C 53.41, H 4.48, N 4.15; found: C 53.3, H 4.5, N 4.2.
15
15
6
Diethyl 2-[(4-Methylphenyl)sulfonyl]-1H-pyrrole-3,4-dicarboxylate (3b). Yield: 180 mg (50%). Col-
orless crystals. M.p. 157–1598. IR (KBr): 3330 (NH); 1735, 1703 (COO); 1323, 1140 (SO ); 1269, 1186
2
1
(
ester CÀO). H-NMR (500 MHz, CDCl
3
): 1.26 (t, J=7.1, 3 H); 1.37 (t, J=7.1, 3 H); 2.41 (s, 3 H);
.23 (q, J=7.1, 2 H); 4.41 (q, J=7.1, 2 H); 7.44 (d, J=8.0, 2 H); 7.65 (d, J=3.2, 1 H); 7.94 (d, J=8.3,
H); 11.98 (br., 1 H). C-NMR (125.7 MHz, CDCl ): 14.02; 14.15; 21.12; 60.56; 61.77; 116.58; 123.19;
27.81; 128.09; 128.82; 130.35; 139.22; 145.30; 162.36; 164.00. EI-MS: 366 (3, [M+1] ), 334 (3), 298
4
2
1
13
3
+
(
(
17), 242 (37), 224 (20), 186 (23), 167 (77), 123 (13), 97 (30), 57 (100). Anal. calc. for C H NO S
17 19 6
365.39): C 55.88, H 5.24, N 3.83; found: C 55.9, H 5.2, N 3.9.
Diisopropyl 2-[(4-Methylphenyl)sulfonyl]-1H-pyrrole-3,4-dicarboxylate (3c). Yield: 330 mg (85%).
Colorless crystals. M.p. 132–1348. IR (KBr): 3255 (NH); 1711 (COO); 1280, 1146 (SO ); 1209, 1179
2
1
(
5
ester CÀO). H-NMR (500 MHz, CDCl ): 1.26 (d, J=6.2, 6 H); 1.41 (d, J=6.2, 6 H); 2.35 (s, 3 H);
3
.12 (quint., J=6.2, 1 H); 5.30 (quint., J=6.2, 1 H); 7.24 (d, J=8.0, 2 H); 7.42 (d, J=3.2, 1 H); 7.86 (d,
13
J=7.5, 2 H); 10.78 (s, 1 H). C-NMR (125 MHz, CDCl ): 21.57; 21.73; 21.85; 68.27; 70.10; 116.90;
22.80; 127.20; 127.58; 127.63; 129.89; 137.98; 145.75; 161.99; 163.75. EI-MS: 394 (7, [M+1] ), 352
3
+
1
(
(
5), 335 (4), 310 (4), 292 (100), 244 (18), 226 (86), 201 (43), 183 (37), 155 (20), 139 (49), 108 (29), 91
86), 43 (61). Anal. calc. for C H NO S (393.45): C 58.00, H 5.89, N 3.56; found: C 58.0, H 5.9, N 3.5.
19
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Helvetica Chimica Acta – Vol. 89 (2006)
Di(tert-Butyl) 2-[(4-Methylphenyl)sulfonyl]-1H-pyrrole-3,4-dicarboxylate (3d). Yield: 400 mg
(
1
95%). Colorless crystals. M.p. 144–1468. IR (KBr): 3185 (NH); 1696 (COO); 1329, 1296 (SO ); 1249,
2
1
145 (ester CÀO). H-NMR (500 MHz, CDCl ): 1.5 (s, 9 H); 1.61 (s, 9 H); 2.39 (s, 3 H); 7.28 (d,
3
13
J=8.5, 2 H); 7.31 (d, J=3.2, 1 H); 7.88 (d, J=8.3, 2 H); 10.03 (s, 1 H). C-NMR (125 MHz, CDCl ):
3
2
1
1.62; 28.07; 28.28; 81.19; 82.98; 118.85; 123.64; 126.20; 127.21; 127.51; 129.86; 138.14; 144.67; 161.43;
62.53. EI-MS: 277 (14), 138 (27), 11 (11), 91 (55), 58 (100), 41 (86), 39 (84). Anal. calc. for
C H NO S (421.50): C 59.84, H 6.46, N 3.32; found: C 59.9, H 6.5, N 3.3.
21
27
6
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Received January 23, 2006