Synthesis of 4-hydroxy-1H-pyrrole-2,3-dicarboxylic acid derivatives: Unusual coupling of acetylenic esters and α-amino acids in the presence of cyclohexyl isocyanide or N,N′-dicyclohexylcarbodiimide

Article abstract of DOI:10.1055/s-2008-1067159

A facile and direct synthetic entry to 4-hydroxy-1H-pyrrole-2,3- dicarboxylic acid derivatives is reported. It is based on the unusual ring annulation of acetylenic esters and α-amino acids with isocyanide or carbodiimide under neutral conditions in a one-step procedure. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067159

2462
PAPER
Synthesis of 4-Hydroxy-1H-pyrrole-2,3-dicarboxylic Acid Derivatives:
Unusual Coupling of Acetylenic Esters and a-Amino Acids in the Presence
of Cyclohexyl Isocyanide or N,N¢-Dicyclohexylcarbodiimide
S
ynthesis of 4-Hyd
b
roxy-1
H
-py
d
rrole-2,3-dic
o
A
c
l
idDeri
a
vative
s
li Alizadeh,* Reza Hosseinpour, Sadegh Rostamnia
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran 18716, Iran
Fax +98(21)88006544; E-mail: aalizadeh@modares.ac.ir
Received 3 April 2008; revised 19 April 2008
unusual coupling of acetylenes and a-amino acids in the
Abstract: A facile and direct synthetic entry to 4-hydroxy-1H-pyr-
role-2,3-dicarboxylic acid derivatives is reported. It is based on the
unusual ring annulation of acetylenic esters and a-amino acids with
isocyanide or carbodiimide under neutral conditions in a one-step
procedure.
presence of carbodiimides such as N,N¢-dicyclohexylcar-
bodiimide led to the same functionalized pyrrole rings in
good yields, better than in the previous method.
To our surprise, in a one-pot reaction between a-amino
acids and dialkyl acetylenedicarboxylates (DAADs) in
the presence of isocyanide or carbodiimide, dialkyl 4-hy-
droxy-5-alkyl(or aryl)-1H-pyrrole-2,3-dicarboxylate de-
rivatives form as products (Table 1). It should be noted
here that the synthesis of dialkyl 4-hydroxy-5-alkyl(or ar-
yl)-1H-pyrrole-2,3-dicarboxylates has been reported ear-
lier by Kolar et al. and also Noguchi via amino esters in
the presence of sodium methoxide in 11% yield.7
Key words: pyrroles, a-amino acids, alkynes, isocyanides, N,N¢-di-
cyclohexylcarbodiimide
Pyrrole derivatives represent a class of compounds of
great importance in heterocyclic chemistry and are useful
for applications in medicine and agriculture.1,2 These
compounds can have intrinsic biological activity and also
constitute the structural feature of many biologically ac-
tive compounds. The synthetic approaches to pyrrole de-
rivatives are mostly multistep and low-yielding.3–7 Thus,
development of new synthetic methods still remains an at-
tractive goal.
The reactions of cyclohexyl isocyanide or N,N¢-dicyclo-
hexylcarbodiimide with a-amino acids 1 in the presence
of dialkyl acetylenedicarboxylates 2 proceeded spontane-
ously at 25 °C in anhydrous N,N-dimethylformamide and
were completed within 24 hours, to produce dialkyl 4-hy-
droxy-5-alkyl(or aryl)-1H-pyrrole-2,3-dicarboxylates 3 in
70–95% yields (Table 1). The structures of compounds
3a–h were deduced from their elemental analyses, IR
spectra, and high-field 1H and 13C NMR spectra. The mass
spectrum of 3a displayed the molecular ion (M+) peak at
m/z = 276; this is consistent with the dialkyl 4-hydroxy-5-
alkyl(or aryl)-1H-pyrrole-2,3-dicarboxylate structure.
The IR spectrum of 3a exhibited absorption bands due to
the carbonyl group of the esters at 1645 and of NH at 3250
cm–1. The 1H NMR spectrum of 3a contained three single
sharp lines, readily recognized as arising from methoxy
(d = 3.83 and 3.86) and hydroxy (d = 8.84) protons. A
fairly broad singlet (d = 10.32) was observed for the NH
group, and the phenyl moiety gave rise to characteristic
signals in the aromatic region of the spectrum. The 1H-de-
coupled 13C NMR spectrum of 3a showed twelve distinct
resonances in agreement with the structure of dimethyl 4-
hydroxy-5-phenyl-1H-pyrrole-2,3-dicarboxylate.
In previous studies, we were interested in developing iso-
cyanide–electron-deficient acetylene reactions (IMCRs/
DAAD) under multicomponent conditions. This research
led to the discovery of the reaction between isocyanides,
acetylenes, and carboxylic acids for the first time.8 In our
recent investigations, treatment of aliphatic carboxylic ac-
ids and derivatives with dialkyl acetylenedicarboxylates
and alkyl isocyanides, at 25 °C, led to the formation of
2,5-diaminofuran derivatives (Scheme 1).9
R2O2C
CO2R2
CO2R2
+
O
O
CH2Cl2
R3
R3
1
2
R
+
N C:
OH
NH
R1
r.t., 48 h
N
R1
O
CO2R2
Scheme 1
Among other interesting syntheses, we could prepare
nicotinamide and isonicotinamides.10 In a related study in
the multicomponent area, we incorporated a-amino acids
under similar conditions. To this end, as a preliminary
step in IMCRs/DAAD and a-amino acids reactions, we
synthesized dialkyl 4-hydroxy-5-alkyl(or aryl)-1H-pyr-
role-2,3-dicarboxylates in good yields. Furthermore, this
Although the mechanistic details of the reaction are not
clearly known, the rationalization presented earlier may
also be invoked here. In the reaction of isocyanide as an
example, it is conceivable8,11 that the initially formed ion
pair 4 results from the reaction between an a-amino acid
and the isocyanide (Scheme 2).11a,b The reaction of ion
pair 4 with acetylene 2 leads to the formation of enamin-
one 5, and the final product 3 results from ring annulation
of enaminone 5 due to intramolecular interactions and
elimination of substituted formamide followed by aroma-
SYNTHESIS 2008, No. 15, pp 2462–2466
x
x.
x
x
.
2
0
0
8
Advanced online publication: 08.07.2008
DOI: 10.1055/s-2008-1067159; Art ID: Z07808SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 4-Hydroxy-1H-pyrrole-2,3-dicarboxylic Acid Derivatives
2463
Table 1 Reactions of a-Amino Acids 1 and Dialkyl Acetylenedicarboxylates 2 in the Presence of Cyclohexyl Isocyanide or N,N¢-Dicyclo-
hexylcarbodiimide
Cy
O
H
O
N
C
N
CO2R2
O
OR2
Cy
Cy
Cy
R1
N
H
N
H
Cy
anhyd DMF
r.t., 24 h
O
or
or
O
+
+
+
H3N
R1
CO2R2
N
H
O
CO2R2
N
C
Cy
N
H
H
1
2
3
a-Amino acid 1
R2
Product 3
Yielda (%) of 3 from
CyNC
DCC
H
O
O
O
OMe
O
Me
Et
3a
80
90
OH
CO2Me
N
H
NH2
H
O
OEt
O
3b
80
90
OH
O
CO2Et
N
H
NH2
H
O
O
O
OMe
Me
Et
3c
3d
3e
3f
85
80
70
70
95
95
85
90
OH
NH2
CO2Me
N
H
H
O
O
OEt
OH
NH2
CO2Et
N
H
H
O
O
O
OMe
Me
Me
OH
CO2Me
NH2
N
H
H
O
O
O
OMe
OH
O
CO2Me
NH2
N
H
OH
H
O
O
OMe
Me
3g
3h
80
80
95
95
NH2
HN
CO2Me
N
H
N
H
O
OH
H
O
O
OEt
Et
NH2
HN
CO2Et
N
H
N
H
a Isolated yields.
Synthesis 2008, No. 15, 2462–2466 © Thieme Stuttgart · New York

2464
A. Alizadeh et al.
PAPER
13C NMR (125 MHz, CDCl3): d = 51.81 and 51.87 (2 OCH3),
104.85 (C5pyrrole), 117.65 (C3pyrrole), 117.80 (C2pyrrole), 124.95 (2 CH
of Ph), 126.77 (CH of Ph), 128.60 (2 CH of Ph), 129.74 (Cipso),
146.44 (C4pyrrole), 160.0 (CO2Me), 167.37 (CO2Me).
MS (EI, 70 eV): m/z (%) = 276 [M+ + 1] (7), 275 [M+] (30), 243
(100), 211 (44), 183 (9), 155 (46), 128 (7), 104 (9), 89 (4), 77 (19),
59 (3), 53 (7).
tization by hydrogen migration (Scheme 2). When N,N¢-
dicyclohexylcarbodiimide is used instead of isocyanide,
the first step is the activation of the a-amino acid by at-
tachment of the acid to N,N¢-dicyclohexylcarbodiimide
and then formation of the enaminone. Pyrrole 3 is formed
by intramolecular ring annulation and aromatization.
Anal. Calcd for C14H13NO5 (275.26): C, 61.09; H, 4.76; N, 5.09.
Found: C, 61.15; H, 4.68; N, 5.10.
O
O
2
Cy
N
C
H2N
H3N
HC
N
O
Cy
O
O
Diethyl 4-Hydroxy-5-phenyl-1H-pyrrole-2,3-dicarboxylate (3b)
Pale yellow crystals; mp 96–98 °C.
R1
R1
4
IR (KBr): 3305 (NH), 1639 (2 CO2Et), 1464 and 1408 (Ph), 1242
(C–O of ester) cm–1.
CO2R2
Cy
H
O
N
O
CO2R2
H
3
1H NMR (500 MHz, CDCl3): d = 1.39 (t, JHH = 7.1 Hz, 3 H,
N
3
Cy
CO2R2
H
N
3
H
O
OCH2CH3), 1.43 (t, JHH = 7.2 Hz, 3 H, OCH2CH3), 4.38 (q,
R1
N
R1
CO2R2
3
3JHH = 7.1 Hz, 2 H, OCH2CH3), 4.43 (q, JHH = 7.2 Hz, 2 H,
5
H
6
3
OCH2CH3), 7.26 (t, JHH = 7.5 Hz, 1 H, CH of Ph), 7.42 (t,
3JHH = 7.7 Hz, 2 H, 2 CH of Ph), 7.76 (d, 3JHH = 7.8 Hz, 2 H, 2 CH
Scheme 2
of Ph), 9.09 (s, 1 H, OH), 9.52 (br s, 1 H, NH).
13C NMR (125 MHz, CDCl3): d = 14.31 and 14.41 (2 OCH2CH3),
61.04 and 61.31 (2 OCH2CH3), 105.04 (C5pyrrole), 117.45 (C3pyrrole),
117.84 (C2pyrrole), 124.59 (2 CH of Ph), 126.99 (CH of Ph), 128.89
(2 CH of Ph), 129.70 (Cipso), 146.94 (C4pyrrole), 160.22 (CO2Et),
167.21 (CO2Et).
MS (EI, 70 eV): m/z (%) = 304 [M+ + 1] (6), 303 [M+] (19), 257
(100), 229 (10), 211 (47), 183 (7), 155 (26), 104 (12), 89 (4), 77 (7),
53 (9).
In conclusion, two one-pot approaches to the addition of
a-amino acids to electron-deficient acetylenes for the syn-
thesis of a series of dialkyl 4-hydroxy-5-alkyl(or aryl)-
1H-pyrrole-2,3-dicarboxylate derivatives have been re-
ported. The present one-pot general method for the addi-
tion of a-amino acids to active acetylenes has the
advantage that not only can the reaction be performed un-
der neutral conditions, but it also affords good yields of
products. The simplicity of the present procedure makes it
an interesting alternative to complex multistep approach-
es.
Anal. Calcd for C16H17NO5 (303.31): C, 63.36; H, 5.65; N, 4.62.
Found: C, 63.40; H, 5.60; N, 4.70.
Dimethyl 5-Benzyl-4-hydroxy-1H-pyrrole-2,3-dicarboxylate
(3c)
Pale yellow crystals; mp 146–148 °C.
Dimethyl and diethyl acetylenedicarboxylates, a-amino acids,
CyNC, and DCC were obtained from Merck (Germany) and Fluka
(Switzerland) and were used without further purification. Melting
points were measured on an Electrothermal 9100 apparatus. Ele-
mental analyses for C, H, and N were performed on a Heraeus
CHN-O-Rapid analyzer. Mass spectra were recorded on a Finnigan-
Matt 8430 mass spectrometer operating at an ionization potential of
70 eV. 1H and 13C NMR spectra were measured (CDCl3 soln) on a
Bruker DRX-500 Avance spectrometer at 500.1 and 125.7 MHz, re-
spectively. IR spectra were recorded on a Shimadzu IR-460 spec-
trometer. Merck silica gel (230–240 mesh) was used for
chromatography columns.
IR (KBr): 3265 (NH), 1647 (2 CO2Me), 1476 and 1437 (Ph), 1283
(C–O of ester) cm–1.
1H NMR (500 MHz, CDCl3): d = 3.83 (s, 3 H, OCH3), 3.94 (s, 3 H,
OCH3), 3.97 (s, 2 H, PhCH2), 7.22 (d, 3JH,H = 7.3 Hz, 2 H, 2 CH of
Ph), 7.26 (t, 3JH,H = 7.8 Hz, 1 H, CH of Ph), 7.32 (t, 3JH,H = 7.5 Hz,
2 H, 2 CH of Ph), 8.27 (s, 1 H, OH), 8.84 (br s, 1 H, NH).
13C NMR (125 MHz, CDCl3): d = 30.09 (PhCH2), 51.87 and 51.88
(2 OCH3), 104.65 (C5pyrrole), 116.38 (C3pyrrole), 117.54 (C2pyrrole),
126.89 (CH of Ph), 128.55 (2 CH of Ph), 128.91 (2 CH of Ph),
137.70 (Cipso), 145.89 (C4pyrrole), 159.82 (CO2Me), 167.19
(CO2Me).
Dimethyl 4-Hydroxy-5-phenyl-1H-pyrrole-2,3-dicarboxylate
(3a); Typical Procedure
MS (EI, 70 eV): m/z (%) = 290 [M+ + 1] (5), 289 [M+] (26), 257
(100), 225 (5), 197 (18), 169 (22), 143 (13), 103 (22), 91 (84), 80
(19), 57 (34).
A soln of CyNC (0.11 g, 1 mmol) or DCC (0.21 g, 1 mmol) in anhyd
DMF (3 mL) was added dropwise over 10 min to a magnetically
stirred soln of amino(phenyl)acetic acid (1a; 0.51 g, 1 mmol) and
dimethyl acetylenedicarboxylate (2a; 0.14 g, 1 mmol) in anhyd
DMF (2 mL) at r.t. The reaction mixture was subsequently stirred
for 24 h. The solvent was removed under reduced pressure, and the
residue was subjected to column chromatography (silica gel, hex-
ane–EtOAc, 5:1).
Anal. Calcd for C15H15NO5 (289.28): C, 62.28; H, 5.23; N, 4.84.
Found: C, 62.30; H, 5.30; N, 4.90.
Diethyl 5-Benzyl-4-hydroxy-1H-pyrrole-2,3-dicarboxylate (3d)
Pale yellow crystals; mp 127–129 °C.
IR (KBr): 3260 (NH), 1635 (2 CO2Et), 1479 and 1443 (Ph), 1268
and 1211 (C–O of ester) cm–1.
Yield: 0.22 g (80%); pale yellow crystals; mp 115–117 °C.
3
1H NMR (500 MHz, CDCl3): d = 1.33 (t, JH,H = 7.1 Hz, 3 H,
IR (KBr): 3250 (NH), 1645 (2 CO2Me), 1464 and 1434 (Ph), 1228
(C–O of ester) cm–1.
3
OCH2CH3), 1.41 (t, JH,H = 7.1 Hz, 3 H, OCH2CH3), 3.97 (s, 2 H,
3
PhCH2), 4.29 (q, JH,H = 7.1 Hz, 2 H, OCH2CH3), 4.40 (q,
1H NMR (500 MHz, CDCl3): d = 3.83 (s, 3 H, OCH3), 3.86 (s, 3 H,
3JH,H = 7.1 Hz, 2 H, OCH2CH3), 7.20 (d, 3JH,H = 7.5 Hz, 2 H, 2 CH
3
3
3
OCH3), 7.16 (t, 3JH,H = 7.4 Hz, 1 H, CH of Ph), 7.32 (t, JH,H = 7.9
of Ph), 7.24 (t, JH,H = 7.2 Hz, 1 H, CH of Ph), 7.30 (t, JH,H = 7.5
Hz, 2 H, 2 CH of Ph), 7.74 (d, 3JH,H = 7.5 Hz, 2 H, 2 CH of Ph), 8.84
Hz, 2 H, 2 CH of Ph), 8.42 (s, 1 H, OH), 9.25 (br s, 1 H, NH).
(s, 1 H, OH), 10.32 (br s, 1 H, NH).
Synthesis 2008, No. 15, 2462–2466 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-Hydroxy-1H-pyrrole-2,3-dicarboxylic Acid Derivatives
2465
13C NMR (125 MHz, CDCl3): d = 14.29 and 14.33 (2 OCH2CH3),
29.99 (PhCH2), 60.82 and 60.96 (2 OCH2CH3), 104.40 (C5pyrrole),
116.55 (C3pyrrole), 117.43 (C2pyrrole), 126.71 (CH of Ph), 128.40 (2
CH of Ph), 128.76 (2 CH of Ph), 137.90 (Cipso), 145.93 (C4pyrrole),
160.17 (CO2Et), 166.96 (CO2Et).
MS (EI, 70 eV): m/z (%) = 318 [M+ + 1] (18), 317 [M+] (33), 243
(13), 225 (14), 214 (7), 197 (16), 169 (16), 143 (8), 103 (17), 91
(27), 80 (11), 53 (7).
(CH), 122.58 (CH), 126.97 (C3aindole), 136.53 (C7aindole), 145.29
(C4pyrrole), 159.73 (CO2Me), 167.32 (CO2Me).
MS (EI, 70 eV): m/z (%) = 329 [M+ + 1] (5), 328 [M+] (28), 296
(13), 263 (2), 235 (1), 207 (1), 180 (6), 148 (7), 132 (10), 117 (100),
104 (5), 90 (9), 77 (3), 53 (2).
Anal. Calcd for C17H16N2O5 (328.32): C, 62.19; H, 4.91; N, 8.53.
Found: C, 62.20; H, 5.00; N, 8.56.
Anal. Calcd for C17H19NO5 (317.34): C, 64.34; H, 6.03; N, 4.41.
Found: C, 64.40; H, 5.98; N, 4.45.
Diethyl 4-Hydroxy-5-(1H-indol-3-ylmethyl)-1H-pyrrole-2,3-di-
carboxylate (3h)
Colorless crystals; mp 194–196 °C.
Dimethyl4-Hydroxy-5-isopropyl-1H-pyrrole-2,3-dicarboxylate
(3e)
Yellow viscous oil.
IR (KBr): 3410 (NH), 3255 (NH),1639 (2 CO2Et), 1481 and 1444
(Ph), 1280 and 1217 (C–O of ester) cm–1.
3
1H NMR (500 MHz, CDCl3): d = 1.32 (t, JH,H = 7.05 Hz, 3 H,
IR (KBr): 3380 (NH), 1727 and 1683 (CO2Me), 1429 and 1341
(Ph), 1254 and 1209 (C–O of ester) cm–1.
OCH2CH3), 1.43 (t, 3JH,H = 7.20 Hz, 3 H, OCH2CH3), 4.12 (s, 2 H,
3
CH2), 4.27 (q, JH,H = 7.05 Hz, 2 H, OCH2CH3), 4.43 (q,
1H NMR (500 MHz, CDCl3): d = 1.29 (d, 3JH,H = 7.0 Hz, 6 H, 2 CH3
3JH,H = 7.15 Hz, 2 H, OCH2CH3), 7.07 (s, 1 H, CH), 7.13 (t,
3JH,H = 7.2 Hz, 1 H, CH), 7.23 (t, 3JH,H = 7.8 Hz, 1 H, CH), 7.39 (d,
3JH,H = 8.0 Hz, 1 H, CH), 7.56 (d, 3JH,H = 7.8 Hz, 1 H, CH), 8.10 (s,
1 H, OH), 8.45 and 8.87 (br s, 2 H, 2 NH).
3
of i-Pr), 3.10 (sept, JH,H = 7.0 Hz, 1 H, CH of i-Pr), 3.88 (s, 3 H,
OCH3), 3.93 (s, 3 H, OCH3), 8.19 (s, 1 H, OH), 8.85 (br s, 1 H, NH).
13C NMR (125 MHz, CDCl3): d = 21.14 (2 CHMe2), 24.87
(CHMe2), 51.79 and 51.84 (2 OCH3), 104.05 (C5pyrrole), 114.95
(C3pyrrole), 124.40 (C2pyrrole), 144.84 (C4pyrrole), 159.98 (CO2Me),
167.33 (CO2Me).
MS (EI, 70 eV): m/z (%) = 242 [M+ + 1] (7), 241 [M+] (8), 210 (13),
186 (100), 126 (37), 91 (20), 71 (36), 57 (71), 55 (70).
13C NMR (125 MHz, CDCl3): d = 14.33 (2 OCH2CH3), 19.96
(CH2), 60.82 (2 OCH2CH3), 104.50 (C5pyrrole), 111.24 (CH), 111.93
(C3indole), 116.05 (C3pyrrole), 117.69 (C2pyrrole), 118.77 (CH), 119.89
(CH), 122.39 (CH), 122.53 (CH), 126.97 (C3aindole), 136.53
(C7aindole), 145.31 (C4pyrrole), 159.93 (CO2Me), 167.08 (CO2Me).
MS (EI, 70 eV): m/z (%) = 357 [M+ + 1] (8), 356 [M+] (31), 310
(18), 263 (2), 235 (1), 207 (1), 194 (4), 130 (6), 117 (100), 103 (1),
90 (3), 77 (2), 53 (2).
Anal. Calcd for C11H15NO5 (241.24): C, 54.77; H, 6.27; N, 5.81.
Found: C, 54.68; H, 6.17; N, 5.78.
Dimethyl 5-sec-Butyl-4-hydroxy-1H-pyrrole-2,3-dicarboxylate
(3f)
Anal. Calcd for C19H20N2O5 (356.37): C, 64.04; H, 5.66; N, 7.86.
Found: C, 64.00; H, 5.70; N, 7.90.
Pale yellow crystals; mp 94–96 °C.
IR (KBr): 3455 (NH), 1717 and 1658 (2 CO2Me), 1484 and 1436
(Ph), 1264 and 1230 (C–O of ester) cm–1.
References
(1) (a) Carson, J. R.; McKinstry, D. N.; Wong, S. J. Med. Chem.
1971, 14, 646. (b) Stork, G.; Nakahara, Y.; Nakahara, Y.;
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G.; Hochgürtel, M.; Volk, C.; Grube, A.; Köck, M.
Tetrahedron Lett. 2004, 45, 8149.
(2) (a) Falk, H. The Chemistry of Linear Oligopyrroles and Bile
Pigments; Springer: Vienna, 1989, 355. (b) Montforts, F.
P.; Schwartz, U. M. Angew. Chem., Int. Ed. Engl. 1985, 24,
775; Angew. Chem. 1985, 97, 767. (c) Dutton, C. J.; Fookes,
C. J. R.; Battersby, A. R. J. Chem. Soc., Chem. Commun.
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(3) Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 1998, 615.
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42, 6027.
(6) Attanasi, O.; Fillipone, P.; Perrulli, F. R.; Santensanio, S.
Tetrahedron 2001, 57, 1387.
(7) (a) Kolar, P.; Tisler, M. Synth. Commun. 1994, 24, 1887.
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Shiro, M.; Noguchi, M. Tetrahedron Lett. 2007, 48, 941.
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62, 5641.
(9) (a) Alizadeh, A.; Rostamnia, S.; Hu, M. L. Synlett 2006,
1592. (b) Alizadeh, A.; Rostamnia, S.; Esmaili, A. A.
Synthesis 2007, 709.
3
1H NMR (500 MHz, CDCl3): d = 0.88 (t, JH,H = 7.4 Hz, 3 H,
3
MeCHCH2Me), 1.27 (d, JHH = 7.1 Hz, 3 H, MeCHCH2Me), 1.64
(m, 2 H, MeCHCH2Me), 2.86 (m, JH,H = 7. 2 Hz, 1 H,
MeCHCH2Me), 3.88 (s, 3 H, OCH3), 3.93 (s, 3 H, OCH3), 8.19 (s,
3
1 H, OH), 8.85 (br s, 1 H, NH).
13C NMR (125 MHz, CDCl3): d = 11.88 (MeCHCH2Me), 18.86
(MeCHCH2Me), 28.87 (MeCHCH2Me), 31.85 (MeCHCH2Me),
51.80 and 51.85 (2 OCH3), 104.68 (C5pyrrole), 115.20 (C3pyrrole),
123.50 (C2pyrrole), 145.32 (C4pyrrole), 159.99 (CO2Me), 167.34
(CO2Me).
MS (EI, 70 eV): m/z (%) = 255 [M+] (16), 224 (10), 223 (41), 208
(7), 194 (100), 162 (18), 106 (19), 80 (13), 53 (30).
Anal. Calcd for C12H17NO5 (255.27): C, 56.46; H, 6.71; N, 5.49.
Found: C, 56.50; H, 6.90; N, 5.50.
Dimethyl 4-Hydroxy-5-(1H-indol-3-ylmethyl)-1H-pyrrole-2,3-
dicarboxylate (3g)
Colorless crystals; mp 200–202 °C.
IR (KBr): 3395 (NH), 3255 (NH), 1649 (2 CO2Me), 1481 and 1449
(Ph), 1283 and 1220 (C–O of ester) cm–1.
1H NMR (500 MHz, CDCl3): d = 3.80 (s, 3 H, OCH3), 3.96 (s, 3 H,
OCH3), 4.13 (s, 2 H, CH2), 7.11 (s, 1 H, CH), 7.13 (t, 3JHH = 7.1 Hz,
1 H, CH), 7.24 (t, 3JHH = 7.2 Hz, 1 H, CH), 7.41 (d, 3JHH = 7.1 Hz,
1 H, CH), 7.54 (d, 3JHH = 7.8 Hz, 1 H, CH), 8.11 (s, 1 H, OH), 8.35
and 8.80 (br s, 2 H, 2 NH).
13C NMR (125 MHz, CDCl3): d = 19.95 (CH2), 51.76 and 51.83 (2
OCH3), 104.50 (C5pyrrole), 111.25 (CH), 111.80 (C3indole), 115.90
(C3pyrrole), 117.90 (C2pyrrole), 118.77 (CH), 119.95 (CH), 122.46
(10) Alizadeh, A.; Oskueyan, Q.; Rostamnia, S. Synthesis 2007,
2637.
Synthesis 2008, No. 15, 2462–2466 © Thieme Stuttgart · New York

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A. Alizadeh et al.
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Tetrahedron Lett. 2006, 47, 4469.
(11) (a) Ugi, I. Isonitrile Chemistry; Academic Press: New York,
1971. (b) Shaabani, A.; Soleimani, E.; Rezayan, A. H.
Tetrahedron Lett. 2007, 48, 6137. (c) Sung, K.; Chen, C. C.
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Synthesis 2008, No. 15, 2462–2466 © Thieme Stuttgart · New York