A simple synthesis of 1-substituted diethyl pyrrole-3,4-dicarboxylates

Article abstract of DOI:10.1515/znb-2009-0614

A series of 1-substituted diethyl 1H-pyrrole-3,4-dicarboxylates 4a - o were prepared in 14-93% yield by acid-catalysed treatment of diethyl 2,3-bis[(E, E)-(dimethylamino)-methylidene]succinate (2) with various aliphatic and (hetero)aromatic primary amines 3a - o. The configuration of the C=C double bonds in the bis-enaminone 2 was determined by 1H NMR and HMBC spectroscopy.

Full text of DOI:10.1515/znb-2009-0614

A Simple Synthesis of 1-Substituted Diethyl Pyrrole-3,4-dicarboxylates
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ˇ
Luka Skrlep, Andreja Cercˇek-Hocˇevar, Renata Jaksˇe, Branko Stanovnik, and Jurij Svete
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Asˇkercˇeva 5, P. O. Box 537,
1000 Ljubljana, Slovenia
Reprint requests to Prof. Jurij Svete. Fax: +386 1 2419 220. E-mail: jurij.svete@fkkt.uni-lj.si
Z. Naturforsch. 2009, 64b, 683 – 688; received March 3, 2009
Dedicated to Professor Gerhard Maas on the occasion of his 60th birthday
A series of 1-substituted diethyl 1H-pyrrole-3,4-dicarboxylates 4a – o were prepared in 14 – 93 %
yield by acid-catalysed treatment of diethyl 2,3-bis[(E,E)-(dimethylamino)-methylidene]succinate
(2) with various aliphatic and (hetero)aromatic primary amines 3a – o. The configuration of the C=C
double bonds in the bis-enaminone 2 was determined by 1H NMR and HMBC spectroscopy.
Key words: Pyrroles, Enaminones, Amines, Cyclisations, Heterocycles
Introduction
propenoates [6], 2-(2-acylvinyl)amino-3-(dimethyl-
amino)-propenoates [7], and trialkyl 1-acylamino-4-
(arylamino)-buta-1,3-diene-1,2,3-tricarboxylates [8],
and by reactions of 1,2-diaza-1,3-butadienes with
2-acylamino-3-(dimethylamino)-propenoates [9]. Di-
ethyl 2,3-bis[(E,E)-(dimethylamino)methylidene]suc-
cinate (2), easily available from diethyl succinate (1)
[10], seems to be a suitable enaminone-type reagent
for a straightforward synthesis of 1-substituted
pyrrole-3,4-dicarboxylates 4. To the best of our
knowledge, however, only two reactions of 2 with
primary amines have been reported in the literature.
In 1983, Kornfeld and Jones synthesised diethyl
1H-pyrrole-3,4-dicarboxylate (4a) by treatment of 2
with ammonium acetate (3a) [11], while 16 years later
Townsend and Magawa prepared the N-[2-(pyridin-
2-yl)ethyl] derivative in an analogous manner [12].
This lack of information was quite intriguing, and
we decided to carry out a series of acid-catalysed
reactions of bis-enamino succinate 2 [10] with various
primary amines 3a – o. Herein, we report the result
of this study – a simple and efficient synthesis of
1-substituted-1H-pyrrole-3,4-dicarboxylates 4a – o.
Pyrrole is an important heterocycle because its
structure is incorporated in a variety of biologically
important compounds, such as heme, chlorophyll, vi-
tamin B12, and bile pigments. Besides, pyrrole and
pyrrolidine partial structures occur in numerous natural
products and synthetically important compounds [1].
Among numerous syntheses of pyrroles reported so
far in the literature, three general methods have to be
outlined: a) the Paal-Knorr synthesis of pyrroles from
1,4-dicarbonyl compounds and primary amines (5+1
cyclocondensation approach), b) the Knorr pyrrole
synthesis from α-amino ketones and 1,3-dicarbonyl
compounds (3+2 cyclocondensation approach), and
c) the van Leusen synthesis of pyrroles from tosyl-
methyl isocyanide (Tosmic) and α,β-unsaturated car-
bonyl compounds (3+2 cycloaddition approach) [1].
2-Substituted alkyl 3-(dimethylamino)prop-2-
enoates and related enaminones are a group of
enamino-masked alkyl α-formylacetates, which are
easily available and are versatile reagents in hetero-
cyclic synthesis [2]. In addition to their extensive
use in the synthesis of various heterocyclic systems,
recent applications of enaminones are mostly oriented
towards the preparation of functionalised heterocyclic
compounds including natural product analogues [2 –
Results and Discussion
Diethyl2,3-bis[(E,E)-(dimethylamino)methylidene]
4] and in combinatorial synthesis of functionalized succinate (2) was prepared from diethyl succin-
heterocycles [5]. In this context, pyrrole derivatives ate (1) and tert-butoxy-bis(dimethylamino)methane
have been prepared by intramolecular cyclisa- (Bredereck’s reagent, TBDMAM) according to a mod-
tion of 2-(2-cyano-vinyl)amino-3-(dimethylamino) ified literature procedure [10]. Heating of the bis-
c
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L. Skrlep et al. · A Simple Synthesis of 1-Substituted Diethyl Pyrrole-3,4-dicarboxylates
Table 1. Selected experimental data of diethyl pyrrole-3,4-
dicarboxylates 4a – o.
Com-
pound Ar
Yield
( %)
3a, 4a
H
42
85
86
3b, 4b OH
3c, 4c NMe2
3d, 4d (S)-3-(1H-indol-3-yl)-1-methoxy-1-oxopropan-2-yl 84
3e, 4e (S)-3-(4-hydroxyphenyl)-1-methoxy-1-oxo-
86
propan-2-yl
3f, 4f
(S)-1,5-diethoxy-1,5-dioxopentan-2-yl
93
90
85
80
84
42
14
37
80
70
3g, 4g (S)-1-methoxy-4-methyl-1-oxopentan-2-yl
3h, 4h CH2CH2COOEt
3i, 4i
3j, 4j
3k, 4k phenyl
3l, 4l
3m, 4m 3-hydroxypyridin-2-yl
3n, 4n 5-methylisoxazol-3-yl
3o, 4o 1H-1,2,4-triazol-5-yl
CH2CN
CH2COOH
4-methylpyridin-2-yl
Fig. 1. Structure
determination of 2
by HMBC spec-
troscopy. The dou-
ble bonds exhibit E
configuration.
Scheme 1. Reaction conditions: (i) tert-Butoxy-bis(dimeth-
ylamino)methane (Bredereck’s reagent), reflux (ref. [10]);
(ii) R-NH2 (3a – o), EtOH-AcOH (2 : 1), reflux.
not obtained in analytically pure form. Their identity
was confirmed by HRMS and 13C NMR data. The
structure of the bis-enaminone 2 was determined by
1H NMR and HMBC spectroscopy. One set of signals
in the 1H NMR spectrum of compound 2 clearly indi-
cated that compound 2 was symmetrical with the same
configuration of both C=C double bonds. The (E)-
configuration of the exocyclic C=C bonds was con-
firmed by HMBC spectroscopy on the basis of a long-
range coupling constant (3JC−H) between the methyli-
dene proton [H–C(2ꢀ)] and the carbonyl carbon atom
[O=C(1)], measured from the antiphase splitting of
enaminone 2 with ammonium formate (3a), hydr-
oxylamine hydrochloride (3b), or 1,1-dimethylhydraz-
ine (3c) in a mixture of ethanol and acetic acid for
∼1 h afforded the diethyl 1H-pyrrole-3,4-dicarboxyl-
ates 4a – c in 42 – 86 % yield. Similarly, reactions of 2
with amino acid derivatives 3d – j proceeded smoothly
to give the corresponding 1-alkylated 1H-pyrrole-3,4-
dicarboxylates 4d – j in 80 – 93 % yield. Quite expect-
edly, reactions of 2 with aniline (3k) and heteroaryl-
amines 3l – o required longer reaction times (∼ 3 h) to
achieve a complete conversion of the starting bis-en-
aminone 2 into the corresponding 1-(hetero)aryl-1H-
pyrrole-3,4-dicarboxylates 4l – o, which were obtained
in 14 – 80% yield. The cyclisation of the bis-enamino
ester 2 with primary amines 3 can be explained by
double substitution of the dimethylamino group, i. e.
Michael addition of the primary amine 3 to the enamin-
one 2, followed by elimination of dimethylamine, leads
to the monosubstituted intermediate 5, which then un-
dergoes the second 1,4-addition-elimination sequence
to furnish the pyrrole derivative 4 (Scheme 1, Table 1).
The structures of the novel compounds 4b – j and
3
cross peaks. Generally, the coupling constant JC−H
for nuclei with cis-configuration of the C=C double
bond is smaller (2 – 6 Hz) than for trans-oriented nu-
clei (8 – 12 Hz) [2, 13]. In compound 2, the magnitude
of the coupling constant, 3JC(1)−−H(2ꢀ) = 5.4 Hz (cis),
indicated (E)-configuration of the C=C double bonds
(Fig. 1).
Conclusion
Diethyl2,3-bis[(E,E)-(dimethylamino)methylidene]
4l – o were determined by spectroscopic (NMR, IR, succinate (2) is an easily available reagent, which
MS) methods and by elemental analyses for C, H, can smoothly be reacted with primary amines 3 af-
and N. Compounds 4b – d, 4f – h, 4j, and 4o were fording 1-substituted diethyl 1H-pyrrole-3,4-dicarb-
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685
oxylates 4. In most cases, this method affords the tions containing the product were combined and evaporated
in vacuo. 4b – i, k, n, o were prepared in this manner.
pyrroles 4 in very good yields after simple workup.
In addition to N-alkylation [14] and N-arylation [15]
of 1-unsubstituted dialkyl 1H-pyrrole-3,4-dicarboxyl-
ates, this method represents a simple complementary
cyclocondensation approach towards the preparation
of the title compounds.
Procedure B. Synthesis of compounds 4a, l, m
A mixture of bis-enaminone 2 (142 mg, 0.5 mmol), pri-
mary amine 3a, l, m (0.5 mmol), ethanol (2 mL), and acetic
acid (1 mL) was heated under reflux for 1 – 3 h. The reaction
mixture was cooled, and volatile components were evapo-
rated in vacuo. The residue was triturated with an appropriate
solvent (1.5 mL) and the precipitate collected by filtration to
give 4a, l, m.
Experimental Section
Melting points were determined on a Kofler micro hot
stage. The NMR spectra were obtained on a Bruker Avance
DPX 300 spectrometer at 300 MHz for 1H and at 75.5 MHz
for 13C, using CDCl3 (with TMS as the internal standard)
as solvent. Mass spectra were recorded on an AutoSpecQ
spectrometer, IR spectra on a Perkin-Elmer Spectrum BX
FTIR spectrophotometer. Microanalyses were performed on
a Perkin-Elmer CHN Analyzer 2400 II. Flash chromatog-
raphy (FC) was performed on silica gel (Fluka, silica gel
60, 0.04 – 0.06 mm). Diethyl succinate (1), tert-butoxy-bis
(dimethylamino)methane (Bredereck’s reagent), and amines
3a – o are commercially available (Sigma Aldrich).
Procedure C. Synthesis of compound 4j
A mixture of bis-enaminone 2 (142 mg, 0.5 mmol),
glycine (3j) (38 mg, 0.5 mmol), ethanol (2 mL), and acetic
acid (1 mL) was heated under reflux for 1 h. The reaction
mixture was cooled, and volatile components were evapo-
rated in vacuo. The residue was suspended in water (10 mL),
the suspension made alkaline with solid NaHCO3 and ex-
tracted with dichloromethane (20 mL). The aqueous phase
was acidified with 1 M hydrochloric acid to pH ∼2 and ex-
tracted again with dichloromethane (20 mL). The organic
phase was dried over anhydrous sodium sulphate, filtered,
and the filtrate evaporated in vacuo to give 4j.
Diethyl (2E,3E)-2,3-bis[(dimethylamino)methylidene]
succinate (2)
This compound was prepared according to a modified
literature procedure [12]. A mixture of diethyl succinate
(1) (10 mL, 60 mmol) and Bredereck’s reagent (30 mL,
145 mmol) was refluxed under argon for 9 h. Then, another
portion of Bredereck’s reagent (5 mL, 24 mmol) was added,
and the mixture was refluxed under argon for 9 h. The re-
action mixture was evaporated in vacuo, the residue was
suspended in water (120 mL) and extracted with hexanes
(2 × 60 mL). The aqueous phase was evaporated in vacuo,
the yellow oily residue dissolved in anhydrous diethyl ether
(30 mL), and the solution left in a refrigerator for one week.
The precipitate was collected by filtration and washed with
hexanes to give compound 2. Yield: 9.55 g (56 %) of yel-
low c◦rystals; m. p. 70 – 72 ◦C (from hexanes), ref. [10]: m. p.
Diethyl 1H-pyrrole-3,4-dicarboxylate (4a)
Compound 4a was prepared from 2 and ammonium for-
mate (3a) (32 mg, 0.5 mmol). Procedure B, reflux for 1 h,
trituration with ethanol. Yield: 45 mg (42 %) of a white solid;
m. p. 147 – 149 ◦C, ref. [11]: m. p. 150 – 151 ◦C. – IR (KBr):
ν = 3240, 1710 cm−1. – 1H NMR (CDCl3): δ = 1.31 (6H, t,
J = 7.1 Hz, 2 × CH2CH3), 4.38 (4H, q, J = 7.1 Hz, 2 × CH2
CH3), 7.45 (2H, s, 2-H, 5-H), 9.95 (1H, br s, NH).
Diethyl 1-hydroxy-1H-pyrrole-3,4-dicarboxylate (4b)
Compound 4b was prepared from 2 and hydroxylamine
hydrochloride (3b) (35 mg, 0.5 mmol). Procedure A, reflux
for 2 h. Yield: 97 mg (85 %) of a yellowish oil. – IR (NaCl):
ν = 3147, 2982, 1724 cm−1. – 1H NMR (CDCl3): δ = 1.23
(6H, t, J = 7.2 Hz, 2 × CH2CH3), 4.15 (4H, q, J = 7.2 Hz,
2 × CH2CH3), 7.39 (2H, s, 2-H, 5-H), 12.20 (1H, br s, OH). –
13C NMR (CDCl3): δ = 14.6, 61.3, 111.7, 124.3, 165.1. –
MS (EI): m/z = 227 [M]+. – HRMS (EI): m/z = 227.0801
(calcd. 227.0794 for C10H13NO5, [M]+).
1
70.5 C. – H NMR (CDCl3): δ = 1.20 (6H, t, J = 7.1 Hz,
2 × CH2CH3), 2.93 (12H, s, 2 × NMe2), 4.15 (4H, q, J =
7.1 Hz, 2 × CH2CH3), 7.50 (2H, s, 2 × CH).
Synthesis of 1-substituted diethyl pyrrole-3,4-dicarboxylates
4a – o. General procedures
Procedure A. Synthesis of compounds 4b – i, k, n, o
A mixture of bis-enaminone 2 (142 mg, 0.5 mmol), pri-
mary amine 3b – i, k, n, o (0.5 mmol), ethanol (2 mL), and
acetic acid (1 mL) was heated under reflux for 1 – 3 h. The
Diethyl 1-dimethylamino-1H-pyrrole-3,4-dicarboxylate (4c)
Compound 4c was prepared from 2 and 1,1-dimethyl-
reaction mixture was cooled, and volatile components were hydrazine (3c) (30 mg, 0.5 mmol); Procedure A, reflux for
evaporated in vacuo. The residue was purified by CC (sil- 1 h. Yield: 109 mg (86 %) of a yellowish oil. – IR (NaCl):
ica gel, ethyl acetate, column dimensions 10 × 1 cm). Frac- ν = 3129, 2961, 1734, 1524 cm−1. – 1H NMR (CDCl3): δ =
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L. Skrlep et al. · A Simple Synthesis of 1-Substituted Diethyl Pyrrole-3,4-dicarboxylates
1.32 (6H, t, J = 7.2 Hz, 2 × CH2CH3), 2.80 (6H, s, NMe2), dure A, reflux for 1 h. Yield: 185 mg (93 %) of a colourless
4.25 (4H, q, J = 7.2 Hz, 2 × CH2CH3), 7.32 (2H, s, 2-H, oil. – [α]2D2 = −9.3 (c = 0.38, CHCl3). – IR (NaCl): ν = 3135,
5-H). – 13C NMR (CDCl3): δ = 14.7, 48.6, 60.6, 114.6, 2983, 1736, 1538 cm−1. – 1H NMR (CDCl3): δ = 1.25, 1.27,
124.2, 163.8. – MS (EI): m/z = 254 [M]+. – MS (FAB): 1.34 (12H, 3t, 1 : 1 : 2, J = 7.2 Hz, 4 × CH2 CH3), 2.33 (4H,
m/z = 255 [M+H]+. – HRMS (EI): m/z = 254.1276 (calcd. m, CH2CH2), 4.14, 4.22, 4.29 (8H, 3q, 1 : 1 : 2, J = 7.2 Hz,
254.1267 for C12H18N2O4, [M]+).
4 × CH2CH3), 4.74 (1H, dd, J = 4.1, 9.8 Hz, CH2CH), 7.28
(2H, s, 2-H, 5-H). – 13C NMR (CDCl3): δ = 14.4, 14.5, 14.7,
28.2, 30.0, 60.7, 61.3, 61.7, 62.7, 117.3, 127.4, 163.8, 169.3,
172.2. – MS (EI): m/z = 397 [M]+. – MS (FAB): m/z = 398
[M+H]+. – HRMS (EI): m/z = 397.1746 (calcd. 397.1737 for
C19H27NO8, [M]+).
Diethyl 1-[(S)-3-(1H-indol-3-yl)-1-methoxy-1-oxopropan-2-
yl]-1H-pyrrole-3,4-dicarboxylate (4d)
Compound 4d was prepared from 2 and (S)-tryptophan
methyl ester hydrochloride (3d) (127 mg, 0.5 mmol). Proce-
dure A, reflux◦for 1 h. Yield: 173 mg (84 %) of white crystals;
m. p. 23 – 25 C. – [α]D22 = −11.3 (c = 0.73, CHCl3). – IR
(KBr): ν = 3360, 3134, 2981, 1730, 1535 cm−1. – 1H NMR
(CDCl3): δ = 1.32 (6H, t, J = 7.2 Hz, 2 × CH2CH3), 3.51
Diethyl 1-[(S)-1-methoxy-4-methyl-1-oxopentan-2-yl]-1H-
pyrrole-3,4-dicarboxylate (4g)
Compound 4g was prepared from 2 and (S)-leucine
(2H, m, CH2CH), 3.76 (3H, s, OMe), 4.27 (4H, q, J = methyl ester hydrochloride (3g) (99 mg, 0.5 mmol). Proce-
7.2 Hz, 2 × CH2CH3), 4.81 (1H, dd, J = 3.4, 9.4 Hz, CH2 dure A, reflux for 1 h. Yield: 152 mg (90 %) of a colourless
CH), 6.67 (1H, d, J = 2.3 Hz, 2ꢀ-H), 7.19 (2H, m, 5ꢀ-H, oil. – [α]D23 = 12.0 (c = 0.38, CHCl3). – IR (NaCl): ν = 3133,
6ꢀ-H), 7.27 (2H, s, 2-H, 5-H), 7.46 (2H, m, 4ꢀ-H, 7ꢀ-H), 8.05 2959, 1738, 1537 cm−1. – 1H NMR (CDCl3): δ = 0.93 (6H,
(1H, br s, NH). – 13C NMR (CDCl3): δ = 14.7, 29.6, 53.4, d, J = 6.8 Hz, Me2CH), 1.34 (6H, t, J = 7.2 Hz, 2 × CH2
60.7, 63.5, 109.2, 111.9, 116.8, 118.3, 120.2, 122.7, 123.6, CH3), 1.43 (1H, m, Me2CH), 1.95 (2H, m, CH2CH), 3.74
127.0, 127.7, 136.5, 163.9, 170.1. – Anal. for C22H24N2O6
(3H, s, OMe), 4.29 (4H, q, J = 7.2 Hz, 2 × CH2CH3), 4.62
1
· /4H2O: calcd. C 63.37, H 5.92, N 6.72; found C 63.42, (1H, dd, J = 7.2, 8.7 Hz, CH2CH), 7.29 (2H, s, 2-H, 5-H). –
H 6.12, N 6.94. – MS (EI): m/z = 412 [M]+. – MS (FAB): 13C NMR (CDCl3): δ = 14.7, 21.8, 23.0, 24.9, 41.6, 53.3,
m/z = 413 [M+H]+. – HRMS (EI): m/z = 412.1649 (calcd. 60.7, 61.2, 117.0, 127.2, 163.9, 170.6. – MS (EI): m/z = 339
412.1634 for C22H24N2O6, [M]+).
[M]+. – MS (FAB): m/z = 340 [M+H]+. – HRMS (EI): m/z =
339.1691 (calcd. 339.1682 for C17H25NO6, [M]+).
Diethyl 1- [(S)-3-(4-hydroxyphenyl)-1-methoxy-1-
oxopropan-2-yl]-1H-pyrrole-3,4-dicarboxylate (4e)
Diethyl 1-(3-ethoxy-3-oxopropyl)-1H-pyrrole-3,4-
dicarboxylate (4h)
Compound 4e was prepared from 2 and (S)-tyrosine
methyl ester hydrochloride (3e) (116 mg, 0.5 mmol). Pro-
Compound 4h was prepared from 2 and β-alanine ethyl
cedure A, reflux for 1 h. Yield: 168 mg (86 %) of white crys- ester hydrochloride (3h) (77 mg, 0.5 mmol). Procedure A,
tals; m. p. 21 – 23 ◦C. – [α]D22 = −22.8 (c = 1.69, CHCl3). – reflux for 1 h. Yield: 109 mg (85 %) of white crystals; m. p.
IR (KBr): ν = 3443, 2984, 1730, 1519 cm−1. – 1H NMR 64 – 66 ◦C. – IR (KBr): ν = 3132, 2982, 1732, 1542 cm−1. –
(CDCl3): δ = 1.31 (6H, t, J = 7.1 Hz, 2 × CH2CH3), 3.13 1H NMR (CDCl3): δ = 1.25, 1.33 (9H, 2t, 1 : 2, J = 7.2 Hz,
(1H, dd, J = 9.1, 14.1 Hz, 1H of CH2CH), 3.34 (1H, dd, 3 × CH2CH3), 2.77 (2H, t, J = 6.9 Hz, CH2COOEt), 4.16
J = 6.1, 14.1 Hz, 1H of CH2CH), 3.72 (3H, s, OMe), 4.26 (2H, q, J = 7.2 Hz, CH2CH3), 4.19 (2H, t, J = 6.9 Hz,
(4H, q, J = 7.1 Hz, 2 × CH2CH3), 4.69 (1H, dd, J = 6.1, CH2N), 4.28 (4H, q, J = 7.2 Hz, 2 × CH2CH3), 7.23 (2H, s,
9.1 Hz, CH2CH), 6.72 and 6.83 (4H, 2d, 1 : 1, J = 8.5 Hz, 2-H, 5-H). – 13C NMR (CDCl3): δ = 14.5, 14.7, 36.2, 45.9,
C6H4), 7.27 (2H, s, 2-H, 5-H), 7.30 (1H, br s, OH). – 60.6, 61.6, 116.9, 128.0, 163.9, 170.6. – MS (EI): m/z = 311
13C NMR (CDCl3): δ = 14.6, 38.9, 53.4, 60.9, 64.8, 116.3, [M]+. – MS (FAB): m/z = 312 [M+H]+. – HRMS (EI): m/z =
116.7, 126.5, 127.8, 130.2, 156.3, 164.2, 169.9. – Anal. for 311.1377 (calcd. 311.1369 for C15H21NO6, [M]+).
C20H23NO7: calcd. C 61.69, H 5.95, N 3.60; found C 61.62,
H 6.11, N 3.65. – MS (EI): m/z = 389 [M]+. – MS (FAB):
Diethyl 1-cyanomethyl-1H-pyrrole-3,4-dicarboxylate (4i)
m/z = 390 [M+H]+. – HRMS (EI): m/z = 389.1486 (calcd.
389.1475 for C20H23NO7, [M]+).
Compound 4i was prepared from 2 and aminoacetonitrile
hydrochloride (3i) (47 mg, 0.5 mmol). Procedure A, re-
flux for 1 h. Yield: 101 mg (80 %) of white crystals; m. p.
99 – 102 ◦C. – IR (KBr): ν = 3138, 2984, 2196, 1731,
1289 cm−1. – 1H NMR (CDCl3): δ = 1.34 (6H, t, J = 7.2 Hz,
Diethyl 1-[(S)-1,5-diethoxy-1,5-dioxopentan-2-yl]-1H-
pyrrole-3,4-dicarboxylate (4f)
Compound 4f was prepared from 2 and (S)-glutamic acid 2 × CH2CH3), 4.30 (4H, q, J = 7.2 Hz, CH2CH3), 4.84 (2H,
diethyl ester hydrochloride (3f) (122 mg, 0.5 mmol). Proce- s, CH2CN), 7.30 (2H, s, 2-H, 5-H). – Anal. for C12H14N2O4:
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◦
calcd. C 57.59, H 5.64, N 11.19; found C 57.87, H 5.90, Yield: 98 mg (64 %) of white crystals; m. p. 140 – 143 C. –
N 11.01.
IR (KBr): ν = 3340, 1720, 1695 cm−1. – 1H NMR (CDCl3):
δ = 1.27 (6H, t, J = 7.2 Hz, 2 × CH2CH3), 4.25 (4H, q, J =
7.2 Hz, CH2CH3), 7.21 – 7.68 (2H, m, 5ꢀ-H, 6ꢀ-H), 8.07 (1H,
dd, J = 2.2, 5.3 Hz, 4ꢀ-H), 8.15 (2H, s, 2-H, 5-H), 11.03 (1H,
br s, OH). – Anal. for C15H16N2O5: calcd. C 59.21, H 5.30,
N 9.21; found C 59.49, H 5.09, N 9.17.
2-(3,4-Bis(ethoxycarbonyl)-1H-pyrrol-1-yl)acetic acid (4j)
Compound 4j was prepared from 2 and glycine (3j)
(38 mg, 0.5 mmol). Procedure C, reflux for 1 h. Yield:
113 mg (84 %) of white crystals; m. p. 105 – 107 C. – IR
◦
(KBr): ν = 3135, 2983, 1723, 1544 cm−1. – 1H NMR
(CDCl3): δ = 1.32 (6H, 2t, J = 7.2 Hz, 2 × CH2CH3), 4.28
(4H, q, J = 7.2 Hz, 2 × CH2CH3), 4.62 (2H, s, CH2N),
5.95 (1H, br s, COOH), 7.26 (2H, s, 2-H, 5-H). – 13C NMR
(CDCl3): δ = 14.6, 51.1, 61.1, 116.8, 129.7, 164.8, 169.9. –
MS (EI): m/z = 269 [M]+. – HRMS (EI): m/z = 269.0909
(calcd. 269.0899 for C12H15NO6, [M]+).
Diethyl 1-(5-methylisoxazol-3-yl)-1H-pyrrole-3,4-
dicarboxylate (4n)
Compound 4n was prepared from 2 and 3-amino-5-
methylisoxazole (3n) (49 mg, 0.5 mmol). Procedure A, re-
flux for 5 h. Yield: 117 mg (80 %) of white crystals; m. p.
79 – 81 ◦C. – IR (KBr): ν = 3348, 1730, 1697, 1620 cm−1. –
1H NMR (CDCl3): δ = 1.35 (6H, t, J = 7.2 Hz, 2 × CH2
CH3), 2.50 (3H, s, 5ꢀ-Me), 4.35 (4H, q, J = 7.2 Hz, CH2
CH3), 7.28 (1H, s, 4ꢀ-H), 7.30 (2H, s, 2-H, 5-H). – Anal. for
C14H16N2O5: calcd. C 57.53, H 5.52, N 9.58; found C 57.90,
H 5.38, N 9.84.
Diethyl 1-phenyl-1H-pyrrole-3,4-dicarboxylate (4k)
Compound 4k was prepared from 2 and aniline (3k)
(47 mg, 0.5 mmol). Procedure A, reflux for 3 h. Yield:
◦
62 mg (42 %) of white crystals; m. p. 46 – 48 C, lit. [16]
m. p. 48 C. – IR (KBr): ν = 1721, 1689 cm−1. – H NMR
(CDCl3): δ = 1.34 (6H, t, J = 7.2 Hz, 2 × CH2CH3), 4.38
(4H, q, J = 7.2 Hz, CH2CH3), 7.40 (5H, s, Ph), 7.65 (2H, s,
2-H, 5-H).
◦
1
Diethyl 1-(1H-1,2,4-triazol-5-yl)-1H-pyrrole-3,4-
dicarboxylate (4o)
Compound 4o was prepared from 2 and 5-amino-1H-
1,2,4-triazole (3o) (42 mg, 0.5 mmol). Procedure A, reflux
for 1.5 h. Yield: 97 mg (70 %) of white crystals; m. p. 170 –
173 ◦C. – IR (KBr): ν = 2980, 1740 cm−1. – 1H NMR
(CDCl3): δ = 1.28 (6H, t, J = 7.2 Hz, 2 × CH2CH3),
4.22 (4H, q, J = 7.2 Hz, 2 × CH2CH3), 7.88 (2H, s, 2-H,
5-H), 8.68 (1H, s, 3-H), 14.35 (1H, br s, NH). – 13C NMR
(CDCl3): δ = 14.6, 61.1, 117.9, 126.2, 144.0, 157.0, 164.3. –
Diethyl 1-(4-methylpyridin-2-yl)-1H-pyrrole-3,4-
dicarboxylate (4l)
Compound 4l was prepared from 2 and 2-amino-3-hydr-
oxypyridine (3l) (47 mg, 0.5 mmol). Procedure B, reflux for
3 h, trituration with cyclohexane-diisopropyl ether. Yield:
20 mg (14 %) of white crystals; m. p. 86 – 88 ◦C. – IR (KBr):
ν = 1718, 1690 cm−1. – 1H NMR (CDCl3): δ = 1.38 (6H, t,
J = 7.2 Hz, 2 × CH2CH3), 2.48 (3H, s, 4ꢀ-Me), 4.40 (4H, q,
J = 7.2 Hz, CH2CH3), 7.15 (1H, dd, J = 3.2, 5.4 Hz, 5ꢀ-H),
7.80 (1H, d, J = 3.2 Hz, 3ꢀ-H), 8.05 (2H, s, 2-H, 5-H), 8.45
(1H, d, J = 5.4 Hz, 6ꢀ-H). – Anal. for C16H18N2O4: calcd.
C 63.56, H 6.00, N 9.27; found C 63.49, H 5.97, N 9.44.
1
Anal. for C12H14N2O4 · /4H2O: calcd. C 50.97, H 5.17,
N 19.81; found C 51.43, H 5.32, N 19.09. – MS (EI): m/z =
278 [M]+. – HRMS (EI): m/z = 278.1024 (calcd. 278.1016
for C12H14NO6, [M]+).
Acknowledgements
Financial support from the Slovenian Research Agency
through grants P0-0502-0103, P1-0179, and J1-6689-0103-
04 is gratefully acknowledged. We thank the pharma-
ceutical companies Krka d.d. (Novo mesto, Slovenia)
and Lek-Sandoz d.d. (Ljubljana, Slovenia for financial
support.
Diethyl 1-(3-hydroxypyridin-2-yl)-1H-pyrrole-3,4-
dicarboxylate (4m)
Compound 4m was prepared from 2 and 3m (55 mg,
0.5 mmol). Procedure B, reflux for 3 h, trituration with water.
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