Substituted pyrroles

Article abstract of DOI:10.3390/50100089

A stepwise synthesis of a-unsubstituted pyrroles with desired substituents in the β-positions of the ring has been devised.

Full text of DOI:10.3390/50100089

Molecules 2000, 5, 89-92
molecules
ISSN 1420-3049
http://www.mdpi.org
Substituted Pyrroles
N. Zh. Mamardashvili*, M. E. Kluyeva and O. A. Golubchicov
Institute of Solution Chemistry of the Russian Academy of Sciences, 153045 Academicheskaya, 1,
Ivanovo, Russia
E-mail: ngm@ihnr.polytech.ivanovo.su
* Author to whom correspondence should be addressed.
Received: 14 December 1999 / Accepted: 22 January 2000 / Published: 26 January 2000
Abstract: A stepwise synthesis of a -unsubstituted pyrroles with desired substituents in the
b-positions of the ring has been devised.
Keywords: pyrroles, b-substitued.
Introduction
Pyrrole synthesis depends strongly on the nature and relative position of the substituents in the
molecule. The methods permitting the synthesis of comparatively simple pyrroles are found to be use-
less for more complex structures. This paper describes the synthesis of a series of pyrrole derivatives
(1-5).
C2H5
CH3
R1
R2
N
H
Figure 1. R1 = CH3 (1, 6), COOC2H5 (2-5); R2 = COOCH2C6H5 (1, 2), COOH (3), I (4), H (5), COOC2H5 (6).
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Molecules 2000, 5
Relatively accessible a -ethoxycarbonylpyrroles are obtained by the condensation of the corre-
sponding alkylpentanediones with nitrosoacetoacetic ester in acetic acid with the reduction [1-8].
However a -unsubstituted pyrroles – the desired product of the synthesis - have a great disadvantage:
they contain large substituents in adjacent b-positions responsible for extra restrictions during conden-
sation. We now report a method that allows the synthesis of structures with these large substituents in
the desired positions while excluding the steric factor influence on pyrrole reactivity.
Results and Discussion
2,4-Dimethyl-3-ethyl-5-benzyloxycarbonylpyrrole (1) was prepared by reaction of 2,4-dimethyl-3-
ethyl-5-ethoxycarbonylpyrrole (6) with benzyl alcohol. 2-Ethoxycarbonyl-3-ethyl-4-methyl-5-
benzyloxycarbonylpyrrol (2) was prepared by oxidizing the a -methyl group of (1) with sulfuryl chlo-
ride and treatment with ethanol. Reduction of (2) with hydrogen over palladium catalyst yields 2-
ethoxycarbonyl-3-ethyl-4-methyl-5-carboxypyrrole (3). Decarboxylation was carried out in two stages.
At first the carboxy-group was substituted by iodine to form 2-ethoxycarbonyl-3-ethyl-4-methyl-5-
iodopyrrole (4) and then the iodine was removed with SnCl2. This sequence gives 2-ethoxycarbonyl-3-
ethyl-4-methylpyrrole (5) in adequate yield. (6) is the key compound in the synthesis of many di- and
tetra-pyrrole compounds of linear and cyclic structure.
To confirm the molecular structures the IR spectra of the synthesized pyrroles were investigated
(Table 1). Together with NMR data, in most cases they reliably prove the presence of the functional
groups in the molecules.
Experimental
General Methods and Materials
1H nuclear magnetic resonance spectra were recorded on a Bruker AC-500 spectrometer operating
at 600 MHz with HMDS as internal standard in deuterochloroform. IR spectra were obtained on a Spe-
cord M80 spectrophotometer in KBr tablets. 2,4-Dimethyl-3-ethyl-5-ethoxycarbonylpyrrole (6) was
synthesized by a known method [2].
2,4-Dimethyl-3-ethyl-5-benzyloxycarbonylpyrrole (1)
2,4-Dimethyl-3-ethyl-5-ethoxycarbonylpyrrole (6, 10 g) in benzyl alcohol (50 mL) were placed into
a flask equipped with a distilling column, Liebig condenser and dropping funnel. The solution was
heated to boiling temperature and then a solution of sodium (0.2 g) in benzyl alcohol (100 mL) was
added to the flask. After all the ethanol was distilled off the reaction mixture was cooled, diluted with
water (200 mL) and then acidified with acetic acid. The resulting precipitate was isolated by filtration
and recrystallized from ethanol. Yield 87%, melting point 166-1680C, NMR: 8.89 (s, 1H, NH), 7.34

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Molecules 2000, 5
(m, 5H, C6H5), 4.22 (m, 2H, OCH2Ph), 2.27 (q, 2H, CH2CH3), 2.21 (s, 3H, 2-CH3), 2.09 (s, 3H, 4-CH3),
0.84 (t, 3H, CH2CH3)
2-Ethoxycarbonyl-3-ethyl-4-methyl-5-benzyloxycarbonylpyrrole (2)
Freshly distilled sulfuryl chloride (8.9 mL) was added to a solution of 2,4-dimethyl-3-ethyl-5-
benzyloxycarbonylpyrrol (1, 9g) in dry ether (100 mL) while the reaction mixture temperature was
kept below 200C. The mixture was kept overnight at room temperature and then the ether was evapo-
rated. Ethanol (150 mL) was added to the residuum. After 1 hour the solution was diluted with water
(200 mL). The organic phase was extracted with ether and washed with water. The ether was evapo-
rated and the resulting product was recrystallized from ethanol. Yield 92%, melting point 51-530C,
NMR: 8.88 (s, 1H, NH), 7.36 (m, 5H, C6H5), 4.32 (m, 2H, OCH2Ph), 4.13 (q, 2H, OCH2CH3), 2.69 (q,
2H, CH2CH3), 2.24 (s, 3H, 4-CH3), 1.27 (t, 3H, OCH2CH3), 0.84 (t, 3H, CH2CH3).
2-Ethoxycarbonyl-3-ethyl-4-methyl-5-carboxypyrrole (3)
Hydrogen was passed through a stirred mixture of 2-ethoxycarbonyl-3-ethyl-4-methyl-5-
benzyloxycarbonylpyrrole (2, 10 g), activated 10% Pd/C (2g), tetrahydrofuran (200 mL) and trieth-
ylamine (2 mL) over 6 hours. Then the solution was evaporated down to 50-mL residual volume and
methanol (100 mL) was added. After evaporating the remaining tetrahydrofuran the methanol solution
was cooled. The resulting precipitate was isolated by filtration and washed with methanol, then ether
and hexane. Yield 96%, melting point 186-1880C, NMR: 9.38 (s, 1H, NH), 4.17 (q, 2H, OCH2CH3),
2.69 (q, 2H, CH2CH3), 2.24 (s, 3H, 4-CH3), 1.32 (t, 3H, OCH2CH3), 0.87 (t, 3H, CH2CH3).
2-Ethoxycarbonyl-3-ethyl-4-methyl-5-iodopyrrole (4)
A solution of sodium bicarbonate (4.5 g) in water (80 mL) was added dropwise to a stirred solution
of 2-ethoxycarbonyl-3-ethyl-4-methyl-5-carboxypyrrole (3, 5g) in ethanol (100 mL). Then the solution
was filtered and a solution of iodine (4.6 g) and KI (5.9 g) in water (50 mL) was added to the filtrate
with stirring at 600C. Stirring was continued for another 10 minutes and then the reaction mixture was
diluted with water (100 mL). The resulting precipitate was isolated by filtration. Yield 86%, melting
point 119-1200C, NMR: 8.90 (s, 1H, NH), 4.21 (q, 2H, OCH2CH3), 2.67 (q, 2H, CH2CH3), 1.90 (s, 3H,
4-CH3), 1.28 (t, 3H, OCH2CH3), 0.86 (t, 3H, CH2CH3).
2-Ethoxycarbonyl-3-ethyl-4-methylpyrrole (5)
Hydrochloric acid (100 mL) was added to a boiling solution of 2-ethoxycarbonyl-3-ethyl-4-methyl-
5-iodopyrrole (4, 5g), SnCl2 (8.5 g) and KI (0.8 g) in ethanol (350 mL). The organic phase was ex-
tracted with ether and washed with water. The ether was evaporated under vacuum at room tempera-

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Molecules 2000, 5
ture. Yield 87%, melting point 22-240C, NMR: 8.94 (s, 1H, NH), 4.20 (q, 2H, OCH2CH3), 2.68 (q, 2H,
CH2CH3), 1.94 (s, 3H, 4-CH3), 1.29 (t, 3H, OCH2CH3), 0.87 (t, 3H, CH2CH3)
Table 1. Infrared spectra of pyrroles (1-5), cm-1.
¹
g(NH)
g(CH)
d(CH)
g(CH)
C-C
1348,
1510
1360,
1530
1338,
1514
1328,
1517
1390,
1517
1357,
1578
C=O
1664
C-O
6
3456
-
1379
1022
1290
1
2
3
4
5
3450
3451
3450
3462
3450
3100,
3138
3100,
3140
-
1380
1380
1377
1384
1382
1010
1015
1090
1116
1000
1670
1690
1685
1687
1680
1280
1287
1273
1268
1295
-
3112
References and Notes
1. Jackson, A.H.; Kenner, G.W.; Wass J. J.Chem.Soc., Perkin Trans I 1972, 1475-1478.
2. Baldwin, J.E.; Crossley, M.J.; Klose I. Tetrahedron 1982, 38, 1475-1478.
3. Ogoshi, H.; Sugimoto, H.; Nishiguchi, E. J. Am. Chem. Soc. 1983, 105, 2699-2703.
4. Callot, H.J.; Tshamber, T. J. Org. Chem. 1977, 42, 1567-1570.
5. Iurgen, W.; Heinz, S.A. Tetrahedron Lett. 1985, 25, 6059-6062.
6. Wijesekera, T.P.; Paine, J.B.; Dolphin, D. J. Am. Chem. Soc. 1983, 105, 6449-6747.
7. Sessler, J.L.; Hugdaht, J.; Jonson, M.R. J. Org. Chem. 1986, 51, 2838-2840.
8. Sessler, J.L.; Jonson, M.R. Angew. Chem. 1987, 99, 679-680.
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© 2000 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.