Synthesis of ethyl pyrrole-2-carboxylates: A regioselective cyclization of enaminones under knorr-type conditions

Article abstract of DOI:10.1081/SCC-120002701

A regioselective formation of ethyl pyrrole-2-carboxylates 4 and 5 is effected by reductive condensation of enaminones 1a-f and ethyl 2-oximinoacetoacetate 2. The structures of the products have been delineated by spectroscopic methods.

Full text of DOI:10.1081/SCC-120002701

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SYNTHESIS OF ETHYL PYRROLE-2-CARBOXYLATES: A
REGIOSELECTIVE CYCLIZATION OF ENAMINONES UNDER
KNORR-TYPE CONDITIONS
Ibrahim Elghamry a
a Division of Organic Chemistry, FB6, Gerhard-Mercator-University Duisburg, Duisburg,
D-47048, Germany
Version of record first published: 16 Aug 2006.
To cite this article: Ibrahim Elghamry (2002): SYNTHESIS OF ETHYL PYRROLE-2-CARBOXYLATES: A REGIOSELECTIVE
CYCLIZATION OF ENAMINONES UNDER KNORR-TYPE CONDITIONS, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 32:6, 897-902
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SYNTHETIC COMMUNICATIONS, 32(6), 897–902 (2002)
SYNTHESIS OF ETHYL PYRROLE-2-
CARBOXYLATES: A REGIOSELECTIVE
CYCLIZATION OF ENAMINONES
UNDER KNORR-TYPE CONDITIONS
IbrahimElghamry
Division of Organic Chemistry, FB6,
Gerhard-Mercator-University Duisburg,
D-47048 Duisburg, Germany
ABSTRACT
A regioselective formation of ethyl pyrrole-2-carboxylates 4
and 5 is effected by reductive condensation of enaminones
1a–f and ethyl 2-oximinoacetoacetate 2. The structures of
the products have been delineated by spectroscopic methods.
Ethyl pyrrole-2-carboxylates are versatile precursors for the total syn-
thesis of synthetic model and naturally occurring tetrapyrroles, porphyrins
and bilirubins.1 The Knorr pyrrole synthesis is one of the most widely used
reactions for the preparation of pyrrole-2-carboxylates. In its initial form,
it involved reductive condensation of 2-oximinoacetoacetate with 1,3-dioxo
compounds in the presence of Zn/AcOH and NaOAc.2,3 Though enami-
nones are useful starting materials in the synthesis of many heterocyclic
compounds,4,5 pyrrole syntheses rarely make use of them, despite the fact
that enaminones as building blocks offer a great variation in the substitution
pattern of the pyrrole ring.6–10
897
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

898
ELGHAMRY
For synthesis of pyrrole-2-carboxylates with an alkyl substituent at
position 3 and an oxoaryl or aryl substituent at position 4, we used enami-
nones 1a-f and ethyl 2-oximino acetoacetate 2 as synthons. As is customary
for Knorr-type pyrrole synthesis, zinc dust was the reducing agent and acetic
acid was the solvent.
Enaminones 1a–f reacted with 2-aminoacetoacetate (generated in situ
from 2 under Zn-Knorr conditions) via dimethylamine elimination to pro-
duce enaminones 3, which cyclize in a regioselective manner. When R1 ¼ H
(enaminones 1a-c), the a-carbon of the enamininone adds to the acyl group
of the acetoacetate and subsequent elimination of water gives pyrrole-2-
carboxylates 4a–c as final products in 30–35% yield.11 (Route A, Scheme 1).
We had initially expected that the products would be the pyrrole-2-
carboxylates 6 which are the products of water elimination and deacylation
of intermediate 3, as similar intramolecular cyclization has been reported
with analogous intermediates upon treatment with NaOEt in EtOH.8,12,13
However mass spectra, microanalysis data, IR and 1H/13C NMR were
instead consistent with pyrrole-2-carboxylates of Structure 4.
When R1 was an electron-withdrawing substituent (as in enaminones
1d–f) the mechanism for the formation of pyrroles 5 is analogous to the
reaction of 1,3-diketo compounds with 2 under similar reaction conditions15
(Route B, Scheme 1). It involves cyclization and aromatization via dehydra-
tion and deacylation (acyl removal is preferred to an alkoxycarbonyl
group)14,15 to afford pyrroles 5a–c in 52–60% yield. Interestingly, com-
pound 4a was obtained via both pathways, starting from two different
enaminones, from 1a via route A (30% yield) or from 1d via route B
(55% yield).
1
It is worth mentioning that the H NMR spectra of all the prepared
pyrroles showed a singlet at 2.43–2.75 ppm and a doublet at 7.12–7.32 ppm
(J ffi 3 Hz) (4a,b and 5b,c) as typical values8,14 for 3-Me and H-5 in the
pyrrole ring respectively.
In conclusion, in this short communication a one pot regioselective
synthesis for pyrrole-2-carboxylates 4 and 5 using enaminones has been
demonstrated. The use of 4-oxoarylpyrrole-2-carboxylates (type 4a,b) as syn-
thons for the total synthesis of linearly ꢀ-extended porphyrins is in progress.
The NMR spectra were recorded on Bruker 300 or 500 MHz spectro-
meters using TMS as internal standard and the deuterated solvent as
lock. J Values are given in Hz. IR spectra were obtained by using a
Perkin-Elmer 983 spectrophotometer. Electron impact ionization mass
spectrometry (EIMS) was performed on a Varian AMD 604 instrument
using 70eV ionization energy. Melting points (mp) are uncorrected. Enami-
nones 1a,b,d–f were prepared by reaction of dimethylformamide dimethyl
acetal (DMFDMA) with alkyl ketones. 1c was prepared following the

ETHYL PYRROLE-2-CARBOXYLATES
899
Scheme 1.
literature procedure16 from 1,3-cyclohexanedione and dimethylamine.
Ethyl 2-oximinoacetoacetate was prepared as described.17 All chromato-
graphic separations were performed by column chromatography with
ethyl acetate/n-hexane (1 : 1) as an eluent.

900
ELGHAMRY
Ethyl Pyrrole-2-carboxylates (4) and (5)
General procedure: a mixture of enaminone 1 (0.1 mol), ethyl 2-oximi-
noacetoacetate 2 (0.1 mol) and sodium acetate (0.3 mol) in glacial acetic acid
(200 ml) was heated to 90ꢀC, then Zn dust (16.3 g, 250mg-atom) was added
in small portions such that the pot temperature of the reaction can be
controlled between 95 and 105ꢀC by air cooling. Then the reaction mixture
was heated at reflux for 3 h. The resulting hot mixture was decanted from
the zinc sludge, before zinc acetate crystallized, into ice-water mixture. The
resulting precipitate was collected by filtration, washed several times with
water air dried and chromatographed on silica gel.
Ethyl 4-Benzoyl-3-methylpyrrole-2-carboxylate (4a 5 5a)
Colorless crystals (from n-hexane), yield: 30% from 1a via route A;
50% from 1d via route B; mp 128–129ꢀC (lit.18 127ꢀC). IR (KBr): n ¼ 3300
1
(NH), 1710(CO), 1668 (ester) cm À1. H NMR (CDCl3): d ¼ 1.39 (t, 3H,
J ¼ 7.13), 2.64 (s, 3H), 4.38 (q, 2H, J ¼ 7.13), 7.19 (d, 1H, J ¼ 3.43), 7.42
(m, 3H), 7.75 (m, 2H), 9.47 (s, 1H). 13C NMR (CDCl3): d ¼ 11.61, 14.53,
60.71, 121.60, 124.74, 128.29, 128.56, 128.81, 129.03, 130.12, 131.70, 140.24,
161.73, 191.91. MS: m/z (%) ¼ 258 (Mþ þ 1, 13.23), 257 (Mþ 75.43), 240
(2.62), 228 (10.82), 210 (100), 182 (17.34), 154 (8.44), 134 (56.42), 105
(55.65). Anal. calcd for C15H15NO3 (257.29): C, 70.02; H, 5.88; N, 5.44.
Found: C, 69.88; H, 5.76; N, 5.23.
Ethyl 4-[4-Bromo-1-naphthoyl]-3-methylpyrrole-2-carboxylate (4b)
Colorless solid (from n-hexane/benzene 2 : 1), (starting material 1b),
yield: 33%; mp 130–131ꢀC. IR (KBr): n ¼ 3310(NH), 1690(CO), 1640
1
(ester) cmÀ1. H NMR (CDCl3): d ¼ 1.41 (t, 3H, J ¼ 7.10), 2.75 (s, 3H),
4.32 (q, 2H, J ¼ 7.10), 7.12 (d, 1H, J ¼ 3.33), 7.81 (m, 4H), 8.18 (m, 2H),
8.95 (s, 1H). 13C NMR (CDCl3): d ¼ 11.52, 14.63, 60.83, 119.52, 122.12,
128.22, 128.51, 129.14, 129.29, 129.54, 129.69, 129.95, 130.34, 130.63,
130.82, 140.11, 140.34, 162.14, 199.29. MS: m/z(%) ¼ 388 (Mþ þ 1, 0.15),
387 (Mþ, 0.10), 345 (59.01), 297 (60.32), 265 (47.43), 235 (8.24), 219 (49.11),
190 (100), 163 (27.23). Anal. calcd for C19H16NO3Br(387.25): C, 58.93; H,
4.16; N, 3.62. Found: C, 58.72; H, 4.03; N, 3.41.

ETHYL PYRROLE-2-CARBOXYLATES
901
Ethyl 3-Methyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-
2-carboxylate (4c)
Colorless solid (from ethanol), (starting material 1c), yield: 35%; mp
165–166ꢀC (lit.19,20 165–167ꢀC). IR (KBr): n ¼ 3165 (NH), 1690(CO), 1640
(ester) cmÀ1. 1H NMR (CDCl3): d ¼ 1.41 (t, 3H, J ¼ 7.10), 2.15 (m, 2H), 2.49
(m, 2H), 2.61 (s, 3H), 2.85 (m, 2H), 4.35 (q, 2H, J ¼ 7.10), 9.65 (s, 1H).
13C NMR (CDCl3): d ¼ 11.56, 14.43, 23.06, 23.39, 38.91, 60.55, 119.64,
120.36, 128.54, 145.46, 162.31, 195.43.
Ethyl 3-Methyl-4-phenylpyrrole-2-carboxylate (5b)
Colorless solid (from n-hexane); (starting material 1e) yield 60%;
À1
mp 92–93ꢀC (lit.10 94ꢀC). IR (KBr): n ¼ 3310(NH), 1645 (ester) cm
.
1H NMR (CDCl3): d ¼ 1.33 (t, 3H, J ¼ 7.1), 2.51 (s, 3H), 4.35 (q, 2H,
J ¼ 7.10), 7.15 (d, 1H, J ¼ 3.19), 7.51 (m, 5H), 9.14 (s, 1H). 13C NMR
(CDCl3): d ¼ 11.51, 14.53, 60.62, 119.72, 120.44, 121.34, 125.7, 126.84,
127.94, 128.33, 128.76, 130.12, 135.32, 160.43.
Ethyl 4-Acetyl-3-methylpyrrole-2-carboxylate (5c)
Colorless solid (from n-hexane); (starting material 1f), yield: 52%;
mp 91–92ꢀC (lit.10 94ꢀC). IR (KBr): n ¼ 3210(NH), 1685 (CO), 1639
1
(ester) cmÀ1. H NMR (CDCl3): d ¼ 1.41 (t, 3H, J ¼ 7.10), 2.43 (s, 3H),
2.53 (s, 3H), 4.35 (q, 2H, J ¼ 7.10), 7.32 (d, 1H, J ¼ 3.23), 9.55 (s, 1H).
13C NMR (CDCl3): d ¼ 11.43, 14.42, 28.45, 60.51, 121.92, 127.28, 127.72,
128.54, 160.53, 192.14.
ACKNOWLEDGMENT
The author is deeply indebted to Alexander von Humboldt
Foundation for award of a research fellowship at Duisburg University
(Germany).
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Received in the Netherlands April 6, 2001