A convenient new synthesis of 1,2-diarylpyrroles from 3-ethoxycarbonyl-4-oxo-4-phenylbutyraldehyde

Article abstract of DOI:10.3987/COM-05-10386

An efficient four-step synthesis of ethyl 1,2-diaryl-3-pyrrole carboxylates (4), an isomeric scaffold of pharmacologically active natural products, is reported. The key synthon 3-ethoxycarbonyl-4-oxo-4-phenylbutyraldehyde (3), whose new synthesis is detai

Full text of DOI:10.3987/COM-05-10386

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HETEROCYCLES, Vol. 65, No. 7, 2005, pp. 1673 - 1678
Received, 24th February, 2005, Accepted, 12th May, 2005, Published online, 13th May, 2005
A CONVENIENT NEW SYNTHESIS OF 1,2-DIARYLPYRROLES FROM
3-ETHOXYCARBONYL- 4-OXO-4-PHENYLBUTYRALDEHYDE
Aurélie Delayen, Laurence Goossens, Raymond Houssin, and Jean-Pierre
Hénichart*
Institut de Chimie Pharmaceutique Albert Lespagnol, Université de Lille 2, EA
2692, BP 83, 59006 Lille, France; E-mail: henicha@pharma.univ-lille2.fr
Abstract – An efficient four-step synthesis of ethyl 1,2-diaryl-3-pyrrole
carboxylates (4), an isomeric scaffold of pharmacologically active natural
products, is reported. The key synthon 3-ethoxycarbonyl-4-oxo-4-
phenylbutyraldehyde (3), whose new synthesis is detailed here, reacts
conveniently with anilines to create the pyrrole ring.
The isolation and synthesis of pyrrole-containing alkaloids remain a very active research area because of
their highly potent activity against various cancer cell lines.1 This is the case, for example, for lamellarin
O and lukianol A derivatives,2 or for ningalin B (Figure 1),3 a natural marine product which was found to
act as a multi-drug resistant reversal agent.4 All of these compounds possess a common 3,4-diaryl-
substituted pyrrole nucleus with a carboxylate on C 2. Several elegant syntheses have been reported for
this scaffold.2,3,5-9
OH
HO
OH
HO
OH
HO
HO
OH
O
O
O
N
N
N
OMe
O
O
O
OH
OMe
OH
OH
Lamellarin O
Lukianol A
Ningalin B
Figure 1

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HETEROCYCLES, Vol. 65, No. 7, 2005
In the field of our continuing search for new therapeutic agents potentially useful in cancer treatment, we
recently published the synthesis of new compounds containing the pyrrole scaffold.10-14 We report here a
flexible method to accede to the 1,2-diarylpyrrole structure bearing a carboxylate on C 3, an isomer of
the above cited heterocycles and an analogue of the diarylpyrazole-3-carboxylate, an efficient precursor
of COX-2/5-LOX inhibitors described as cell proliferation inhibitors of human prostate cancer cell
lines.15
The selected reaction sequence is shown in Scheme 1. To our knowledge, only one approach has been
described for the preparation of 3-ethoxycarbonyl-4-oxo-4-phenylbutyraldehyde (3), the inconvenient
ozonolysis of the corresponding alkene.16 We have developed a more versatile and efficient approach to
obtain this tricarbonyl aromatic molecule through
a
three-step synthesis. 3-Benzoyl-3-
ethoxycarbonylpropionic acid (1) was first obtained by alkylation of ethyl benzoylacetate with 2-
bromoacetic acid in the presence of sodium ethoxide, as previously described.17 The main problem was
to reduce the carboxylic acid function into formyl group - rather poorly described in publications - which
must here be chemoselective as regards the presence of carbonyl and ester groups. A few reagents such
as lithium in dimethylamine,18 thexylborane,19 isobutylmagnesium bromide/dichloro bis (η-
cyclopentadienyl)titanium20 and bis(4-methylpiperazinyl)aluminium hydride21 have been mentioned but
generally lack selectivity and are inconvenient to use.
O
O
COOH
a
b
COOEt
COOEt
COOEt
1
OH
O
O
CHO
c
COOEt
2
3
†Reagents and conditions: a) 1. BrCH2COOH, EtONa, EtOH, reflux, 15 h; 2. 3N HCl, 0°C, 15 min b) BH3•Me2S, THF, reflux,
-
+
1 h c) 1. K2CrO4, CH2Cl2, 30% H2SO4 , n-Bu4N HSO4 , 0°C, 15 min; 2. 10% FeSO4, rt, 10 min.
Scheme 1†
One-pot conversion with DIBALH22 seemed to be the most appropriate process, but here, surprisingly,
the reaction did not evolve. Using BH3•Me2S complex enabled us to selectively reduce the carboxylic

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function of compound (1) into a primary hydroxy group which, in turn, was immediately converted into
formyl function. This oxidation step was found effective with potassium chromate under phase-transfer
catalysis, at 0°C.23 Under these conditions the primary alcohol, insoluble in the aqueous phase, was
rapidly oxidized into aldehyde (15 min), without over-reaction into the corresponding carboxylic acid.
Although all the reactions can be scaled up to 5 g without any difficulty, aldehyde (3) is not stable
enough to be purified (chromatography or crystallization). Due to the formation of two unidentified side
products, the yield of the oxidation reaction cannot be determined; nevertheless the IR spectrum of 3 is
consistent with the formation of aldehyde as the major product: ν = 1764 cm-1 (formyl), 1729 cm-1 (ester)
and 1683 cm-1 (carbonyl), while disappearance of ν = 3490 cm-1 (hydroxy).
For these reasons, 3-ethoxycarbonyl-4-oxo-4-phenylbutyraldehyde (3) must be immediately reacted with
substituted anilines to give the expected pyrroles (4) in moderate yields (50% from alcohol (2)), via an
acetic acid-catalysed Paal-Knorr condensation (Scheme 2).
R
CHO
O
R
N
EtOH, CH3COOH
reflux, 3 h
+
COOEt
NH2
COOEt
3
4a R = H
4b R = SO2Me
Scheme 2
In conclusion, we have developed a new procedure for the preparation of ethyl 1,2-diaryl-3-pyrrole-
carboxylates, by condensing anilines with 3-ethoxycarbonyl-4-oxo-4-phenylbutyraldehyde (3). This
method offers several advantages including an easier experimental work-up procedure than previously
described,16 shorter reaction times and good yields. Apart from pyrrole, the 1,4-dicarbonyl electrophile
(3) represents a key intermediate for the synthesis of various and potentially active heterocycles
substituted by an ester, a flexible and reactive functional group.24-27
EXPERIMENTAL
General. THF was distilled from sodium/benzophenone prior to use. All other reagents and solvents
were obtained from commercial sources and used without further purification. Analytical TLC was
performed on precoated Kieselgel 60F254 plates (Merck); compounds were visualized by UV and/or with

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iodine. Silica gel Kieselgel Si 60 (230-400 mesh, Merck) was used for chromatography. Melting points
were determined with a Büchi 530 capillary melting point apparatus and remain uncorrected. The
structures of all compounds were supported by IR spectrum (FT-Bruker Vector 22 instrument) and, if
possible, by 1H NMR spectrum at 300 MHz on a Bruker DPX-300 spectrometer. Chemical shifts (δ) are
reported in ppm downfield from TMS, J values are in hertz. APCI+ mass spectra were obtained on a LC-
MS system Thermo Electron Surveyor MSQ. Elemental analyses were performed by the “Service Central
d’Analyses” at the CNRS, Vernaison, France.
3-Benzoyl-3-ethoxycarbonylpropionic acid (1) - Ethyl benzoylacetate (5.0 mL, 28.9 mmol) was added
dropwise to a stirred solution of EtONa (prepared from 2.0 g (86.9 mmol) of Na and 45 mL of EtOH).
After stirring for 30 min at rt, 2-bromoacetic acid (10.0 g, 71.0 mmol) was added. The mixture was
refluxed for 15 h. EtOH was then removed under reduced pressure and the viscous residue was diluted
with H2O (30 mL). After acidification to pH 1 with 3 N aqueous HCl, the product was extracted with
EtOAc (2 × 30 mL). The organic layer was dried (MgSO4) and the solvent was removed under vacuum
to give acid (1) as a yellow oil (5.7 g, 79%); IR (neat) 1736, 1712, 1687 cm-1; 1H NMR (CDCl3) 1.11 (t,
3H, J = 7.1), 3.05 (d, 1H, J = 7.0), 3.10 (d, 1H, J = 7.0), 4.10 (q, 2H, J = 7.1), 4.82 (t, 1H, J = 7.0), 7.46
(dd, 2H, J = J’ = 7.4), 7.55 (dd, 1H, J = J’ = 7.4), 8.00 (m, 2H).
Ethyl 2-benzoyl-4-hydroxybutanoate (2) - BH3•Me2S in THF (2 M, 15.0 mL, 30.0 mmol) was added to
a solution of acid (1) (5.0 g, 20.0 mmol) in 100 mL of THF and the mixture was stirred at reflux. After 1
h, the reaction mixture was cooled to rt, then 1 N aqueous HCl and H2O were added cautiously to quench
the reaction. The product was extracted with EtOAc (3 × 50 mL). The organic layer was washed
successively with 10% aqueous NaHCO3, brine and dried (MgSO4). The solvent was removed under
vacuum to give ester (2) as a yellow oil (4.4 g, 94%); IR (neat) 3490, 1734, 1684 cm-1; 1H NMR (CDCl3)
1.21 (t, 3H, J = 7.1), 3.13 (td, 2H, J = 9.8, J’ = 8.7), 4.14 (q, 2H, J = 7.1), 4.54 (t, 2H, J = 9.8), 4.83 (t,
1H, J = 8.8), 7.27-7.40 (m, 3H), 7.76 (m, 2H).
3-Ethoxycarbonyl-4-oxo-4-phenylbutyraldehyde (3) - A solution of K2CrO4 (2.8 g, 14.9 mmol) in
30% aqueous H2SO4 (30 mL) was added dropwise to a stirred solution of ester (2) (4.4 g, 18.6 mmol) and
-
n-Bu4N+HSO4 (0.6 g, 1.8 mmol) in 80 mL CH2Cl2, keeping the inner temperature between –5°C and
0°C. The mixture was stirred vigorously for 15 min, then 30 mL of an aqueous solution of 10% FeSO4
was added. After 10 min of additional stirring, the layers were separated. The organic layer was washed
successively with 10% aqueous K2CO3, brine and then dried (MgSO4). The solvent was removed under

HETEROCYCLES, Vol. 65, No. 7, 2005
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vacuum to give a reddish oil, which was immediately used in the next reaction. IR (neat) 1764, 1729,
1683 cm-1.
Ethyl 1,5-diphenyl-1H-pyrrole-2-carboxylate (4a) - A solution of crude aldehyde (3) (4.5 g), aniline
(2.1 mL, 22.9 mmol) and AcOH (0.2 mL) in 25 mL EtOH was refluxed for 3 h. The solvent was
removed under vacuum and the residue diluted with 40 mL of EtOAc. The organic layer was washed
successively with 1 N aqueous HCl, brine and then dried (MgSO4). The crude product was purified by
chromatography on silica gel using heptane/EtOAc (95/5 v/v) as eluent. Recrystallization from MeOH
1
gave pyrrole (4a) as white crystals (2.9 g, 54% from 2); mp 107-109°C; IR (neat) 1686 cm-1; H NMR
(CDCl3) 1.20 (t, 3H, J = 7.0), 4.19 (q, 2H, J = 7.0), 6.85 (d, 1H, J = 2.9), 6.90 (d, 1H, J = 2.9), 7.06 (m,
2H), 7.28 (m, 3H), 7.32 (m, 5H); MS m/z 292 (MH+). Anal. Calcd for C19H17NO2: C, 78.33; H, 5.88; N,
4.81. Found: C, 78.21; H, 5.80; N, 4.80.
Ethyl 5-(4-methanesulfonylphenyl)-1-phenyl-1H-pyrrole-2-carboxylate (4b) - Prepared from
aldehyde (3) (4.5 g, 19.1 mmol) and 4-methanesulfonylaniline (3.6 g, 21.1 mmol) in a similar way to that
described above for the preparation of pyrrole (4a). The crude product was purified by chromatography
on silica gel using heptane/EtOAc (8/2 v/v) as eluent. Solvent evaporation gave pyrrole (4b) as a yellow
oil (3.4 g, 49% from 2); IR (neat) 1735 cm-1; 1H NMR (CDCl3) 1.17 (t, 3H, J = 7.2), 3.03 (s, 3H), 4.15 (q,
2H, J = 7.2), 6.87 (d, 1H, J = 2.5), 6.91 (d, 1H, J = 2.5), 7.21-7.30 (m, 7H), 7.81 (d, 2H, J = 8.3); MS m/z
370 (MH+). Anal. Calcd for C20H19NO4S: C, 65.02; H, 5.18; N, 3.79. Found: C, 65.36; H, 5.20; N, 3.77.
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