Synthesis of 6-aryl- and 5-aroylcomanic acids from 5-aroyl-2-carbethoxy-4- pyrones via a deformylative rearrangement and ring-opening/ring-closure sequence

Article abstract of DOI:10.1016/j.tetlet.2013.11.066

The reaction of 1-aryl-2-(dimethylaminomethylene)butane-1,3-diones with diethyl oxalate in the presence of sodium hydride in THF gave ethyl 5-aroyl-4-oxo-4H-pyran-2-carboxylates, from which 4-oxo-6-aryl-4H-pyran-2- carboxylic acids (6-arylcomanic acids) w

Full text of DOI:10.1016/j.tetlet.2013.11.066

Accepted Manuscript
Synthesis of 6-aryl- and 5-aroylcomanic acids from 5-aroyl-2-carbethoxy-4-
pyrones via a deformylative rearrangement and ring-opening/ring-closure se-
quence
Dmitrii L. Obydennov, Gerd-Volker Röschenthaler, Vyacheslav Ya.
Sosnovskikh
PII:
S0040-4039(13)02013-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.11.066
TETL 43861
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 September 2013
28 October 2013
14 November 2013
Please cite this article as: Obydennov, D.L., Röschenthaler, G-V., Sosnovskikh, V.Y., Synthesis of 6-aryl- and 5-
aroylcomanic acids from 5-aroyl-2-carbethoxy-4-pyrones via a deformylative rearrangement and ring-opening/ring-
closure sequence, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.11.066
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Graphical abstract
________________________________________________________________________________
Synthesis of 6-aryl- and 5-aroylcomanic acids from 5-aroyl-2-carbethoxy-4-pyrones via a deformylative
rearrangement and ring-opening/ring-closure sequence
Dmitrii L. Obydennov∗, Gerd-Volker Röschenthaler, Vyacheslav Ya. Sosnovskikh
________________________________________________________________________________________________________________________
∗ Corresponding author. Fax: +7 343 261 59 78;
e-mail: dobydennov@mail.ru

Synthesis of 6-aryl- and 5-aroylcomanic acids from 5-aroyl-2-carbethoxy-4-
pyrones via a deformylative rearrangement and ring-opening/ring-closure
sequence
Dmitrii L. Obydennov a,*, Gerd-Volker Röschenthaler b, Vyacheslav Ya. Sosnovskikh a
dobydennov@mail.ru
a Department of Chemistry, Ural Federal University, prosp. Lenina 51, 620000 Ekaterinburg, Russia
b School of Engineering and Science, Jacobs University Bremen, Campus Ring 1, 28759 Bremen, Germany
A B S T R A C T
The reaction of 1-aryl-2-(dimethylaminomethylene)butane-1,3-diones with diethyl oxalate in the
presence of sodium hydride in THF gave ethyl 5-aroyl-4-oxo-4H-pyran-2-carboxylates, from which
4-oxo-6-aryl-4H-pyran-2-carboxylic acids (6-arylcomanic acids) were obtained in high yields via
acid-catalyzed deformylative rearrangement. 5-Aroyl-4-oxo-4H-pyran-2-carboxylic acids (5-
aroylcomanic acids) were prepared via а ring-opening/ring-closure sequence by the reaction of 5-
aroyl-2-carbethoxy-4-pyrones with piperidine and subsequent basic hydrolysis and acidification.
Keywords: Claisen condensation; 1-Aryl-2-(dimethylaminomethylene)butane-1,3-diones; Diethyl
oxalate; 5-Aroyl-2-carbethoxy-4-pyrones; Rearrangement; 6-Arylcomanic acids; Hydrolysis; 5-
Aroylcomanic acids.
It is known that certain derivatives of 4-oxo-6-phenyl-4H-pyran-2-carboxylic acid (6-
phenylcomanic acid) selectively inhibit cyclooxygenase-2 enzymes (COX-2) in preference to COX-
1, and are useful in the treatment of COX-2 mediated diseases, such as inflammation, pain, fever,
and asthma, with fewer side effects.1 At the same time, these compounds are an important class of
γ-pyrones which can serve as the starting materials for the syntheses of a broad range of important
heterocycles due to the presence of four electrophilic centers in their molecules (the C-2, C-4 and
C-6 atoms of the pyrone system and the carbonyl carbon of the 2-CO2R group).2 The diverse range
of properties of substituted γ-pyrones is due to the fact that, being highly reactive enones with a
good leaving group at the α- and α´-carbon atoms, whose role is played by the enolate anion, they
2

have the ability to undergo additional transformations related to γ-pyrone ring-opening and
heterocyclizations.3
Earlier, 6-phenylcomanic acid was obtained by cyclodehydrobromination of ethyl 5,6-dibromo-
2,4-dioxo-6-phenylhexanoate at reflux with KOAc in anhydrous ethanol with subsequent acid
hydrolysis of the ethyl 6-phenylcomanate thus formed,4 as well as by cyclodehydration of 6-phenyl-
2,4,6-trioxohexanoic acid, prepared from benzoylacetone and dimethyl oxalate, on heating in acetic
acid,5 and by condensation of 4-phenylbut-3-yn-2-one with diethyl oxalate in the presence of
NaOEt.6 The synthesis of 6-phenylcomanic acid derivatives with a substituent on the aromatic ring,
from the corresponding ethyl 6-aryl-5,6-dibromo-2,4-dioxohexanoates under the action of 1,5-
diazabicyclo[4.3.0]non-5-ene (DBN)7 and diisopropylamine,2c has also been described.
The present communication reports a novel synthesis of 6-arylcomanic acids 4 via acid-
catalyzed deformylative rearrangement of ethyl 5-aroyl-4-oxo-4H-pyran-2-carboxylates 3.
Additionally, the preparation of 5-aroyl-4-pyrone-2-carboxylic acids (5-aroylcomanic acids, 6) from
3 via a ring-opening/ring-closure sequence is presented. Although the chemistry of comanic acid
derivatives has been well documented,8 compounds 6 are hitherto unreported.
Within the framework of a research program on the synthetic opportunities offered by the γ-
pyrone system in the preparation of organic molecules of potential interest in biomedicinal
chemistry and materials science,9 we required large quantities of ethyl 5-aroyl-4-oxo-4H-pyran-2-
carboxylates 3. To the best of our knowledge, there has only been one report on the preparation of
these compounds via the reactions of 1-aryl-2-(dimethylaminomethylene)butane-1,3-diones 1 with
diethyl oxalate in the presence of sodium ethoxide in ethanol (no product yields were reported).10
This is the reason why pyrones 3 belong to a poorly explored class of polycarbonyl compounds, the
chemical properties of which have not been investigated.
We found that the Claisen condensation of enaminodiones 1 with diethyl oxalate in the presence
of sodium hydride in THF at reflux for eight hours was the method of choice for the preparation of
pyrones 3. After cooling, the reaction mixture was quenched with hydrochloric acid to give 5-aroyl-
3

2-carbethoxy-4-pyrones 3a–d in 73–82% yields. It turned out that if the hydrolysis of the sodium
salts 2 was carried out under milder conditions (4 M HCl, 0 °C, 30 min), the reaction could be
stopped at the pyrones 3, whereas reflux of 3 in dilute HCl (1:1) for eight hours gave 6-arylcomanic
1
acids 4a–d in 68–85% yields. In the H NMR spectra of 3, protons H-3 and H-6 appeared as
singlets at δ 7.23–7.25 and δ 8.13–8.20 (CDCl3), while H-3 and H-5 in 4 appeared as doublets with
J = 2.2 Hz at δ 6.98–7.16 and δ 6.84–6.90 (DMSO-d6), respectively.
A plausible pathway leading to the formation of acids 4 via intermediates A–D is outlined in
Scheme 1. It is clear from this reaction that the ester 3 reacts with water exclusively at its 6-position
and in a 1,4-manner, followed by deformylative rearrangement. This transformation represents an
alternative route to synthesize acids 4 and makes it possible to obtain these compounds from 1,3-
diketones in three steps in 25–60% overall yields. Previously, ethyl 5-chloro- and 5-hydroxy-6-
phenyl-4-oxo-4H-pyran-2-carboxylates were prepared from epoxypyrones using a similar
rearrangement in the presence of formic or perchloric acid.10a
4

Ar
Yield (%)
73
Pyrone 4 Yield (%)
Pyrone 3
68
Ph
3a
3b
3c
3d
4a
72
85
79
4-MeOC6H4
4-ClC6H4
2-C4H3S
69
82
73
4b
4c
4d
Scheme 1. Synthesis of 4-pyrones 3 and 4.
In connection with this simple rearrangement, the direct hydrolysis of 3 into 5-aroyl-4-pyrone-
2-carboxylic acids (5-aroylcomanic acids, 6) proved impossible, therefore an alternative method for
the preparation of compounds 6 was required. We envisaged that the reaction of 3 with piperidine
would produce the corresponding enaminotriones 5 bearing a carbethoxy group activated towards
nucleophilic attack. In fact, we found that pyrones 3 reacted readily with piperidine in ethanol at 0
°C for one hour to produce enamines 5 in 57–82% yields. This reaction involved attack of the NH
group at C-6 of 3 with concomitant opening of the pyrone ring to give compounds 5, which are
reactive polycarbonyl intermediates with an intramolecular hydrogen bond. The 1H NMR spectra of
5 displayed broad signals for the piperidine function as a result of its only slightly hindered rotation
and there was no evidence of two geometric isomers.11 Treatment of enamines 5 with dilute HCl led
to the starting pyrones 3, however, in line with our expectations, basic hydrolysis of 5 at 0 °C for 15
minutes in the presence of KOH followed by acidification with HCl successfully removed the
ethoxy group to give 5-aroylcomanic acids 6 in 61–89% yields12 as a result of a ring-opening/ring-
closure sequence (Scheme 2). Despite their rather simple structures, neither compounds 6 nor their
acyclic precursors 5 have previously been prepared. It is pertinent to note that the behavior of
compounds 5 closely resembles that already reported by us for 2,5-dicarbethoxy-4-pyrone, which
under the same conditions gives 5-carbethoxy-4-pyrone-2-carboxylic acid.13 Thus, γ-pyrones 3, due
to activation of the conjugated system by two electron-withdrawing groups, are highly electrophilic
substrates, which are able to react with O- and N-nucleophiles, with opening of the pyrone ring.
5

H
O
O
O
O
N
O
NH
HCl
Ar
Ar
CO2Et
O
CO2Et
3a-d
5a-d
O
O
O
O
OH
CO2Et
1) KOH
2) HCl
Ar
Ar
O
CO2H
N
6a-d
Ar
Ph
Yield (%)
82
Pyrone 6 Yield (%)
Aminoenone 5
5a
6a
6b
6c
6d
69
61
89
80
4-MeOC6H4 5b
79
57
66
4-ClC6H4
2-C4H3S
5c
5d
Scheme 2. Synthesis of compounds 5 and 6.
In summary, we have developed a novel synthesis of biologically potent 6-arylcomanic acids,
which involves the deformylative rearrangement of 5-aroyl-2-carbethoxy-4-pyrones in the presence
of hydrochloric acid. Compared with the previously reported procedures, our method shows several
advantages, the main of which are simplicity, efficiency and the ready availability of the starting
materials. In addition, 5-aroylcomanic acids were obtained in good yields, for the first time. Taking
into account the ability to transform the γ-pyrone system into other compounds, the comanic acid
derivatives described here are valuable building blocks for the construction of various heterocyclic
systems.
Acknowledgment
This work was carried out under the terms of the Ural Federal University development program
with financial support for young scientists. The authors also thank Deutsche
Forschungsgemeinschaft for financial support (grant No. RO 362/45-1).
References and notes
6

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7

12. General procedure for the synthesis of compounds 3a–d. A mixture of enaminodione 1 (5.0 mmol),
diethyl oxalate (0.88 g, 6.0 mmol) and NaH (60% dispersion in oil, 0.24 g, 6.0 mmol) in THF (15 mL)
was refluxed for 8 h. After cooling, the reaction mixture was treated with 4 M HCl until pH = 1, stirred
at 0 °C for 30 min, extracted with EtOAc (3 × 15 mL), and evaporated under reduced pressure. The
resulting residue was quenched with EtOH to give pyrones 3 as colorless or yellowish crystals.
General procedure for the synthesis of compounds 4a–d. A suspension of the pyrone 3 (1.0 mmol) in
dilute HCl (1:1, 2 mL) was stirred at 100 °C for 8 h. The solid that formed was filtered and dried to give
pyrones 4 as a white or grey powders.
Ethyl 4-oxo-5-(2-thienoyl)-4H-pyran-2-carboxylate (3d). Yield 73%, mp 97–98 °С, colorless crystals. IR
(ATR): 3087, 2983, 2923, 2853, 1728, 1655, 1641, 1621, 1578 cm–1; 1Н NMR (400 MHz, CDCl3) δ 1.42
(t, J = 7.1 Hz, 3H, Me), 4.45 (q, J = 7.1 Hz, 2H, CH2O), 7.14 (dd, J = 4.9, 3.9 Hz, 1H, H-4'), 7.24 (s, 1Н,
H-3), 7.67 (dd, J = 3.9, 1.1 Hz, 1H, H-3'), 7.75 (dd, J = 4.9, 1.1 Hz, 1H, H-5'), 8.18 (s, 1Н, H-6); 13С
NMR (100 MHz, DMSO-d6): δ 14.3, 63.3, 120.2, 129.5, 129.7, 137.4, 137.6, 143.5, 153.3, 157.7, 159.7,
175.6, 182.5. Anal. Calcd for C13H10O5S: C, 56.11; H, 3.62. Found: С, 56.02; Н, 3.53.
4-Oxo-6-(2-thienyl)-4H-pyran-2-carboxylic acid (4d). Yield 79%, grey powder, mp 252–253 °С. IR
(ATR): 3108, 3085, 1730, 1623, 1594, 1573 cm–1; 1Н NMR (400 MHz, DMSO-d6) δ 6.84 (d, J = 2.3 Hz,
1H, H-5), 6.98 (d, J = 2.3 Hz, 1H, H-3), 7.27 (dd, J = 5.0, 3.9 Hz, 1H, H-4'), 7.93 (dd, 1Н, J = 3.9, 1.1
Hz, H-3'), 7.95 (dd, 1Н, J = 5.0, 1.1 Hz, H-5'), 12.0–15.5 (br s, 1H, OH); 13С NMR (100 MHz, DMSO-
d6): δ 110.6, 118.4, 129.4, 129.9, 132.4, 133.7, 153.2, 159.5, 161.3, 178.8. Anal. Calcd for C10H6O4S: C,
54.05; H, 2.72. Found: С, 54.03; Н, 2.75.
Ethyl 2-hydroxy-4-oxo-6-(piperidin-1-yl)-5-(2-thienoyl)hexa-2,5-dienoate (5d). Yield 66%, yellow
1
powder, mp 125–126 °С. IR (ATR): 3131, 3069, 2998, 2984, 2951, 1725, 1604, 1586 cm–1; Н NMR
(400 MHz, DMSO-d6) δ 1.22 (t, J = 7.1 Hz, 3H, Me), 1.35–1.70 (br s, 6H, 3CH2), 2.9–3.8 (br s, 4H,
(CH2)2N), 4.19 (q, J = 7.1 Hz, 2H, СH2O), 6.29 (s, 1H, =СH), 7.21 (dd, J = 4.9, 3.9 Hz, 1Н, H-4'), 7.65
(dd, J = 3.9, 1.2 Hz, 1Н, H-3'), 8.03 (dd, J = 4.9, 1.2 Hz, 1H, H-5'), 8.06 (s, 1H, =CHN), 15.0–16.5 (br s,
1 H, OH); 13С NMR (100 MHz, DMSO-d6): δ 14.4, 22.8, 22.9, 44.3, 61.9, 100.0, 107.0, 129.3, 134.6,
136.2, 146.4, 154.7, 161.9, 163.0, 187.6, 188.6. Anal. Calcd for C18H21NO5S: C, 59.49; H, 5.82; N, 3.85.
Found: С, 59.45; Н, 5.72, N, 3.72.
4-Oxo-5-(2-thienoyl)-4H-pyran-2-carboxylic acid (6d). Yield 80%, yellowish powder, mp 218–220 °С.
1
IR (ATR): 3452, 3097, 1727, 1651, 1627 cm–1; Н NMR (400 MHz, DMSO-d6) δ 1Н NMR (400 MHz,
DMSO-d6) δ 7.02 (s, 1H, H-3), 7.26 (dd, J = 4.8, 4.0 Hz, 1Н, H-4'), 7.83 (dd, J = 4.0, 1.2 Hz, 1H, H-3'),
8.15 (dd, J = 4.8, 1.2 Hz, 1H, H-5'), 8.71 (s, 1H, H-6) (the OH proton was not observed due to
broadening); 13С NMR (100 MHz, DMSO-d6): δ 119.9, 129.5, 129.6, 137.4, 137.5, 143.5, 154.4, 157.8,
161.1, 175.9, 182.7. Anal. Calcd for C11H6O5S·H2O: С, 49.25; Н, 3.01. Found: С, 49.51; Н, 2.98.
13. Obydennov, D. L.; Röschenthaler, G.-V.; Sosnovskikh, V. Y. Tetrahedron Lett. 2013, 54, 6545.
8