Preparative synthesis of ethyl 5-acyl-4-pyrone-2-carboxylates and 6-aryl-, 6-alkyl-, and 5-acylcomanic acids on their basis

Article abstract of DOI:10.1007/s11172-016-1574-x

A simple and efficient method for the synthesis of ethyl 5-alkanoyl- and 5-aroyl-4-pyrone-2-carboxylates was developed, which is based on the condensation of 1-R-2-(dimethyl-aminomethylidene)butane-1,3-diones, obtained from 1,3-diketones and dimethylforma

Full text of DOI:10.1007/s11172-016-1574-x

Russian Chemical Bulletin, International Edition, Vol. 65, No.9, pp. 2233—2242, September, 2016
2233
Preparative synthesis of ethyl 5ꢀacylꢀ4ꢀpyroneꢀ2ꢀcarboxylates
and 6ꢀarylꢀ, 6ꢀalkylꢀ, and 5ꢀacylcomanic acids on their basis*
D. L. Obydennov, A. O. Goncharov, and V. Ya. Sosnovskikh
Institute of Natural Sciences of the Ural Federal University named after the first President of Russia B. N. Yeltsin,
51 prosp. Lenina, 620000 Ekaterinburg, Russian Federation.
Eꢀmail: dmitry.obydennov@urfu.ru
A simple and efficient method for the synthesis of ethyl 5ꢀalkanoylꢀ and 5ꢀaroylꢀ4ꢀpyroneꢀ
2ꢀcarboxylates was developed, which is based on the condensation of 1ꢀRꢀ2ꢀ(dimethylꢀ
aminomethylidene)butaneꢀ1,3ꢀdiones, obtained from 1,3ꢀdiketones and dimethylformamide
dimethyl acetal, with diethyl oxalate in the presence of NaH in THF. Ethyl 5ꢀacylꢀ4ꢀpyroneꢀ2ꢀ
carboxylates were used in the synthesis of 6ꢀRꢀ and 5ꢀRCOꢀcomanic acids.
Key words: Claisen condensation, dimethylformamide dimethyl acetal, 1,3ꢀdiketones,
enaminodiones, ethyl 5ꢀacylcomanoates, comanic acids.
4ꢀPyrones are an important class of oxygenꢀcontainꢀ
ing heterocyclic compounds, which simultaneously are
masked polycarbonyl systems and cyclic enones. The
structural specific features of 4ꢀpyrones determine their
large synthetic potential, due to which they are widely
used as building blocks for the preparation of pharmaceuꢀ
tical agents1 and materials for electronics.2
3ꢀAcylꢀ4ꢀpyrone derivatives in their reactivity, prevaꢀ
lence in the nature, and useful properties take a special
place among numerous representatives of γꢀpyrones. They
include such natural compounds, as funicone,3 rapicone,3
carbonarone A,4 and pestalamide A4. Many funicones,
3ꢀaroylꢀ4ꢀpyrone derivatives, manifest antifungal, anticanꢀ
cer, and antiꢀHIV activity.3 Apart from that, 3ꢀhydroxyꢀ
4ꢀpyroneꢀ2,5ꢀdicarboxylic acid derivatives are used for the
preparation of dolutegravir, which is a second generation
inhibitor of HIV integrase.5—7
However, despite the importance of 3ꢀacylꢀ4ꢀpyrones,
the scope of methods for the synthesis of these compounds
remains very limited, apparently, due to their high chemiꢀ
cal activity related to the electron density deficiency on
the atom C(2). It is obvious that the introduction of ester
or acyl substituent into 4ꢀpyroneꢀ2ꢀcarboxylic acid (coꢀ
manic acid, 1) should even further increase the heterocyꢀ
cle electrophilicity and develop additional difficulties in
the preparation of isochelidonic 2 and 5ꢀacylcomanic acid
esters 3, which are prone to ready γꢀpyrone ring opening.
5ꢀCarbalkoxyꢀ and 5ꢀacylꢀ4ꢀpyroneꢀ2ꢀcarboxylic acꢀ
ids 2 and 3 contain five carbonyl groups, two of which are
opening upon treatment with water molecule. There are
only several literature examples of the synthesis of esters 2
and 3 via acylation of enaminodiones formed by the reacꢀ
tion of 1,3ꢀdicarbonyl compounds with dimethylformꢀ
amide dimethyl acetal (DMF DMA).5—9 Isochelidonic
in the masked state and appear only after the pyrone ring
* Based on the materials of the International Congress on the
Heterocyclic Chemistry "KOSTꢀ2015" (October 17—23, 2015,
Moscow, Russia).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 2233—2242, September, 2016.
1066ꢀ5285/16/6509ꢀ2233 © 2016 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 65, No. 9, September, 2016
Obydennov et al.
Scheme 1
Reagents and conditions: i. C6H6, ~20 °C (24 h), reflux (1 h); ii. THF, (CO2Et)2, NaH; iii. HCl, 0 °C.
esters 2 have been obtained earlier5—7 from enaminodiꢀ
ones with ethyloxalyl chloride in THF in the presence of
lithium hexamethyldisilazane at –78 °C, whereas 5ꢀacylꢀ
4ꢀpyroneꢀ2ꢀcarboxylic esters 3 were obtained by the conꢀ
densation of enaminodiones with diethyl oxalate in the
presence of EtONa upon heating in ethanol.8,9 However,
despite synthetic significance of the last mentioned comꢀ
pounds, no detailed procedures for their preparation are
available, whereas all our attempts to reproduce the synꢀ
thesis of 5ꢀacylcomanic esters 3, the yields for which were
not reported,8,9 did not lead to the desirable results.
that in the last large review devoted to the synthesis and
chemical properties of 1,3ꢀdiketones, the information on
the reaction of 1ꢀRꢀbutaneꢀ1,3ꢀdiones 4 with DMF DMA
is completely absent.16 We found that the stirring of dikeꢀ
tones 4a—i with DMF DMA (1.3 equiv.) in anhydrous
benzene for 24 h at room temperature with subsequent
reflux of the reaction mixture for 1 h are the optimal conꢀ
ditions for their enamination. In this case, 1ꢀRꢀ2ꢀ(diꢀ
methylaminomethylidene)butaneꢀ1,3ꢀdiones 5a—i were
obtained as yellow or orange powders in from 59 to 88%
yields (Scheme 1, Table 1).
The present work deals with the search for simple and
reliable method for the synthesis of ethyl 5ꢀacylcomanoates
in order to obtain these compounds on a multiꢀgram scale,
avoiding chromatographic isolation and purification of the
final products (for preliminary communication, see Ref. 10).
We report the full data on ethyl 5ꢀalkanoylꢀ and 5ꢀaroylꢀ
4ꢀpyroneꢀ2ꢀcarboxylates obtained by a new procedure via
the condensation of the corresponding enaminodiones with
diethyl oxalate in the presence of NaH in THF. The hyꢀ
drolysis of these esters gave 6ꢀaryl(alkyl)ꢀ and 5ꢀacylcoꢀ
manic acids, depending on the reaction conditions.
The reaction gives high yields of the products with
both aromatic and aliphatic substituents, whereas the lowꢀ
est yield (59%) was observed for compound 5e with the
electronꢀwithdrawing pꢀnitrophenyl substituent. Since we
failed to obtain corresponding enaminodiones from 1ꢀtriꢀ
fluoromethylꢀ and 1ꢀ(pyridꢀ2ꢀyl)butaneꢀ1,3ꢀdiones under
the indicated above conditions (the formation of a comꢀ
plex mixture of products or resinification was always obꢀ
served), a conclusion can be drawn on the unfavorable
influence of the electronꢀwithdrawing substituents in 1,3ꢀdiꢀ
ketones 4 on the course of their reaction with DMF DMA.
It is interesting that the bulky tertꢀbutyl group not only
does not hinder this reaction, but, vice versa, promotes the
formation of pivaloyl enamine 5h in the highest yield
(88%). In the 1H NMR spectra of products 5a—g, the
methyl groups of the Me2N fragment are observed in the
Results and Discussion
In continuation of our studies in the area of substituted
comanic acids,11—14 we attempted to synthesize little
known, but very promising for synthetic purposes ethyl
5ꢀacylcomanoates. First of all, it was necessary to study in
greater details than so far8,9 the reaction of 1,3ꢀdiketones
4 with DMF DMA, that would provide us with a wide
spectrum of starting enaminodiones 5. Then, we had to
develop a new procedure for carrying out the condensaꢀ
tion at the acetyl group of enamines 5 with diethyl oxꢀ
alate, which would give us a possibility of obtaining ethyl
5ꢀacylcomanoates 7 in good yields and make these useful
building blocks available for preparative purposes.
It is known that 1ꢀRꢀbutaneꢀ1,3ꢀdiones 4 react with
DMF DMA at the methylene group with the formation of
pushꢀpull enaminodiones 5. Despite the fact that these
enamines are widely used in the synthesis of various heteroꢀ
cycles,15 they have been obtained only based on diketones
4a—c,i and described without indication of yields for the
products 5b,c (see Ref. 9). Note also the illustrative fact
Table 1. Yields of products 5 and 7
Diketone
R
Enamine Yield of 5 Pyrone Yielda of 7
4
5
(%)
7
(%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
Ph
4ꢀClC6H4
5a
5b
5c
5d
5e
5f
5g
5h
5i
64
80
86
76
59
68
77
88
87
7a
7b
7c
7d
7e
7f
7g
7h
7i
73
82
69
78
42b
68
73
53b
31b
4ꢀMeOC6H4
4ꢀMeC6H4
4ꢀNO2C6H4
2ꢀC10H7
2ꢀC4H3S
But
Me
a Salt 6 was treated with dilute HCl (1 : 2).
b The condensation was carried out at ~20 °C for 5 days.

Ethyl 5ꢀacylꢀ4ꢀpyroneꢀ2ꢀcarboxylates
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 9, September, 2016 2235
Scheme 2
region of δ 2.3—3.6 as strongly broadened signals because
of the hindered rotation of the amino group around the
double bond.17 In enaminodione 5h, the Me2N group was
found as a sharp singlet at δ 2.91 (6 H), which, most likely,
is related to the stabilization of the Eꢀisomeric form by the
tertꢀbutyl substituent.
As it was noted above, the known methods8,9 for acylaꢀ
tion of the methyl group in enaminodiones 5 with diethyl
oxalate gave low yields of ethyl 5ꢀacylcomanoates 7 and
required chromatographic isolation of the products. In
this connection, we carried out a thorough search for the
condensation system, which would allow us to eliminate
these disadvantages and make pyrones 7 available in the
multiꢀgram scaled amounts. The following systems were
studied: EtONa—EtOH, ButOK—Et2O, ButOK—THF,
and NaH—THF, of which the latter turned out to be the
most efficient (a 60% suspension of NaH in mineral oil
and anhydrous THF). It was found that the condensation
of enaminodiones 5 with diethyl oxalate can be carried out
both upon reflux for 8 h and upon continuos stirring at
~20 °C for 5 days (the reaction begins in the second or
even third day). Both methods give close results (except
for enamines 5e,h,i), but the second method (stirring at
room temperature) is more preferable. This reaction turned
out to be very sensitive to the reagents quality, especially
to that of sodium hydride, and the probability of proꢀ
ceeding side processes related to stale or lowꢀquality NaH
decreases under milder conditions. In the case of enamꢀ
ines 5e,i, at room temperature the yields of products 7e,i
are 42 and 31%, respectively, while heating leads either to
the decrease in the yield to 9% (for 7e), or strong resinifiꢀ
cation (for 7i). The initially formed sodium salts 6 were
not isolated in the pure state, but were subjected to hyꢀ
drolysis with dilute HCl (1 : 2) at 0 °C to acyclic polyꢀ
carbonyl intermediates, which under these conditions
spontaneously cyclize to pyrones 7a—i in 31—82% yields
(see Scheme 1, Table 1).
7h : 8a = 3 : 1
Reagents and conditions: 1) (CO2Et)2, NaH, THF, Δ; 2) HCl, 0 °C.
1
position, as well as from the H and 13C NMR spectroꢀ
scopy data (Tables 2 and 3). The most relevant examples
of such compounds described in the literature are methyl
3ꢀphenylꢀ2ꢀpyroneꢀ6ꢀcarboxylate (8b)18 and ethyl 6ꢀphenylꢀ
2ꢀpyroneꢀ3ꢀcarboxylate (8c).19 It should be noted that in
the series of 2ꢀpyrones, the spinꢀspin coupling constant
between the protons of the C(3)=C(4) double bond has
the value within the 8—10 Hz range, whereas for the
C(5)=C(6) bond it is considerably smaller (J = 5—6 Hz),
that allows us to exclude such structures from considerꢀ
ation.20,21
Reflux of enaminodione 5h (R = But) with diethyl
oxalate in the system NaH—THF for 8 h unexpectedly
gave a mixture of the target pyrone 7h with the isomeric
product in the ratio of 3 : 1, from which pyrone 7h and its
isomer were isolated in the pure form by fractional recrysꢀ
tallization from ethanol at –20 °C in 33 and 11% yields,
respectively. Based on the spectral data, the side isomer
was identified as 6ꢀcarbethoxyꢀ3ꢀpivaloylꢀ2ꢀpyrone (8a)
(Scheme 2). Since no formation of the rearrangement
products was detected with other enaminodiones 5 under
similar conditions, it can be suggested that this specific
feature of compound 5h is related to the presence of
a bulky tertꢀbutyl group, affecting its reactivity. Carrying
out the reaction at room temperature for 5 days allowed us
to completely avoid the formation of 2ꢀpyrone 8a and to
increase the yield of 4ꢀpyrone 7h from 33 to 53%.
Table 2. Chemical shifts for protons H(3) and H(6) in pyrones
7a—i and for protons H(4) and H(5) in 2ꢀpyrones 8a—c (CDCl3)
Compound
δ , J/Hz
Assignment
H
7a—g
7.22—7.28
8.11—8.31
C(3)H
C(6)H
C(3)H
C(6)H
C(3)H
C(6)H
C(4)H
C(5)H
C(4)H
C(5)H
C(4)H
C(5)H
sꢀtransꢀ7h
7.13
7.80
7.22
8.44
sꢀcisꢀ7i
8a
7.61 (d, 1 H, J = 6.7)*
7.20 (d, 1 H, J = 6.7)*
7.54 (d, 1 H, J = 7.0)
7.23 (d, 1 H, J = 7.0)
8.29 (d, 1 H, J = 7.4)
6.77 (d, 1 H, J = 7.4)
8b
8c
The structure of compound 8a was established based
on elemental analysis, which confirmed its isomeric comꢀ
* DMSOꢀd6.

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Russ.Chem.Bull., Int.Ed., Vol. 65, No. 9, September, 2016
Obydennov et al.
Table 3. Chemical shifts for the C=O group in pyꢀ
rones 7h and 8a
derivative 7h, an opposite picture is observed: the highꢀ
field signal (δ 7.80) for proton H(6) indicates the sꢀtransꢀ
conformation. 5ꢀAroylcomanoates 7a—g with averaged
chemical shifts for this proton exist in solution of deuteroꢀ
chloroform as mixtures of approximately equal amounts
of sꢀcisꢀ and sꢀtransꢀconformers, the equilibrium between
which begins to shift to the side of the former conformer
as the electronꢀwithdrawing character of substituent in
the benzene ring increases (for pꢀnitrophenyl derivative
7e, δH(6) 8.31).
Comꢀ
pound
δ
C
ButC=O
EtOC=O
Cpyr=O
7h
8a
206.7
207.4
159.5
159.0
175.6
157.4
The photochemical isomerization of 4ꢀpyrones to
2ꢀpyrones is a well known process,22 however, in our case,
when taking into account drastic enough reaction condiꢀ
tions, it can be suggested that the isomerization process is
explained by the reaction center transition in the initially
formed enolate A and the emergence of cyclobutene interꢀ
mediates B and C (Scheme 3). The latter sequentially
undergoes the ring opening reaction upon treatment with
ethoxide anion and the condensation with diethyl oxalate
to form intermediate D, the cyclization of which under
acidic conditions gives 2ꢀpyrone 8a.
Scheme 3
In the next step of the work, already having a simple,
efficient, and easily reproducible procedure for the synꢀ
thesis of ethyl 5ꢀacylcomanoates 7, we set a goal to conꢀ
vert esters 7 to the corresponding acids. It is known that
comanic acids containing aliphatic or aromatic substituꢀ
ents exhibit antiprolipherative activity23 and can be used
for treatment of metabolic syndrome.24 Apart from that,
they are active substrates in the synthesis of various heteroꢀ
cyclic systems, including 3ꢀpyrazolylindoles,25,26 3ꢀ(hetꢀ
arylmethyl)quinoxalinones,27 and 3ꢀ(1Hꢀ1,5ꢀbenzodiazeꢀ
pinꢀ2(3H)ꢀylidenemethyl)quinoxalinꢀ2(1H)ꢀones.14 In
connection with high biological activity and synthetic imꢀ
portance of γꢀpyroneꢀderived carboxylic acids, the sugꢀ
gested hydrolysis of the ethoxycarbonyl group in coꢀ
manoates 7 is a relevant synthetic problem, which seems
simple only at first glance. In fact, taking into account the
readiness of γꢀpyrone ring opening in both the acidic and
the basic media, as well as the absence in the literature of
any data on chemical properties of compounds 7 (the oxiꢀ
dation of esters 7a,i with mꢀchloroperbenzoic acid to epꢀ
oxydes is only described8), the transformation of ethyl
5ꢀacylcomanoates 7 to 5ꢀacylcomanic acids deserves speꢀ
cial attention, since it does not mean just a routine hydrolꢀ
ysis of the ester group.
The structure of 4ꢀpyrones 7a—i also deserves a brief
comment. The analysis of chemical shift values for proꢀ
tons H(3) and H(6) in the 1H NMR spectra of these comꢀ
pounds recorded in solution of CDCl3 leads to certain
conclusions about conformation preferences of the acyl
substituent (see Table 2). In compound 7i, the proton
H(6) is found in the lowest field as a singlet (δ 8.44) beꢀ
cause of the deshielding influence of the carbonyl group of
the acetyl substituent, which indicates that pyrone 7i preꢀ
dominantly exists as a sꢀcisꢀconformer. In the pivaloyl
We found that esters 7a—h upon heating in dilute hyꢀ
drochloric acid at 100 °C underwent rearrangement and
gave, instead of expected 5ꢀRCOꢀcomanic acids, 6ꢀRꢀ
comanic acids 9a—h in high yields (68—94%), of which
acids 9f—h were obtained for the first time. In the case of
esters 7a—e,g,h, the reaction proceeded in HCl (1 : 1) during
8 h, whereas for 2ꢀnaphthyl derivative 7f more prolonged
heating was required (32 h) and more concentrated hydroꢀ

Ethyl 5ꢀacylꢀ4ꢀpyroneꢀ2ꢀcarboxylates
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 9, September, 2016 2237
chloric acid (2 : 1), that can be explained by the low soluꢀ
bility of pyrone 7f in HCl because of the presence of large
and hydrophobic naphthyl residue. A plausible mechaꢀ
nism of the reaction includes the addition of a water molꢀ
ecule at the atom C(6) with subsequent pyrone ring openꢀ
ing and deformylation (Scheme 4, Table 4). The structure
of 6ꢀaroylcomanic acids 9a—g was unambiguously inferred
from their 1H NMR spectra, which exhibited characteristic
doublets for protons H(5) and H(3) with J = 2.1—2.3 Hz
at δ 6.84—6.92 and 6.93—7.29, respectively; in pivaloyl
derivative 9h, the signal for the proton H(5) is upfield
shifted by 0.55 ppm (δ 6.29) and that of H(3) by 0.16 ppm
(δ 6.77) (DMSOꢀd6).
The described reaction constitutes a new threeꢀstep
method for the synthesis of a wide number of 6ꢀRꢀcomanꢀ
ic acids from 1,3ꢀdiketones in 20—56% total yield. Enamꢀ
ination with DMF DMA protects the active methylene
group and promotes selective acylation, whereas treatꢀ
ment with hydrochloric acid removes this protection. Earꢀ
lier, 6ꢀarylcomanic acids were obtained by a fourꢀstep
transformation of benzylideneacetones,28 whereas direct
acylation of 1ꢀRꢀbutaneꢀ1,3ꢀdiones (R = Ar, Het, Alk)
with oxalic esters is known only for a limited number of
examples.28,29 The method for the preparation of 6ꢀsubꢀ
stituted comanic acids suggested in this work includes fewer
number of steps and allows one to obtain not only 6ꢀarylꢀ,
but also 6ꢀhetarylꢀ and 6ꢀalkylcomanic acids. At the same
time, these results show that ethyl 5ꢀacylcomanoates 7
cannot be converted to 5ꢀacylcomanic acids in acidic
medium.
Scheme 4
Earlier,30 we have developed a method for selective
hydrolysis of one of two carbethoxy groups in diethyl isoꢀ
chelidonate 10. The essence of the method consists in the
following: the reaction of diester 10 with piperidine gives
enamine 11 stables under basic conditions, in which the
5ꢀCO2Et group is deactivated because of the electronꢀ
donating influence of the nitrogen atom. As a result, only
2ꢀCO2Et group undergoes alkaline hydrolysis. This allows
one to obtain monoethyl ester of isochelidonic acid 12
under mild conditions and in good yield (Scheme 5).
We decided to use this approach for the preparation of
5ꢀacylcomanic acids from esters 7, which allowed us to
protect atom C(6) from the secondary attack by the nuꢀ
cleophile and, thus, to avoid the undesirable step of deꢀ
formylation. Treatment of esters 7a—c,f,g with piperidine
at 0 °C for 1 h led to polycarbonyl enamines 13a—c,f,g
(66—82% yields) as a result of the attack at the atom C(6)
with subsequent pyrone ring opening. Hydrolysis of these
enamines in the presence of KOH at 0 °C for 15—20 min
with subsequent acidification with HCl to pH 1 gave the
target 5ꢀacylꢀ4ꢀpyroneꢀ2ꢀcarboxylic acids 14a—c,f,g in
54—89% yields (Scheme 6, Table 5). This sequence of
reactions constitutes a simple method for obtaining earlier
unknown 5ꢀaroylcomanic acids 14. In the 1H NMR spectra
of the pushꢀpull enamines 11 and 13, the signals from the
piperidine fragment are strongly broadened, that indicates
its hindered rotation around the double bond; in acids 14,
two singlets for the protons H(3) and H(6) are observed at
δ 6.97—7.02 and 8.56—8.71, respectively (DMSOꢀd6). The
strongly deshielded signal for the proton H(6) leads to
a conclusion that 5ꢀaroylcomanic acids 14 in solution
predominantly exist in the form of sꢀcisꢀconformer.
In conclusion, we have developed a simple and effiꢀ
cient synthesis of ethyl 5ꢀalkanoylꢀ and 5ꢀaroylꢀ4ꢀpyroneꢀ
2ꢀcarboxylates from 1,3ꢀdiketones, DMF DMA, and diꢀ
ethyl oxalate. We showed that these compounds in acidic
medium can readily undergo rearrangement to 6ꢀsubstiꢀ
tuted comanic acids, whereas their treatment with piperiꢀ
Table 4. Yields of 6ꢀRꢀcomanic acids 9
Acid 9
R
Yielda (%)
9а
9b
9c
9d
9e
9f
Ph
68
85
92
92
81
94b
89
68
4ꢀClC6H4
4ꢀMeOC6H4
4ꢀMeC6H4
4ꢀNO2C6H4
2ꢀC10H7
2ꢀC4H3S
But
9g
9h
a The reactions were carried out upon standing of pyrꢀ
ones 7 at 100 °C in HCl (1 : 1).
b The reaction was carried out in HCl (2 : 1) for 32 h.

2238
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 9, September, 2016
Obydennov et al.
Scheme 5
Scheme 6
Table 5. Yields of products 13 and 14
Synthesis of enaminodiones 5a—i (general procedure). Dimeꢀ
thylformamide dimethyl acetal (15.49 g, 0.13 mol) was added to
1,3ꢀdiketone 4 (0.1 mol) in anhydrous benzene (46 mL), the
reaction mixture was stirred for 24 h at room temperature and
then refluxed for 1 h, using a reflux condenser equipped with
a calcium chloride drying tube. Then the solvent and an excess of
DMF DMA were removed at reduced pressure, the residue was
recrystallized from a proper solvent.
2ꢀ(Dimethylaminomethylene)ꢀ1ꢀphenylbutaneꢀ1,3ꢀdione (5a).
The yield was 13.91 g (64%), yellow crystals, m.p. 83—84 °C
(Et2O) (Ref. 33: m.p. 72—74 °C). 1H NMR corresponded to the
literature data.33,34
R
Yield (%)
13
14
Ph
82
71
79
82
66
69
89
61
54
80
4ꢀClC6H4
4ꢀMeOC6H4
2ꢀC10H7
2ꢀC4H3S
2ꢀ(Dimethylaminomethylene)ꢀ1ꢀ(4ꢀchlorophenyl)butaneꢀ1,3ꢀ
dione (5b). The yield was 20.14 g (80%), a yellow powder,
m.p. 115—116 °C (toluene : hexane, 1 : 1) (Ref. 9: m.p. 122 °C).
1H NMR (DMSOꢀd6), δ: 2.08 (s, 3 H, Me); 2.45—3.30 (m, 6 H,
NMe2); 7.52 (d, 2 H, H(3), HAr(5), J = 8.5 Hz); 7.73 (s, 1 H,
=CH); 7.85 (d, 2 H, H(2), HAr(6), J = 8.5 Hz).
dine with subsequent basic hydrolysis gives 5ꢀaroylꢀ4ꢀpyꢀ
roneꢀ2ꢀcarboxylic acids.
Experimental
2ꢀ(Dimethylaminomethylene)ꢀ1ꢀ(4ꢀmethoxyphenyl)butaneꢀ
1,3ꢀdione (5c). The yield was 21.27 g (86%), a yellow powder,
m.p. 126—127 °C (toluene) (Ref. 9: m.p. 126 °C). H NMR
IR the spectra were recorded on a Perkin—Elmer Spectrum
BXꢀII spectrometer using a frustrated total internal reflection
1
1
(FTIR) appliance. H and 13C NMR spectra were recorded on
(CDCl3), δ: 2.00 (s, 3 H, Me); 2.32—3.51 (m, 6 H, NMe2); 3.87
(s, 3 H, MeO); 6.93 (d, 2 H, H(3), HAr(5), J = 8.7 Hz); 7.73 (s, 1 H,
=CH); 7.85 (d, 2 H, H(2), HAr(6), J = 8.7 Hz).
2ꢀ(Dimethylaminomethylene)ꢀ1ꢀ(4ꢀmethylphenyl)butaneꢀ1,3ꢀ
dione (5d). The yield was 17.58 g (76%), a yellow powder, m.p.
113—115 °C (toluene : hexane, 2 : 1). Found (%): C, 72.85;
H, 7.33; N, 6.07. C14H17NO2. Calculated (%): C, 72.70; H, 7.41,
N, 6.06. IR, ν/cm–1: 2922, 1647, 1573, 1393, 1302, 930,
837, 758. 1H NMR (CDCl3), δ: 1.99 (s, 3 H, Me); 2.41 (s, 3 H,
Me); 2.52—3.28 (m, 6 H, NMe2); 7.24 (d, 2 H, H(3), HAr(5),
a Bruker Avance II spectrometer (400 and 100 MHz, respectively)
in DMSOꢀd6 and CDCl3, using SiMe4 an internal standard.
Elemental analysis was performed on a PE 2400 automated anaꢀ
lyzer. Melting points were determined on a SMP30 heating stage.
Solvents used in the work were distilled, NaH (a 60% suspension
in mineral oil) and DMF DMA were purchased from Sigma
Aldrich. Benzene and THF were refluxed over sodium metal
and distilled. Benzoylacetone31 and other 1,3ꢀdiketones32 were
obtained according to the known procedures.

Ethyl 5ꢀacylꢀ4ꢀpyroneꢀ2ꢀcarboxylates
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 9, September, 2016 2239
J = 7.8 Hz); 7.73 (s, 1 H, =CH); 8.24 (d, 2 H, H(2), HAr(6),
J = 8.7 Hz).
H(2), HPh(6), J = 8.0, J = 1.4); 8.15 (s, 1 H, Hpyr(6)). 13C NMR
(CDCl3, δ: 14.1, 63.5, 121.3, 128.7, 129.7, 130.6, 134.2, 136.2,
152.9, 157.5, 159.4, 175.8, 190.6.
Ethyl 5ꢀ(4ꢀchlorobenzoyl)ꢀ4ꢀoxoꢀ4Hꢀpyraneꢀ2ꢀcarboxylate
(7b). The yield was 1.26 g (82%), a beige powder, m.p. 113—114 °C
(Ref. 9: m.p. 108—109 °C). IR, ν/cm–1: 3085, 1740, 1654, 1621,
1580. 1H NMR (CDCl3), δ: 1.43 (t, 3 H, Me, J = 7.1 Hz); 4.46
(q, 2 H, CH2O, J = 7.1 Hz); 7.23 (s, 1 H, Hpyr(3)); 7.44 (d, 2 H,
H(3), HAr(5), J = 8.3 Hz); 7.75 (d, 2 H, H(2), HAr(6), J = 8.3 Hz);
8.18 (s, 1 H, Hpyr(6)).
2ꢀ(Dimethylaminomethylene)ꢀ1ꢀ(4ꢀnitrophenyl)butaneꢀ1,3ꢀ
dione (5e). The yield was 15.47 g (59%), orange crystals, m.p.
146—148 °C (toluene). Found: m/z 263.1030 [MH]+. C13H14N2O4.
Calculated: M = 263.1032. IR, ν/cm–1: 2927, 1646, 1577,
1
1511, 1301, 935, 850. H NMR (DMSOꢀd6), δ: 2.11 (s, 3 H,
Me); 2.31—3.64 (br.s, 6 H, NMe2); 7.77 (s, 1 H, =CH); 7.86
(d, 2 H, H(3), HAr(5), J = 8.7 Hz); 8.24 (d, 2 H, H(2), HAr(6),
J = 8.7 Hz).
2ꢀ(Dimethylaminomethylene)ꢀ1ꢀ(2ꢀnaphthyl)butaneꢀ1,3ꢀdiꢀ
one (5f). The yield was 18.18 g (68%), yellow crystals, m.p.
102—104 °C (Et2O). Found (%): C, 76.50; H, 6.68; N, 5.01.
C17H17NO2. Calculated (%): C, 76.38; H, 6.41, N, 5.24. IR,
ν/cm–1: 3013, 2954, 2924, 1652, 1616, 1308, 925. 1H NMR
(CDCl3), δ: 2.01 (s, 3 H, Me); 2.44—3.39 (br.s, 6 H, NMe2);
7.54 (td, 1 H, HNaph(6), J = 8.0 Hz, J = 1.3 Hz);* 7.59 (td, 1 H,
HNaph(7), J = 8.0 Hz, J = 1.3 Hz); 7.82 (s, 1 H, =CH); 7.86—7.94
(m, 3 H, H(4), H(5), HNaph(8)); 7.98 (dd, 1 H, HNaph(3), J = 8.5 Hz,
J = 1.5 Hz); 8.32 (s, 1 H, HNaph(1)).
Ethyl 5ꢀ(4ꢀmethoxybenzoyl)ꢀ4ꢀoxoꢀ4Hꢀpyraneꢀ2ꢀcarboxylate
(7c). The yield was 1.04 g (69%), light yellow crystals, m.p.
89—90 °C (Ref. 9: m.p. 81—84 °C). IR, ν/cm–1: 3072, 1731,
1655, 1594. 1H NMR (CDCl3), δ: 1.42 (t, 3 H, Me, J = 7.1 Hz);
3.88 (s, 3 H, MeO); 4.46 (q, 2 H, CH2O, J = 7.1 Hz); 6.93 (d, 2 H,
H(3), HAr(5), J = 9.0 Hz); 7.23 (s, 1 H, Hpyr(3)); 7.82 (d, 2 H,
H(2), HAr(6), J = 9.0 Hz); 8.11 (s, 1 H, Hpyr(6)).
Ethyl 5ꢀ(4ꢀmethylbenzoyl)ꢀ4ꢀoxoꢀ4Hꢀpyraneꢀ2ꢀcarboxylate
(7d). The yield was 1.12 g (78%), light yellow crystals, m.p.
127—128 °C. Found (%): C, 67.31; H, 4.89. C16H14O5. Calcuꢀ
lated (%): C, 67.13; H, 4.93. IR, ν/cm–1: 3209, 3032, 1754,
1651, 1614, 1309, 1001, 796. 1H NMR (CDCl3), δ: 1.42 (t, 3 H,
Me, J = 7.2 Hz); 2.42 (s, 3 H, Me); 4.46 (q, 2 H, CH2O, J = 7.2 Hz);
7.22 (s, 1 H, Hpyr(3)); 7.26 (d, 2 H, H(3), HAr(5), J = 8.0 Hz);
7.72 (d, 2 H, H(2), HAr(6), J = 8.0 Hz); 8.12 (s, 1 H, Hpyr(6)).
Ethyl 5ꢀ(4ꢀnitrobenzoyl)ꢀ4ꢀoxoꢀ4Hꢀpyraneꢀ2ꢀcarboxylate
(7e). A precipitate obtained after the dilution with EtOH was
refluxed with toluene (50 mL) for removal of polymeric impuriꢀ
ties. Then, the toluene solution was decanted, concentrated to
10 mL, and diluted with hexane (20 mL), a precipitate formed
was collected by filtration. The yield was 0.67 g (42%), an orange
powder, m.p. 164—165 °C. Found (%): C, 57.06; H, 3.45; N, 4.49.
C15H11NO7. Calculated (%): C, 56.79; H, 3.49; N, 4.42. IR,
ν/cm–1: 3117, 3075, 2990, 1746, 1649, 1596, 1519, 849. 1H NMR
(CDCl3), δ: 1.43 (s, 3 H, Me, J = 7.2 Hz); 4.48 (q, 2 H, CH2O,
J = 7.2 Hz); 7.25 (s, 1 H, Hpyr(3)); 7.93 (d, 2 H, H(3), HAr(5),
J = 8.9 Hz); 8.30 (d, 2 H, H(2), HAr(6), J = 8.9 Hz); 8.31 (s, 1 H,
Hpyr(6)).
2ꢀ(Dimethylaminomethylene)ꢀ1ꢀ(2ꢀthienyl)butaneꢀ1,3ꢀdione
(5g). The yield was 17.19 g (77%), yellow crystals, m.p. 71—72 °C
(Et2O). Found (%): C, 59.33; H, 5.69; N, 6.22. C11H13NO2S.
Calculated (%): C, 59.17; H, 5.87, N, 6.27. IR, ν/cm–1: 3101,
1
3053, 2924, 1643, 1578, 1307, 847, 728. H NMR (DMSOꢀd6),
δ: 2.07 (s, 3 H, Me); 2.55—3.19 (m, 6 H, NMe2); 7.17 (dd, 1 H,
HTh(4), J = 4.9 Hz, J = 3.8 Hz);** 7.52 (dd, 1 H, HTh(3), J = 3.7 Hz,
J = 1.2 Hz); 7.67 (s, 1 H, =CH); 7.92 (dd, 1 H, HTh(5), J = 4.9 Hz,
J = 1.2 Hz).
3ꢀ(Dimethylaminomethylene)ꢀ5,5ꢀdimethylhexaꢀ2,4ꢀdione
(5h). The yield was 17.36 g (88%), yellowish crystals, m.p.
68—69 °C (benzene). Found (%): C, 66.82; H, 7.73; N, 7.18.
C11H19NO2. Calculated (%): C, 66.97; H, 9.71, N, 7.10. IR,
ν/cm–1: 2966, 2870, 1653, 1581, 1300, 999. 1H NMR (CDCl3),
δ: 1.22 (s, 9 H, But); 2.17 (s, 3 H, Me); 2.91 (s, 6 H, NMe2); 7.16
(s, 1 H, =CH).
3ꢀ(Dimethylaminomethylene)pentaneꢀ2,4ꢀdione (5i). The
yield was 13.50 g (87%), yellow crystals, m.p. 51—53 °C (Et2O—
1
hexane) (Ref. 35: m.p. 52—54 °C). H NMR corresponded to
Ethyl 5ꢀ(2ꢀnaphthoyl)ꢀ4ꢀoxoꢀ4Hꢀpyraneꢀ2ꢀcarboxylate (7f).
The yield was 1.10 g (68%), a beige powder, m.p. 148—149 °C.
Found (%): C, 70.84; H, 4.39. C19H14O5. Calculated (%):
C, 70.80; H, 4.38. IR, ν/cm–1: 3078, 3059, 2989, 1737, 1646,
the literature data.35
Synthesis of ethyl 5ꢀacylcomanoates 7a—i (general proceꢀ
dure). A mixture of enaminodione 5 (5 mmol), diethyl oxalate
(0.88 g, 6 mmol), and NaH (0.24 g, 6 mmol, a 60% dispersion in
mineral oil) in anhydrous THF (15 mL) was stirred for 5 days
(refluxed for 8 h). Then, the reaction mixture was treated with
4 M HCl to pH = 1 with cooling and stirred for 30 min at 0 °C.
The product was extracted with EtOAc (3×15 mL), the extract
was sequentially washed with H2O (10 mL) and saturated aqueꢀ
ous solution of NaCl (5 mL) and dried with Na2SO4. The solvent
was evaporated at reduced pressure, the residue was diluted with
EtOH. A precipitate formed was filtered, washed with cold
EtOH, and, if necessary, recrystallized from EtOH.
Ethyl 5ꢀbenzoylꢀ4ꢀoxoꢀ4Hꢀpyraneꢀ2ꢀcarboxylate (7a)8. The
yield was 0.95 g (73%), light yellow crystals, m.p. 88—89 °C.
1H NMR (CDCl3, δ: 1.43 (t, 3 H, Me, J = 7.1); 4.46 (q, 2 H, CH2O,
J = 7.1); 7.24 (s, 1 H, Hpyr(3));*** 7.47 (t, 2 H, H(3), H(5) Ph,
J = 7.7); 7.60 (tt, 1 H, HPh(4), J = 7.4, J = 1.2); 7.81 (dd, 2 H,
1
1572, 1296, 935, 784. H NMR (CDCl3), δ: 1.44 (t, 3 H, Me,
J = 7.1 Hz); 4.48 (q, 2 H, CH2O, J = 7.1 Hz); 7.28 (s, 1 H,
Hpyr(3)); 7.54 (td, 1 H, HNaph(7), J = 7.6 Hz, J = 1.1 Hz); 7.62
(td, 1 H, HNaph(6), J = 7.6 Hz, J = 1.2 Hz); 7.88 (d, 1 H,
HNaph(4), J = 8.0 Hz); 7.90—7.95 (m, 3 H, HAr); 8.20 (s, 1 H,
Hpyr(6)); 8.29 (d, 1 H, HNaph(1), J = 0.8 Hz).
Ethyl 4ꢀoxoꢀ5ꢀ(2ꢀthenoyl)ꢀ4Hꢀpyraneꢀ2ꢀcarboxylate (7g).10
The yield was 1.02 g (73%), colorless crystals, m.p. 97—98 °C.
Found (%): C, 56.02; H, 3.53. C13H10O5S. Calculated (%):
C, 56.11; H, 3.62. IR, ν/cm–1: 3087, 2983, 2923, 2853, 1728,
1655, 1641, 1621, 1578. 1H NMR (CDCl3), δ: 1.42 (t, 3 H, Me,
J = 7.1 Hz); 4.45 (q, 2 H, CH2O, J = 7.1 Hz); 7.14 (dd, 1 H,
HTh(4), J = 4.9 Hz, J = 3.9 Hz); 7.24 (s, 1 H, Hpyr(3)); 7.67 (dd,
1 H, HTh(3), J = 3.9 Hz, J = 1.1 Hz); 7.75 (dd, 1 H, HTh(5),
J = 4.9 Hz, J = 1.1 Hz); 8.18 (s, 1 H, Hpyr(6)). 13C NMR
(DMSOꢀd6), 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.
* HNaph are the protons of the naphthaline ring.
** HTh are the protons of the thiophene ring.
*** Hpyr are the protons of the pyrone ring.
Ethyl 4ꢀoxoꢀ5ꢀpivaloylꢀ4Hꢀpyraneꢀ2ꢀcarboxylate (7h) was
obtained from enaminodione 5h by the reaction at 20 °C for

2240
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 9, September, 2016
Obydennov et al.
5 days. After extraction and evaporation of the solvent at reꢀ
duced pressure, the residue was diluted with EtOH (4 mL) and
allowed to stand for 24 h at –20 °C. A precipitate was collected
by filtration, washed with cold EtOH, and dried. The yield was
0.67 g (53%), colorless crystals, m.p. 106—107 °C. Found (%):
C, 62.30; H, 6.75. C13H16O5. Calculated (%): C, 61.90; H, 6.39.
IR, ν/cm–1: 3055, 2974, 2924, 2855, 1739, 1699, 1646, 1615,
J = 2.3 Hz); 7.33 (d, 2 H, H(3), HAr(5), J = 8.2 Hz); 7.83 (d, 2 H,
H(2), HAr(6), J = 8.2 Hz); the OH proton was not detected.
6ꢀ(4ꢀNitrophenyl)ꢀ4ꢀoxoꢀ4Hꢀpyraneꢀ2ꢀcarboxylic acid (9e).
The yield was 0.267 g (81%), a grey powder, m.p. 253—254 °C
(Ref. 28: m.p. 248—250 °C). 1H NMR (DMSOꢀd6), δ: 6.92 (d, 1 H,
H(5), J = 2.2 Hz); 7.29 (d, 1 H, H(3), J = 2.2 Hz); 8.25 (d, 2 H,
Ar, J = 9.0 Hz); 8.36 (d, 2 H, Ar, J = 9.0 Hz); the OH proton
was not detected.
1
1463, 1086, 935, 783. H NMR (CDCl3), δ: 1.24 (s, 9 H, But);
1.41 (t, 3 H, Me, J = 7.1 Hz); 4.44 (q, 2 H, CH2O, J = 7.1 Hz);
7.13 (s, 1 H, H(3)); 7.80 (s, 1 H, H(6)). 13C NMR (CDCl3), δ: 14.1,
26.1, 45.1, 63.3, 120.5, 132.9, 152.8, 153.3, 159.5, 175.6, 206.7.
Ethyl 5ꢀacetylꢀ4ꢀoxoꢀ4Hꢀpyraneꢀ2ꢀcarboxylate (7i).8 After
evaporation of the solvent from the extract, EtOH (4 mL) was
added, and the resulting mixture was allowed to stand for 1 days
at –20 °C. A precipitate was collected by filtration, washed with
cold EtOH, and dried. The yield was 0.33 g (31%), orange crysꢀ
6ꢀ(2ꢀNaphthyl)ꢀ4ꢀoxoꢀ4Hꢀpyraneꢀ2ꢀcarboxylic acid (9f). The
reaction used HCl (6 mL, 2 : 1) and was carried out for 32 h. The
yield was 0.311 g (94%), a grey powder, m.p. 283—284 °C.
Found (%): C, 71.67; H, 3.69. C16H10O4. Calculated (%): C, 72.18;
H, 3.79. 1H NMR (DMSOꢀd6), δ: 6.91 (d, 1 H, H(5), J = 2.3 Hz);
7.23 (d, 1 H, H(3), J = 2.3 Hz); 7.57—7.67 (m, 2 H, H(6),
HNaph(7)); 7.96—8.10 (m, 4 H, HNaph); 8.57 (d, 1 H, HNaph(1),
J = 1.2 Hz); 13.9—15.2 (br.s, 1 H, OH).
4ꢀOxoꢀ6ꢀ(2ꢀthienyl)ꢀ4Hꢀpyraneꢀ2ꢀcarboxylic acid (9g).10
The yield was 0.285 g (89%), a grey powder, m.p. 252—253 °C.
Found (%): C, 54.03; H, 2.75. C10H6O4S. Calculated (%): C,
54.05; H, 2.72. IR, ν/cm–1: 3108, 3085, 1730, 1623, 1594, 1573.
1H NMR (DMSOꢀd6), δ: 6.84 (d, 1 H, H(5), J = 2.3 Hz); 6.98
(d, 1 H, H(3), J = 2.3 Hz); 7.27 (dd, 1 H, HTh(4), J = 5.0 Hz,
J = 3.9 Hz); 7.93 (dd, 1 H, HTh(3), J = 3.9 Hz, J = 1.1 Hz); 7.95
(dd, 1 H, HTh(5), J = 5.0 Hz, J = 1.1 Hz); 12.0—15.5 (br.s, 1 H,
OH). 13C NMR (DMSOꢀd6), δ: 110.6, 118.4, 129.4, 129.9, 132.4,
133.7, 153.2, 159.5, 161.3, 178.8.
6ꢀ(tertꢀButyl)ꢀ4ꢀoxoꢀ4Hꢀpyraneꢀ2ꢀcarboxylic acid (9h). The
yield was 0.212 g (68%), a colorless powder, m.p. 235—237 °C.
Found: m/z 197.0819 [MH]+. C10H13O4. Calculated: M =
= 197.0814. IR, ν/cm–1: 3055, 2974, 2924, 2855, 1739, 1699,
1646, 1655, 1463, 1292, 1244, 1086, 935, 783. 1H NMR
(DMSOꢀd6), δ: 1.26 (s, 9 H, But); 6.29 (d, 1 H, H(5), J = 2.3 Hz);
6.77 (d, 1 H, H(3), J = 2.3 Hz); 13.9—15.0 (br.s, 1 H, OH).
Diethyl 2ꢀhydroxyꢀ4ꢀoxoꢀ5ꢀ(piperidinꢀ1ꢀylmethylidene)hexꢀ
2ꢀenedioate (11). Diester 10 (0.242 g, 1.0 mmol) was added to
a solution of piperidine (0.102 g, 1.20 mmol) in EtOH (2 mL) at
0 °C. The resulting suspension was stirred for 2 h at 0 °C and then
allowed to stand for 2 days at –20 °C. A precipitate formed was
collected by filtration and washed with cold EtOH. The yield
was 0.192 g (59%), a yellow powder, m.p. 71—72 °C. Found (%):
C, 59.06; H, 7.29; N, 4.27. C16H23NO6. Calculated (%): C, 59.06;
H, 7.13; N, 4.31. IR, ν/cm–1: 3144, 2986, 2929, 2852, 1740,
1686, 844, 785. 1H NMR (DMSOꢀd6), δ: 1.31 (t, 3 H, Me,
J = 7.1 Hz); 1.32 (t, 3 H, Me, J = 7.1 Hz); 1.62—1.82 (br.s, 6 H,
3 CH2); 2.8—3.8 (br.s, 4 H, (CH2)2N); 4.18 (q, 2 H, CH2O,
J = 7.1 Hz); 4.24 (q, 2 H, CH2O, J = 7.1 Hz); 6.70 (s, 1 H, =CH);
7.91 (s, 1 H, =HCN); 14.0—16.0 (br.s, 1 H, OH).
Synthesis of enamines 13a—c,f,g (general procedure). A thorꢀ
oughly triturated pyrone 7a (1.0 mmol) was added to a solution
of piperidine (0.102 g, 1.20 mmol) in EtOH (3 mL) at 0 °C. The
resulting suspension was stirred for 1 h at 0 °C, a precipitate
formed was collected by filtration and washed with cold EtOH.
Ethyl 5ꢀbenzoylꢀ2ꢀhydroxyꢀ4ꢀoxoꢀ6ꢀ(piperidinꢀ1ꢀyl)hexaꢀ
2,5ꢀdienoate (13a). The yield was 0.293 g (82%), a yellow powꢀ
der, m.p. 127—128 °C. Found (%): C, 67.20; H, 6.35; N, 3.86.
C20H23NO5. Calculated (%): C, 67.21; H, 6.49; N, 3.92. IR,
ν/cm–1: 2994, 2947, 1786, 1577, 941, 779. 1H NMR (DMSOꢀd6),
δ: 1.26 (t, 3 H, Me, J = 7.1 Hz); 1.34—1.74 (br.s, 6 H, 3 CH2);
2.70—3.30 (br.s, 4 H, (CH2)2N); 4.17 (q, 2 H, CH2O, J = 7.1 Hz);
6.17 (s, 1 H, =CH); 7.48 (t, 2 H, H(3), HPh(5), J = 7.5 Hz); 7.57
(tt, 1 H, HPh(4), J = 7.3 Hz, J = 1.2 Hz); 7.78 (d, 2 H, H(2),
1
tals, m.p. 65—67 °C. H NMR (CDCl3), δ: 1.41 (t, 3 H, Me,
J = 7.1 Hz); 2.66 (s, 3 H, Me); 4.44 (q, 2 H, CH2O, J = 7.1 Hz);
7.22 (s, 1 H, H(3)); 8.44 (s, 1 H, H(6)). 13C NMR (CDCl3), δ:
14.1, 31.5, 63.5, 122.4, 127.8, 152.6, 159.3, 160.9, 176.3, 195.9.
Ethyl 2ꢀoxoꢀ3ꢀpivaloylꢀ2Hꢀpyraneꢀ6ꢀcarboxylate (8a) was
obtained from enaminodione 5h upon reflux for 8 h. After exꢀ
traction and evaporation of the solvent at reduced pressure, the
residue was diluted with EtOH (4 mL) and allowed to stand for
1 h at –20 °C, a precipitate of 7h was filtered off. The filtrate was
additionally allowed to stand for 24 h at –20 °C. A precipitate
was collected by filtration and recrystallized from hexane with
a small amount of toluene. The yield was 0.14 g (11%), colorless
crystals, m.p. 78—81 °C. Found (%): C, 61.86; H, 6.48. C13H16O5.
Calculated (%): C, 61.90; H, 6.39. IR, ν/cm–1: 2989, 2970, 1734,
1
1689, 1270, 1129, 767. H NMR (DMSOꢀd6), δ: 1.20 (s, 9 H,
But); 1.37 (t, 3 H, Me, J = 7.0 Hz); 4.36 (q, 2 H, CH2O, J = 7.0 Hz);
7.20 (d, 1 H, H(5), J = 6.7 Hz); 7.61 (s, 1 H, H(4), J = 6.7 Hz).
13C NMR (CDCl3), δ: 14.2, 26.5, 45.1, 62.9, 109.4, 133.8, 139.3,
150.3, 157.4, 159.0, 207.4.
Synthesis of 6ꢀsubstituted comanic acids 9a—h (general proꢀ
cedure). A suspension of ethyl ester 7 (0.400 g) in HCl (4 mL)
(1 : 1) was heated in a bath at 100 °C for 8 h, a precipitate formed
was collected by filtration and dried.
4ꢀOxoꢀ6ꢀphenylꢀ4Hꢀpyraneꢀ2ꢀcarboxylic acid (9a). The yield
was 0.216 g (68%), a grey powder. m.p. 247—248 °C (Ref. 29:
m.p. 250—252 °C). 1H NMR (DMSOꢀd6), δ: 6.89 (d, 1 H, H(5),
J = 2.2 Hz); 7.13 (d, 1 H, H(3), J = 2.2 Hz); 7.50—7.62 (m, 3 H,
Ph); 7.98 (dd, 2 H, Ph, J = 8.6 Hz, J = 1.9 Hz); 13.0—16.0 (br.s,
1 H, OH).
6ꢀ(4ꢀChlorophenyl)ꢀ4ꢀoxoꢀ4Hꢀpyraneꢀ2ꢀcarboxylic acid (9b).
The yield was 0.278 g (85%), a grey powder, m.p. 284—285 °C
(Ref. 28: m.p. 264—265 °C). 1H NMR (DMSOꢀd6), δ: 6.88 (d, 1 H,
H(5), J = 2.1 Hz); 7.15 (d, 1 H, H(3), J = 2.1 Hz); 7.65 (d, 2 H,
H(3), HAr(5), J = 8.6 Hz); 7.99 (d, 2 H, H(2), HAr(6), J = 8.6 Hz);
13.0—16.0 (br.s, 1 H, OH).
6ꢀ(4ꢀMethoxyphenyl)ꢀ4ꢀoxoꢀ4Hꢀpyraneꢀ2ꢀcarboxylic acid
(9c). The yield was 0.300 g (92%), a grey powder, m.p. 266—267 °C
(Ref. 28: m.p. 250—253 °C). 1H NMR (DMSOꢀd6), δ: 3.85 (s, 3 H,
MeO); 6.84 (d, 1 H, H(5), J = 2.3 Hz); 7.00 (d, 1 H, H(3),
J = 2.3 Hz); 7.11 (d, 2 H, H(3), HAr(5), J = 8.9 Hz); 7.92 (d, 2 H,
H(2), HAr(6), J = 8.9 Hz); 12.0—16.0 (br.s, 1 H, OH).
6ꢀ(4ꢀMethylphenyl)ꢀ4ꢀoxoꢀ4Hꢀpyraneꢀ2ꢀcarboxylic acid (9d).
The yield was 0.296 g (92%), a colorless powder, m.p. 246—248 °C
(Ref. 28: m.p. 237—238 °C). 1H NMR (DMSOꢀd6), δ: 2.42 (s, 3 H,
Me); 6.85 (d, 1 H, H(5), J = 2.3 Hz); 6.93 (d, 1 H, H(3),

Ethyl 5ꢀacylꢀ4ꢀpyroneꢀ2ꢀcarboxylates
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 9, September, 2016 2241
HPh(6), J = 7.5 Hz); 8.04 (s, 1 H, =HCN); 15.0—16.0 (br.s,
1 H, OH).
J = 7.5 Hz, J = 1.2 Hz); 7.85 (dd, 2 H, H(2), HPh(6), J = 8.4 Hz,
J = 1.3 Hz); 8.65 (s, 1 H, Hpyr(6)); the OH proton was not
detected.
Ethyl 5ꢀ(4ꢀchlorobenzoyl)ꢀ2ꢀhydroxyꢀ4ꢀoxoꢀ6ꢀ(piperidinꢀ1ꢀ
yl)hexaꢀ2,5ꢀdienoate (13b). The yield was 0.278 g (71%), a yelꢀ
low powder, m.p. 123—124 °C. Found (%): C, 61.24; H, 5.63;
N, 3.35. C20H22ClNO5. Calculated (%): C, 61.30; H, 5.66; N, 3.57.
IR, ν/cm–1: 2949, 2856, 1721, 1582, 941, 781. 1H NMR
(DMSOꢀd6), δ: 1.24 (t, 3 H, Me, J = 7.2 Hz); 1.30—1.68 (br.s, 6 H,
3 CH2); 2.60—3.90 (br.s, 4 H, (CH2)2N); 4.17 (q, 2 H, CH2O,
J = 7.2 Hz); 6.24 (s, 1 H, =CH); 7.51 (d, 2 H, H(3), HAr(5),
J = 8.5 Hz); 7.76 (d, 2 H, H(2), HAr(6), J = 8.5 Hz); 8.06 (s, 1 H,
=HCN); 14.0—16.0 (br.s, 1 H, OH).
Ethyl 2ꢀhydroxyꢀ5ꢀ(4ꢀmethoxybenzoyl)ꢀ4ꢀoxoꢀ6ꢀ(piperidinꢀ
1ꢀyl)hexaꢀ2,5ꢀdienoate (13c). The yield was 0.313 g (79%),
a yellow powder, m.p. 107—108 °C. Found (%): C, 63.27; H, 6.67;
N, 3.43. C21H25NO6•0.5H2O. Calculated (%): C, 63.62; H, 6.61;
N, 3.53. IR, ν/cm–1: 2941, 2857, 1721, 1589, 902, 767. 1H NMR
(DMSOꢀd6), δ: 1.23 (t, 3 H, Me, J = 7.1 Hz); 1.32—1.72 (br.s,
6 H, 3 CH2); 2.9—3.7 (br.s, 4 H, (CH2)2N); 3.85 (s, 3 H, MeO);
4.18 (q, 2 H, CH2O, J = 7.2 Hz); 6.14 (s, 1 H, =CH); 7.00 (d, 2 H,
H(3), HAr(5), J = 8.5 Hz); 7.76 (d, 2 H, H(2), HAr(6), J = 8.5 Hz);
8.01 (s, 1 H, =HCN); 15.0—16.0 (br.s, 1 H, OH).
Ethyl 2ꢀhydroxyꢀ5ꢀ(2ꢀnaphthoyl)ꢀ4ꢀoxoꢀ6ꢀ(piperidinꢀ1ꢀyl)ꢀ
hexaꢀ2,5ꢀdienoate (13f). The yield was 0.334 g (82%), a light
yellow powder, m.p. 130—132 °C. Found (%): C, 70.39; H, 6.15;
N, 3.40. C24H25NO5. Calculated (%): C, 70.74; H, 6.18, N, 3.44.
IR, ν/cm–1: 3060, 2938, 2858, 1730, 1617, 1236, 966. 1H NMR
(DMSOꢀd6), δ: 1.19 (t, 3 H, Me, J = 7.1 Hz); 1.2—1.8 (br.s, 6 H,
3 CH2); 2.7—3.9 (m, 4 H, (CH2)2N); 4.14 (q, 2 H, CH2O,
J = 7.1 Hz); 6.24 (s, 1 H, =CH); 7.56 (td, 1 H, HNaph, J = 7.2 Hz,
J = 0.7 Hz); 7.62 (td, 1 H, HNaph, J = 7.6 Hz, J = 0.8 Hz); 7.88
5ꢀ(4ꢀChlorobenzoyl)ꢀ4ꢀoxoꢀ4Hꢀpyraneꢀ2ꢀcarboxylic acid
(14b). The yield was 77 mg (89%), a yellowish powder, m.p.
230—232 °C. Found (%): C, 54.43; H, 2.65. C13H7ClO5•0.5H2O.
Calculated (%): C, 54.80; H, 2.80. IR, ν/cm–1: 3071, 2878, 2609,
1
1738, 1656, 1632, 1584, 1289, 905. H NMR (DMSOꢀd6), δ:
7.02 (s, 1 H, Hpyr(3)); 7.60 (d, 2 H, H(3), HAr(5), J = 8.6 Hz);
7.86 (d, 2 H, H(2), HAr(6), J = 8.6 Hz); 8.67 (s, 1 H, Hpyr(6));
the OH proton was not detected.
5ꢀ(4ꢀMethoxybenzoyl)ꢀ4ꢀoxoꢀ4Hꢀpyraneꢀ2ꢀcarboxylic acid
(14c). The yield was 50 mg (61%), a light yellow powder, m.p.
125—126 °C (acetone—H2O). Found (%): C, 61.23; H, 3.51.
C14H10O6. Calculated (%): C, 61.32; H, 3.68. IR, ν/cm–1: 3069,
2872, 2602, 1738, 1651, 1586, 1293, 909. 1H NMR (DMSOꢀd6),
δ: 3.87 (s, 3 H, CH3O); 7.00 (s, 1 H, Hpyr(3)); 7.05 (d, 2 H, H(3),
HAr(5), J = 8.8 Hz); 7.83 (d, 2 H, H(2), HAr(6), J = 8.8 Hz); 8.59
(s, 1 H, Hpyr(6)); the OH proton was not detected.
5ꢀ(2ꢀNaphthoyl)ꢀ4ꢀoxoꢀ4Hꢀpyraneꢀ2ꢀcarboxylic acid (14f).
The reaction was carried out in H2O—THF (2.5 mL, 4 : 1) for
20 min, the product 14f was additionally refluxed with toluene
for 1 min. The yield was 50 mg (54%), a light yellow powder,
m.p. 243—244 °C. Found (%): C, 66.40; H, 3.34. C17H10O5•
•0.67H2O. Calculated (%): C, 66.65; H, 3.73. IR, ν/cm–1: 3078,
1
2923, 1742, 1670, 1647, 1300. H NMR (DMSOꢀd6), δ: 6.97
(s, 1 H, Hpyr(3)); 7.57 (t, 1 H, HNaph(6), J = 7.3 Hz); 7.64 (t, 1 H,
HNaph(7), J = 7.2 Hz); 7.90 (d, 1 H, HNaph, J = 8.5 Hz); 7.96
(m, 2 H, HNaph); 8.03 (d, 1 H, HNaph, J = 8.1 Hz); 8.40 (s, 1 H,
HNaph(1)); 8.56 (s, 1 H, Hpyr(6)); the OH proton was not detected.
4ꢀOxoꢀ5ꢀ(2ꢀthenoyl)ꢀ4Hꢀpyraneꢀ2ꢀcarboxylic acid (14g).10
(dd, 1 H, HNaph, J = 8.6 Hz, J = 1.3 Hz); 7.94 (dd, 1 H, HNaph
J = 8.1 Hz); 7.98 (dd, 1 H, HNaph, J = 8.6 Hz); 8.04 (d, 1 H,
,
The yield was 64 mg (80%), a light yellow powder, m.p.
218—220 °C. Found (%): C, 49.51; H, 2.98. C11H6O5S•H2O.
Calculated (%):C, 49.25; H, 3.01. IR, ν/cm–1: 3452, 3097, 1727,
1651, 1627. 1H NMR (DMSOꢀd6), δ: 7.02 (s, 1 H, Hpyr(3)); 7.26
(dd, 1 H, HTh(4), J = 4.8 Hz, J = 4.0 Hz); 7.83 (dd, 1 H, HTh(3),
J = 4.0 Hz, J = 1.2 Hz); 8.15 (dd, 1 H, HTh(5), J = 4.8 Hz,
J = 1.2 Hz); 8.71 (s, 1 H, Hpyr(6)); the OH proton was not
detected. 13C NMR (DMSOꢀd6), δ: 119.9, 129.5, 129.6, 137.4,
137.5, 143.5, 154.4, 157.8, 161.1, 175.9, 182.7.
HNaph, J = 8.0 Hz); 8.13 (s, 1 H, HNaph(1)); 8.34 (s, 1 H, =CHN);
15.0—16.2 (s, 1 H, OH).
Ethyl 2ꢀhydroxyꢀ4ꢀoxoꢀ6ꢀ(piperidinꢀ1ꢀyl)ꢀ5ꢀ(2ꢀthenoyl)ꢀ
hexaꢀ2,5ꢀdienoate (13g).10 The yield was 0.291 g (66%), a yellow
powder, m.p. 125—126 °C. Found (%): C, 59.45; H, 5.72, N, 3.72.
C18H21NO5S. Calculated (%): C, 59.49; H, 5.82; N, 3.85. IR,
ν/cm–1: 3131, 3069, 2998, 2984, 2951, 1725, 1604, 1586. 1H NMR
(DMSOꢀd6), δ: 1.22 (t, 3 H, Me, J = 7.1 Hz); 1.35—1.70 (br.s,
6 H, 3 CH2); 2.9—3.8 (br.s, 4 H, (CH2)2N); 4.19 (q, 2 H, CH2O,
J = 7.1 Hz); 6.29 (s, 1 H, =CH); 7.21 (dd, 1 H, HTh(4), J = 4.9 Hz,
J = 3.9 Hz); 7.65 (dd, 1 H, HTh(3), J = 3.9 Hz, J = 1.2 Hz); 8.03
(dd, 1 H, HTh(5), J = 4.9 Hz, J = 1.2 Hz); 8.06 (s, 1 H, =CHN);
15.0—16.5 (br.s, 1 H, OH). 13C NMR (DMSOꢀd6), 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.
Synthesis of 5ꢀacylcomanic acids 14a—c,f,g (general proceꢀ
dure). Enamine 13 (107 mg, 0.3 mmol) was added to a solution
of KOH (84 mg, 1.50 mmol) in water (2 mL) with cooling to
0 °C. The resulting suspension was stirred until complete dissoꢀ
lution of the precipitate over 15—20 min at 0 °C, then the reacꢀ
tion mixture was acidified with 4 M HCl to pH = 1, a precipitate
of the target acid was collected by filtration.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 14ꢀ03ꢀ31925).
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Received March 1, 2016;
in revised form June 3, 2016