Heterocyclic analogs of prostaglandines: IV. Synthesis of 3,7-interphenylene 3,10(11)-dioxa-13-azaprostanoids and 9-oxa-7-azaprostanoids based on tetronic acid and aromatic aldehydes

Article abstract of DOI:10.1134/S1070428008050047

An approach was developed to the synthesis of stable in metabolism 3,7-interphenylene 3,10-dioxa-13-aza-and 3,11-dioxa-13-azaprostanoids, and also 9-oxa-7-azaprostanoids with interphenylene and terminal phenyl fragments in the ω-chain based on 3-(alkoxybenzylidene)-and 3-(3-phenylallylidene) tetrahydrofuran-2,4-diones obtained by Knoevenagel condensation of tetronic acid with alkoxy-substituted aromatic aldehydes and cinnamic aldehyde.

Full text of DOI:10.1134/S1070428008050047

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 5, pp. 657−670. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © F.S. Pashkovskii, E.M. Shchukina, M.G. Gribovskii, F.A. Lakhvich, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44,
No. 5, pp. 667−680.
Heterocyclic Analogs of Prostaglandines: IV.*
Synthesis of 3,7-Interphenylene 3,10(11)-Dioxa-13-azaprostanoids
and 9-Oxa-7-azaprostanoids Based on Tetronic Acid and
Aromatic Aldehydes
F. S. Pashkovskii, E. M. Shchukina, M. G. Gribovskii, and F. A. Lakhvich
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus’, Minsk, 220141 Belarus’
e-mail: pashkovsky61@mail.ru
Received May 30, 2007
Abstract—An approach was developed to the synthesis of stable in metabolism 3,7-interphenylene 3,10-dioxa-
13-aza- and 3,11-dioxa-13-azaprostanoids, and also 9-oxa-7-azaprostanoids with interphenylene and terminal
phenyl fragments in the ω-chain based on 3-(alkoxybenzylidene)- and 3-(3-phenylallylidene)tetrahydrofuran-
2,4-diones obtained by Knoevenagel condensation of tetronic acid with alkoxy-substituted aromatic aldehydes
and cinnamic aldehyde.
DOI: 10.1134/S1070428008050047
One of the principal shortcomings of natural
prostaglandines and related eicosanoids for application
as drugs is their metabolic instability and an excessively
wide range of biological action. A significant place in
the metabolic decomposition of eicosanoids takes the
β-oxidation of the α-chain involving successive stages
of eliminating two molecules of acetic acid yielding
biologically inert dinor and tetranor derivatives [2].
Introducing an oxygen atom into the position 3 of
the prostanic acid skeleton [3] or 3,7-interphenylene
fragment, and also a replacement of the carboxy group
by other finctional moieties [2] block the β- oxidation of
the α-chain thus significantly increasing the metabolic
stability of such prostanoids and related compounds
without decrease in their activity in most cases.
7-azaprostanoids with interphenylene and terminal phenyl
fragments in the ω-prostanoid chain based in tetronic
acid. Prostanoids with a phenyl fragment in the ω-chain
are widely used in veterinary practice [2], and also in
ophthalmology (Latanoprost) in glaucoma treatment [3].
The most obvious approach to the synthesis of β-di-
carbonyl precursors I of 3,7-interphenylene hetero-
prostanoids consists in preparation of the corresponding
3-benzoyltetrahydrofuran-2,4-diones II based on
tetronic acids III and aromatic acids IV containing as
a substituent the C1–C3 fragment of the α-prostanoid
chain with subsequent selective hydrogenolysis of the
carbonyl group in their acyl side chain. In thus obtained
β-di-carbonyl precursors I the carbon atom of the carboxy
group of aromatic acid becomes C7 atom of the prostanic
skeleton (in keeping with prostaglandine nomenclature),
and the enolized cyclic β-dicarbonyl system is used
further to form the ω-prostanoid chain (Scheme 1).
We report here on the approach to the synthesis of
stable in metabolism 3,7-interphenylene 3,10-dioxa-13-
aza- and 3,11-dioxa-13-azaprostanoids, and also 9-oxa-
Scheme 1.
O
O
O
O
1
O
1
1
7
CO2R'
CO2R'
7
2
CO2R'
2
7
2
+
HO
O
O
O
O
O
O
3
3
3
O
O
O
R
R
R
I
III
IV
II
*For communication III, see [1].
657

PASHKOVSKII et al.
658
The published data on the synthesis and properties
methoxybenzoyl)tetronic acid (XVI) was obtained in
a pure state in a moderate yield. The structure of the latter
was confirmed by 1H NMR and IR spectra (Scheme 2).
of 3-benzoyltetronic acids are scanty [4]. Like the other
cyclic β-tricarbonyl compounds the 3-benzoyltetronic
acids can be obtained by the O–C-isomerization of the
corresponding enol acylates [(5-oxo-2,5-dihydrofuran-3-
yl)alkoxybenzoates]. However the classic isomerization
catalysts [chlorides of aluminum, zinc, and tin, imid-
azole, 4-(dimethylamino)pyridine] are unsuitable for
the synthesis of 2-aroylcycloalkane-1,3-diones [5] and
their heterocyclic analogs. For the synthesis of
2-aroyl-cycloalkane-1,3-diones [5] and a series of their
heterocyclic analogs [6] isomerization methods of the
corresponding enol acylates were developed under the
action of sources of cyanide ions (potassium cyanide,
acetone cyanohydrin) leading to the formation of target
triacylmethanes in high yields.
At an attempt to reduce the carbonyl group of the
benzoyl moiety in compound XVI by triethylsilane in
trifluoroacetic acid as we had previously described for
the other 3-acyltetronic acids [7] instead of the target
β-dicarbonyl compound only deacylation products of
the initial compound were found in the reaction mixture.
Thus the instability of 3-benzoyltetronic acids impedes
both their isolation in preparative quantity and further
reduction under acid conditions.
In this connection we suggested for the synthesis
of heterocyclic interphenyleneoxaprostanoids to use
alternative to 3-benzoyltetronic acids 3-arylidene-
tetrahydrofuran-2,4-diones XVIII obtained by Knoeve-
nagel condensation of tetronic acids with aromatic
aldehydes [8–10]. Compounds XVIII under reduction
are synthetically equivalent to the 3-benzoyltetronic
acids since they should result in the same reaction
products, 3-(alkoxybenzyl)tetronic acids I. In contrast
to 3-arylidenetetrahydrofuran-2,4-diones XVIII their
carbocyclic and some heterocyclic analogs are highly
reactive and form only as intermediates in various
multicomponent reactions involving β-dicarbonyl
compounds and aromatic aldehydes [11].
The reaction of tetronic acid IIIa with acids VII and
VIII preparedbyalkylatingaldehydesXaandXbfollowed
by Jones oxidation of the corresponding aldehydes Va
and Vb, and also with p-methoxybenzoic acid (IX) by
procedure [7] but without 4-(dimethylamino)pyridine led
to the formation of the corresponding O-acyl derivatives
XI–XIII in high yields. Enol acylates XI–XIII treated
with acetone cyanohydrin in acetonitrile rearranged
into 3-benzoyltetronic acids XIV–XVI as showed the
characteristic coloration of spots at TLC analysis of
the reaction mixtures when developed with iron(III)
chloride. However these compounds suffer deacylation
already at the workup of the reaction mixture and
at further purification. Therefore we failed to obtain
compounds XIV and XV in individual state. Only 3-(4-
Compounds XVIII may be prepared in two ways: by
condensation of hydroxyl-containing aromatic aldehydes
with tetronic acids III with subsequent O-alkylation of
hydroxybenzylidene derivatives XVII by a synthons
Scheme 2.
R
R
R
BuOH/
NaOH
H2Cr2O7
HO2C
O
OHC
O
Br
+
OHC
OH
(CH3)2CO
Xa, Xb
VII, VIII
Va, Vb
O
O
O
O
_
(CH3)2C(CN)OH, Et3N
CH3CN
R
O
VII IX
DCC, Et3N, CH2Cl2
O
O
O
O
R'
R
O
XI_XIII
O
O
XIV_XVI
IIIa
R'
O
H+, H2O
IIIa + VII_IX
= C4H9 (XI, XIV), CH3 (XIII, XVI); R = OCH3, R = C4H9 (XII,
R = H (Va,VII, Xa), OCH3 (Vb,VIII, Xb); R = H, R
'
'
XV).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008

HETEROCYCLIC ANALOGS OF PROSTAGLANDINES: IV.
659
Scheme 3.
O
1
CO2R'
7
2
H
O
O
O
7
1
O
1
3
7
CO2R'
CO2R'
2
2
O
O
O
O
O
B
3
3
O
O
O
R
R
I
VIII
X
R
III
O
2
3
OH
1
H
7
A
Hlg
CO2R'
2
1
Hlg
CO2R'
O
O
7
7
[H]
3
3
O
OH
O
OH
C
O
O
R
R
XVII
XIX
of C1–C2-α-prostanoid chain (A), or by condensation
of tetronic acids with aldehydes supplied with already
formed structure of the interphenylene α-chain (B). The
(C) version of the synthesis of key compounds I involving
primary reduction of the cross-conjugated multiple bond
in the hydroxybenzylidenetetronic acids XVII seems less
probable for the O-alkylation of the reduction products
XIX can occur both at the phenol hydroxy group and at
the enolized cyclic β-dicarbonyl system (Scheme 3).
that the hydroxybenzylidenetetronic acids XX and XXI
formed in 40–47% yield at melting the tetronic acid with
excess hydroxyaldehydes without catalyst. Presumably
autocatalysis occurred also in this reaction.
We tried to alkylate compounds XX and XXI with
butyl bromide in the presence of a base but failed to obtain
the target 3-arylidenetetronic acids XXIII and XXIV.
Under the given conditions the heterocycle of the initial
substances suffered degradation.
To test the probability of the way A tetronic acid IIIa
was put into condensation with 4-hydroxybenzaldehyde
(Xa) and vanillin (Xb) in the presence of concn. HCl [8]
(Scheme 4). However we failed to obtain in this case the
target hydroxybenzylidenetetrahydrofuran-2,4-diones
XX and XXI for under the given conditions a tarring
of the reaction mixture occurred. The replacement of
HCl by p-toluenesulfonic acid also did not help to avoid
tarring.
Unlike hydroxyaldehydes anisaldehyde (VI), 4-butoxy-
benzaldehyde(Va), and4-butoxy-3-methoxybenzaldehyde
(Vb) cleanly reacted with tetronic acid under the action
of concn. HCl giving the corresponding alkoxy-
benzylidenetetronic acids XXII–XXIV in high yields.
The condensation of tetronic acid IIIa with cinnamic
aldehyde easily proceeded both in the presence of concn.
HCl and under autocatalysis conditions in methanol
solution. In the latter case the yield of 3-(3-phenylallyli-
dene)tetrahydrofuran-2,4-dione (XXV) was 56%.
In [9] the Knoevenagel condensation of tetronic acid
with a series of heteroaromatic aldehydes was performed
in anhydrous ethanol. In this procedure the reaction was
catalyzed by acid protons of the enolyzed cyclic
β-dicarbonyl compound. The application of this method to
4-hydroxybenzaldehyde and vanillin showed that although
the condensation of acid IIIa occurred with both aldehydes
(as seen from the gradual change of the reaction mixture
color from colorless to bright yellow), the reaction was fast
enough only with vanillin proceeding with precipitation
of reaction product XXI formed in 89% yield. We found
From the above mentioned studies it was concluded
that the building of the structure of the key β-dicarbonyl
precursors I of interphenyleneoxaprostanoids should be
more feasible to perform by condensation of tetronic acid
with alkoxy derivatives of aromatic aldehydes.
Therefore we prepared by O-alkylation of phenolates
of 4-hydroxybenzaldehyde, 3-hydroxybenzaldehyde,
vanillin, and isovanillin with chloroacetic acid by
method [12] formylphenoxyacetic acids XXVI–XXIX.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008

PASHKOVSKII et al.
660
Scheme 4.
O
R
Xa, Xb
_H2O
O
OH
_
O
BuBr/OH
(E,Z)-XX, XXI
O
R
Va, Vb, VI
IIIa
O
_H2O
OR'
O
(E,Z)-XXII_XXIV
O
O
H
O
_H2O
O
(E,E +Z,E)-XXV
' '
R = H (XX), OCH3 (XXI); R = H, R = CH3 (XXII), C4H9 (XXIII); R = OCH3, R = C4H9 (XXIV).
The treatment of the latter with diazomethane led to the
formation of methyl esters XXX–XXXIII (Scheme 5).
Compounds XXVI–XXXIII are synthons for preparation
3-oxa-3,7-inter-para- or -meta-phenylene α-chains both
of various type and substitution character of the aromatic
ring. The residue of the acetic acid serves as a fragment
C1–C2 of the α-chain, and the formyl group would
be a binding unit between the α-chain and the cyclic part of
the future prostanoid and C7 atom of its carbon skeleton.
acid under autocatalytic conditions, and the condensation
product XXXVI formed in 48% yield. It proved that the
presence of an ester group in the oily methyl ester XXXI
did not prevent the use of concn. HCl as a condensation
agent, and the corresponding arylidene derivative XXXV
1
was obtained in 65% yield. According to the H NMR
spectrum of compound XXXV it contained over 92% of
ester. Inasmuch as under the action of concn. HCl the
condensation proceeded readily only with liquid and
difficultly crystallizable aldehydes in reactions of tetronic
acid with solid esters of formylphenoxyacetic acids XXX
Among the esters of formylphenoxyacetic acids XXX–
XXXIII only compound XXXII reacted with tetronic
Scheme 5.
7
1
2
OHC
_
OHC
ClCH2CO2H, OH- H2O
CO2H (R')
3
O
OH
R
R
XXVI_XXIX
O
O
7
2
1
7
CH2N2/Et2O
CO2CH3 (R')
3
O
2
1
IIIa
OHC
CO2CH3 (R')
3
O
R
O
R
(E,Z)-XXXIV_XXXVII
= p-OCH2CO2H (XXVI), m-OCH2CO2H (XXVII), p-OCH2CO2CH3 (XXX, XXXIV), m-OCH2CO2CH3
(XXXI, XXXV); R = m-OCH3, R = p-OCH2CO2H (XXVIII), p-OCH2CO2CH3 (XXXII, XXXVI); R = p-OCH3, R
m-OCH2CO2H (XXIX), m-OCH2CO2CH3 (XXXIII, XXXVII). (Position of R and R in aromatic ring is indicated with
respect to C7-substituent).
XXX_XXXIII
R = H, R
'
'
'
=
'
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HETEROCYCLIC ANALOGS OF PROSTAGLANDINES: IV.
661
and XXXIII we used as catalyst aluminum chloride (2
equiv) in THF [10]. The instability of the ester group in
the course of reaction mixture workup for neutralization
of the catalyst reduced the yield of condensation products
XXXIV and XXXVII to 27–29%.
The reduction of compounds XXXIV and XXXVII by
method b is complicated by the hydrolysis of ester group;
however the process under controlled conditions followed
by a fast workup of the reaction mixture provided the
corresponding esters in good yield. For instance, ester
XLII was thus obtained in 59% yield.
A double set of some signals in the 1H and 13C NMR
spectra of 3-arylidenetetronic acids XX–XXIV, XXXIV–
XXXVII indicates that these compounds are mixtures
of Ε- and Z-isomers. In the 1H NMR spectra the greatest
difference in the chemical shifts (Δ 0.11–0.12 ppm) is
observed for the singlets of methylene group protons of
the heterocycle of both isomers in the region 4.60–4.76
ppm. The measuring of the ratio of integral intensity
of these signals indicated that the ratio of geometrical
isomers of compounds XX–XXIV, XXXIV–XXXVII
in the mixture equaled ~1:2. In the case of 3-(3-phen-
ylallylidene)tetronic acid (XXV) the ratio of (Ε,Ε)- and
(Z,E)-isomers in the mixture was ~ 1:1. The ratio in the
mixture of isomers of the cited compounds virtually did
not depend on the method of their preparation.
Unlike 3-arylidenetetronic acids XXII–XXIV,
XXXIV–XXXVII 3-(3-phenylallylidene)tetronic acid
XXV containing two conjugated multiple bonds in the
side chain under the treatment with triethylsilane in
trifluoroacetic acid was converted in to intractable mixture
of substances. Yet the reaction of compound XXV with
the sodium cyanoborohydride in a mixture of THF with
2 N aqueous HCl yielded a product of reduction of one
double bond of the side chain. Hypothetically the partial
reduction of the 1,3-diene system of 3-(3-phenylallylide
ne)tetronic acid XXV may result in 3-cinnamyltetronic
acid (XLV) or in its regioisomer 3-(3-phenylpropen-1-
1
yl)tetronic acid XLVI. However the H NMR and IR
spectra do not unambiguously indicate the position of
the double bond.
The final stage of building up the 3,7-interphenylene
α-prostanoid chain involves the reduction of the activated
exocyclic cross-conjugated (E,Z)-double bond of the
mixture of isomeric 3-aryloxybenzylidenetetronic acids
XXII–XXIV, XXXIV–XXXVII. To this end we applied
the methods developed for selective hydrogenolysis
of a carbonyl group of the acyl side chain of cyclic β-
tricarbonyl compounds: the treatment with triethylsilane
in trifluoroacetic acid (method a) and with the sodium
cyanoborohydride in a system THF–2 N aqueous HCl
(method b) [7].
To establish the location of the double bond the
reduction product was treated with diazomethane, and we
obtained a mixture (~2:1) of regioisomeric enol methyl
ethers XLVII and XLVIII. In the 1H NMR spectrum of
the mixture the greatest difference in the chemical shifts is
observed for the doublets of the protons of the methylene
group in the side chain of both isomers (Δδ 0.18 ppm),
whereas Δδ of the doublet of triplets belonging to vinyl
proton contiguous to the methylene group amounts to
0.05 ppm, and Δδ of the doublets of the second vinyl
proton is 0.02 ppm. Hence the methylene group of the
chain in the mentioned enol ethers is adjacent to the
chemically modified heterocyclic β-dicarbonyl system.
This fact unambiguously testifies to structure XLV of their
precursor and not to structure XLVI where the methylene
group is maximally remote from the heterocycle.
As expected, the cross-conjugated double bond of
compounds XXII–XXIV, XXXIV–XXXVII selectively
and equally efficiently was reduced by both methods;
therewith the reaction by method a did not require
catalysis by Lewis acids.
(E,Z)-XXII_XXIV, XXXIV_XXXVII
The reaction of 3-cinnamyltetronic acid (XLV) with
triethylsilane in trifluoroacetic acid led to the formation
of 3-(3-phenylpropyl)tetronic acid (XLIX) in 79% yield.
Hence the reduction of the double bond of the cinnamyl
fragment of compound XLV is related to the increase
in the acidity of the reaction medium. Apparently these
experiments suggest that by varying the pH of the medium
it would be possible to control the degree of selectivity
of reduction with cyanoborohydride system of the diene
moiety in the 3-(3-phenylallylidene)tetronic acid (XXV).
However the increase in HCl concentration from 2N to
12N in the reaction mixture during compound XXV
Et3SiH, CF3CO2H (a),
O
7
NaBH3CN/ THF
aqueous HCl (b)
R'
2
N
O
R
O
XXXVIII_XLIV
'
= p-OCH3 (XXII, XXXVIII), p-OC4H9
R = H, R
(XXIII, XXXIX), p-OCH2CO2CH3 (XXXIV, XLI),
m-OCH2CO2CH3 (XXXV, XLII); R = m-OCH3,
R
'
= p-OC4H9 (XXIV, XL), p-OCH2CO2CH3 (XXXVI,
XLIII); R = p-OCH3, R = m-OCH2CO2CH3 (XXXVII,
XLIV).
'
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008

PASHKOVSKII et al.
662
Scheme 6.
6.40
6.20
6.42
3.18
6.25
a
reduction with sodium cyanoborohydride did not result
in formation even of traces of 3-(3-phenylpropyl)tetronic
acid (XLIX), and the only product was compound XLV
(Scheme 6).
The alkylation of 3-(4-butoxybenzyl)tetronic acid
tetrabutylammonium salt (XXXIX) with dimethyl
sulfate led to the formation of 4-methoxy derivative
LI. The boiling of the latter with heptylamine gave
3,7-interphenylene 3,10-dioxa-13-azaprostanoid (LII)
without a characteristic for natural prostaglandines
terminal carboxy group in the α-chain (Scheme 7).
The results obtained are totally different from the
results of reduction of 3-cinnamoyltetronic acid (L). The
reduction of compound L both by method a and method b
using 2N HCl involved the hydrogenolysis of the carbonyl
group and the reduction of the double bond of the acyl
chain conjugated with the carbonyl resulting in a high
yield of 3-(3-phenylpropyl)tetronic acid (XLIX) as the
only reaction product.
The stringent conditions of the reaction between
4-methoxy derivatives of tetrahydrofuran-2,4-diones
and amines hamper the preparation of 10-oxa-13-
azaprostanoids with an ester group in the α-chain, for in
this event the amine competitively reacts with the latter.
In contrast to 4-methoxy-2,5-dihydrofuran-2-ones the
5-ethoxy-2,3-dihydrofuran-3-ones obtained by treating
the corresponding 3-substituted tetronic acids with
triethyloxonium tetrafluoroborate cleanly react with
amines at room temperature providing in high yield
11-oxa-13-aza-prostanoids with an ester group in the
α-chain [1]. A phenoxy group in the interphenylene
α-chain of the obtained prostanoid precursors activates
3-Arylalkyl-substituted tetrahydrofuran-2,4-diones
XXXVIII–XLV and XLIX possess the β-dicarbonyl
system of the initial tetronic acid indispensable for
building in the nitrogen-containing ω-prostanoid
chains. The methods of introducing these chains into
the β-dicarbonyl precursors of heteroprostanoids were
described in detail in the previous communication [1].
Here we consider some important examples.
Scheme 7.
Bu4N+OH_/MeOH,
O
O
H2NC7H15
(CH3)2SO4, C6H6
O
O
XXXIX
O
O
N
OCH3
H
LI
LII
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008

HETEROCYCLIC ANALOGS OF PROSTAGLANDINES: IV.
663
Scheme 8.
O
_
CO2CH3
Et3O+BF4 /CH2Cl2
O
O
XLI, XLII
O
LIII, LIV
O
O
H2NC7H15
20oC
N
O
H
O
N
H
LV, LVI
Scheme 9.
7
H
N
CO2CH3
9
O
O
_
8
.
HCl H2N(CH2)5CO2CH3
MeONa/MeOH
O
Et3O+BF4 /CH2Cl2
10
12
O
XL
17
O
11
O
13
O
O
LVII
LVIII
O
the ester group that reacts with amine even at room
temperature. For instance, reaction of compounds LIII
and LIV with heptylamine led to the formation of
products LV and LVI originating from the amine attack
on two reaction centers in 58 and 47% yield respectively
(Scheme 8).
in 9-oxa-7-azaprostanoids LXI and LXII with a benzene
ring in the ω-chain of various degree of saturation
(Scheme 10).
EXPERIMENTAL
The use as a source of amino group amino acids
esters in the reaction with 4-substituted 5-ethoxy-2,3-
dihydrofuran-3-ones results in 9-oxa-7-azaprostanoids.
For instance, the reaction of enol derivative LVII with
methyl ε-aminocaproate gave 9,17-dioxa-7-aza-13,17-
inter-p-phenylene prostanoid (LVIII) (Scheme 9).
Melting points of compounds obtained were measured
on a Boёtius heating block. IR spectra were recorded on
a spectrophotometer UR-20 from samples in films or
1
pellets with KBr. H (500 MHz) and 13C (125.7 MHz)
NMR spectra were registered on a spectrometer Bruker
Avance-500, internal reference TMS. Mass spectra were
taken on MKh-1320 instrument at ionizing electrons
energy 70 eV.
In its turn the reaction of 5-ethoxy-2,3-dihydrofuran-3-
ones LIX and LX with methyl ε-aminocaproate resulted
Scheme 10.
_
Et3O+BF4 /
O
H
CO2CH3
N
.
O
HCl H2N(CH2)5CO2CH3,
CH2Cl2
XLV, XLIX
O
MeONa/MeOH
O
O
LXI, LXII
LIX,
LX
LIII, p-OCH2CO2CH3, LIV, m-OCH2CO2CH3, LV, p-OCH2CONHC7H15, LVI, m-OCH2CONHC7H15.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008

PASHKOVSKII et al.
664
4-Butoxybenzaldehyde (Va) and 4-butoxy-3-methoxy-
(2Harom, 3J 9.0 Hz). 13C NMR spectrum (CDCl3), δ, ppm:
55.7 (CH3), 68.7 (CH2), 100.6 (CH), 114.4 (2CH), 119.0
(C), 132.9 (2CH), 161.3 (C), 165.1 (C), 169.5 (C), 172.5
(C). Found, %: C 61.43; H 4.23. [M]+ 234. C12H10O5.
Calculated, %: C 61.54; H 4.30.
benzaldehyde (Vb) were prepared by boiling phenolates
of 4-hydroxybenzaldehyde (Xa) and vanillin (Xb)
with butyl bromide in 1-butanol in 80 and 81% yield
respectively. 4-Butoxybenzoic acid (VII) and 4-butoxy-
3-methoxybenzoic acid (VIII) were obtained by oxidation
of compounds Va and Vb with Jones reagent in 54–58%
yield.
Izomerization of 5-oxo-2,5-dihydrofuran-3-yl-
alkoxybenzoates XI–XIII under the action of acetone
cyanohydrin. To a solution of 12 mmol of enol acylate
XI–XIII in 10 ml of CH3CN was added 24 mmol of Et3N
and 0.4 ml of acetone cyanohydrin. The reaction mixture
was stirred at room temperature for 24 h. The acetonitrile
was removed in a vacuum, the residue was treated with 25
ml of 1.5 N HCl, the reaction product was extracted from
the water phase into chloroform (3×30 ml). The combined
extracts were washed with water and dried over Na2SO4.
After filtration and evaporation of the solvent in a vacuum
the residue was recrystallized from ethyl acetate.
The synthesis of 5-oxo-2,5-dihydrofuran-3-
ylalkoxy-benzoates XI–XIII were performed by a
published procedure [7] except for the use of 4-(di-
methylamino)pyridine.
5-Oxo-2,5-dihydrofuran-3-yl-4-butoxybenzoate
(XI). Yield 67%, mp 89–91°C (from ethyl acetate). IR
spectrum, cm–1: 1260 (max), 1610, 1630, 1750 sh, 1760,
1
1780. H NMR spectrum (CDCl3), δ, ppm: 1.00 t [3H,
O(CH2)3CH3, 3J 7.5 Hz], 1.51 sextet [2H, O(CH2)2CH2CH3,
3J 7.5 Hz], 1.81 quintet (2H, OCH2CH2CH2CH3, 3J 7.0 Hz),
3-(4-Methoxybenzoyl)tetrahydrofuran-2,4-dione
(XVI). Yield 45%, mp 126–128°C (from ethyl acetate).
IR spectrum, cm–1: 1515, 1545, 1590, 1615, 1685, 1750.
1H NMR spectrum (CDCl3), δ, ppm: 3.92 s (3H, OCH3),
4.06 t [2H, OCH2(CH2)2CH3, 3J 6.5 Hz], 5.06 narrow d
4
(2H, CH2 of cycle, J 1.0 Hz), 6.11 narrow t (1Hvinyl
,
4J 1.0 Hz), 6.98 d (2Harom, 3J 8.5 Hz), 8.05 d (2Harom, 3J
8.5 Hz). 13C NMR spectrum (CDCl3), δ, ppm: 13.8 (CH3),
19.2 (CH2), 31.0 (CH2), 68.2 (CH2), 68.8 (CH2), 100.6
(CH), 114.8 (2CH), 118.7 (C), 132.9 (2CH), 161.3 (C),
3
4.67 br.s (2H, CH2), 7.01 d (2Harom, J 9.0 Hz), 8.49 d
(2Harom, 3J 9.0 Hz).
Formylphenoxyacetic acids XXVI–XXIX were
prepared by procedure [12] in 49–59% yield. Methyl
esters of formylphenoxyacetic acids XXX–XXXIII
were obtained in 98–99% yield treating compounds
XXVI–XXIX with diazomethane solution in ether.
164.7 (C), 169.5 (C), 172.6 (C). Found, %: C 65.07;
H
5.79. [M]+ 276. C15H16O5. Calculated, %: C 65.21;
H 5.84.
5-Oxo-2,5-dihydrofuran-3-yl-4-butoxy-3-methoxy-
benzoate (XII). Yield 70%, mp 110–112°C (from
ether). IR spectrum, cm–1: 1275 (max), 1605, 1630,
1745, 1765, 1775 sh. 1H NMR spectrum (CDCl3), δ,
Condensation of tetronic acid IIIa with substituted
aromatic aldehydes by Knoevenagel reaction. a. To
a dispersion of 0.2 g (2 mmol) of tetronic acid in 6 mmol
of an appropriate aldehyde was added at stirring 0.18 ml
(2.2 mmol) of concn. HCl. After 2 h the solid reaction
product was dispersed in ethyl ether. After cooling the
dispersion to 0°C the precipitate was filtered off, washed
with ether, then with distilled water, dried in air, and
recrystallized.
3
ppm: 1.00 t [3H, O(CH2)3CH3, J 7.5 Hz], 1.52 sextet
3
[2H, O(CH2)2CH2CH3, J 7.5 Hz], 1.88 quintet (2H,
3
OCH2CH2CH2CH3, J 7.0 Hz), 3.94 s (3H, OCH3),
4.12 t [2H, OCH2(CH2)2CH3, J 6.5 Hz], 5.06 narrow d
4
(2H, CH2 of cycle, J 1.5 Hz), 6.11 narrow t (1Hvinyl
,
4J 1.5 Hz), 6.94 d (1H5arom, J 8.5 Hz), 7.54 narrow d
(1H2arom, 4J 2.5 Hz), 7.75 d.d (1H6arom, 3J 8.5, 4J 2.5 Hz).
13C NMR spectrum (CDCl3), δ, ppm: 13.8 (CH3), 19.1
(CH2), 30.9 (CH2), 56.2 (CH3), 68.8 (CH2), 68.9 (CH2),
100.7 (CH), 111.5 (CH), 112.8 (CH), 118.7 (C), 125.3
(CH), 149.4 (C), 154.6 (C), 161.4 (C), 169.5 (C), 172.5
(C). Found, %: C 62.59; H 5.87. [M]+ 306. C16H18O6.
Calculated, %: C 62.74; H 5.92.
3
b. A solution of 0.5 g (5 mmol) of tetronic acid and
15 mmol of aromatic aldehyde in 5 ml of anhydrous
methanol was stirred for 24–48 h at room temperature.
The solid reaction product was filtered off, washed with
ethyl ether, dried in air, and recrystallized.
c. A mixture of 0.3 g (3 mmol) of tetronic acid and
9 mmol of hydroxyl-containing aromatic aldehyde was
heated at stirring till the reaction mixture melted. After
the formation of water drops on the walls of reactor ended
the reaction mixture was cooled to room temperature.
The solid residue was washed with ethyl ether and
recrystallized.
5-Oxo-2,5-dihydrofuran-3-yl-4-methoxybenzoate
(XIII). Yield 75%, mp 117–119°C (from ether). IR spec-
1
trum, cm–1: 1255 (max), 1610, 1630, 1750, 1770. H
NMR spectrum (CDCl3), δ, ppm: 3.91 s (3H, OCH3),
4
5.06 nar-row d (2H, CH2, J 1.5 Hz), 6.12 narrow t
4
(1Hvinyl, J 1.5 Hz), 7.00 d (2Harom, 3J 9.0 Hz), 8.07 d
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HETEROCYCLIC ANALOGS OF PROSTAGLANDINES: IV.
665
d. To a mixture of 0.54 g (5.4 mmol) of tetronic acid
and 5.7 mmol of aromatic aldehyde in 35 ml of THF was
added in one portion 1.42 g (10.6 mmol) of anhydrous
aluminum chloride. The reaction mixture was stirred for
46 h at room temperature. The solid product was filtered
off, dried in air, and recrystallized. The treatment of
the organic phase with Na2CO3 along procedure [10]
did not provide additional portion of the condensation
product.
3J 7.5 Hz], 1.52 sextet [2H, O(CH2)2CH2CH3, 3J 7.5 Hz],
1.82 quintet (2H, OCH2CH2CH2CH3, 3J 7.0 Hz), 4.10 t,
4.11 t [2H, OCH2(CH2)2CH3, J 6.5 Hz], 4.60 s (1.3H,
3
CH2 of cycle) and 4.71 s (0.7H, CH2 of cycle), 7.01 d
3
(2Harom, J 9.0 Hz), 7.92 s (0.65H, Hvinyl) and 7.94 s
3
(0.35H, Hvinyl), 8.53 d and 8.54 d (2Harom, J 9.0 Hz).
13C NMR spectrum (CDCl3), δ, ppm: 13.8 (2CH3), 19.1
(2CH2), 31.0 (2CH2), 68.5 (2CH2), 71.6 (CH2), 72.6
(CH2), 113.3 (C), 113.5 (C), 115.2 (2CH), 115.4 (2CH),
125.0 (C), 126.3 (C), 138.3 (2CH), 139.3 (2CH), 153.5
(CH), 155.6 (CH), 165.5 (C), 165.9 (C), 168.2 (C), 171.1
(C), 194.4 (C), 196.5 (C). Found, %: C 69.12; H 6.16.
[M]+ 260. C15H16O4. Calculated, %: C 69.22; H 6.20.
(E,Z)-3-(4-Hydroxybenzylidene)tetrahydrofura
n-2,4-dione (XX). Yield 40% (c). IR spectrum, cm–1:
1175 (max), 1560, 1585 sh, 1625, 1705, 1750. 1H NMR
spectrum (CDCl3+CD3OD), δ, ppm: 3.95 br.s (1H,
OHphenol), 4.62 s (1.4H, CH2) and 4.73 s (0.6H, CH2),
(E,Z)-3-(4-Butoxy-3-methoxybenzylidene)tetra-
hydrofuran-2,4-dione (XXIV). Yield 79% (a). IR
spectrum, cm–1: 1165, 1575 br, 1615, 1705, 1765. 1H NMR
spectrum (CDCl3), δ, ppm: 1.00 t [3H, O(CH2)3CH3,
3J 7.5 Hz], 1.52 sextet [2H, O(CH2)2CH2CH3, 3J 7.5 Hz],
1.89 quintet (2H, OCH2CH2CH2CH3, 3J 7.0 Hz), 3.98 s
(1.05H, OCH3) and 4.01 s (1.95H, OCH3), 4.16 t and
4.17 t [2H, OCH2(CH2)2CH3, 3J 6.5 Hz], 4.60 s (1.3H,
CH2 of cycle) and 4.72 s (0.7H, CH2 of cycle), 6.96 d
3
6.96 d (2Harom, J 9.0 Hz), 7.90 s (0.7H, Hvinyl) and
7.94 s (0.3H, Hvinyl), 8.50 d (2Harom, 3J 9.0 Hz). Found,
%: C 64.58; H 3.87. [M]+ 204. C11H8O4. Calculated, %:
C 64.71; H 3.95.
(E,Z)-3-(4-Hydroxy-3-methoxybenzylidene)-
tetrahydrofuran-2,4-dione (XXI). Yield 89 (a), 47%
(b). IR spectrum, cm–1: 1175, 1570 (max), 1620, 1700,
1
1750. H NMR spectrum (CDCl3), δ, ppm: 4.04 s (1.05H,
5
(0.35H, H5arom, J 8.0 Hz) and 6.97 d (0.65H, Harom
,
3
OCH3) and 4.07 s (1.95H, OCH3), 4.61 s (1.3H, CH2)
3J 8.5 Hz), 7.74 br.d (0.35H, H6arom, 3J 8.0 Hz) and 7.76
br.d (1H, H6arom, 3J 8.5 Hz), 7.90 s (0.65H, Hvinyl) and 7.91
s (0.35H, Hvinyl), 8.74 br.s (0.65H, H2arom) and 8.79 br.s
(0.35H, H2arom). 13C NMR spectrum (CDCl3), δ, ppm:
13.8 (2CH3), 19.1 (2CH2), 30.8 (2CH2), 56.1 (2CH3),
69.1 (2CH2), 71.6 (CH2), 72.7 (CH2), 111.7 (2CH), 113.1
(C), 113.4 (C), 115.8 (CH), 116.7 (CH), 125.4 (C), 126.7
(C), 133.1 (CH), 134.2 (CH), 149.2 (C), 149.4 (C), 154.0
(CH), 155.7 (C), 156.1 (C), 156.3 (CH), 168.5 (C), 171.2
(C), 194.6 (C), 196.5 (C). Found, %: C 66.03; H 6.19.
[M]+ 290. C16H18O5. Calculated, %: C 66.19; H 6.25.
and 4.73 s (0.7H, CH2), 7.04 d and 7.05 d (1H, H5
,
arom
3J 8.5 Hz), 7.64 d.d (0.35H6arom, J 8.5, J 2.0 Hz) and
3
4
3
4
7.69 d.d (0.65H6arom, J 8.5, J 2.0 Hz), 7.92 s (0.65H,
Hvinyl) and 7.93 s (0.35H, Hvinyl), 8.86 d (0.65H, H2
,
arom
4J 2.0 Hz) and 8.94 d (0.35H, H2arom, 4J 2.0 Hz). Found,
%: C 61.46; H 4.21. [M]+ 234. C12H10O5. Calculated, %:
C 61.54; H 4.30.
(E,Z)-3-(4-Methoxybenzylidene)tetrahydrofuran-
2,4-dione (XXII). Yield 66% (a). IR spectrum, cm–1:
1170, 1570 sh, 1585 (max), 1625, 1705, 1755. 1H NMR
spectrum (CDCl3), δ, ppm: 3.94 s (1.05H, OCH3) and
3.95 s (1.95H, OCH3), 4.61 Cs(1.3H, CH2) and 4.72 s
(0.7H, CH2), 7.04 d (2Harom, 3J 9.0 Hz), 7.93 s (0.65H,
Hvinyl) and 7.95 s (0.35H, Hvinyl), 8.55 d and 8.56 d
(2Harom, 3J 9.0 Hz). 13C NMR spectrum (CDCl3), δ, ppm:
55.8 (2CH3), 71.6 (CH2), 72.6 (CH2), 113.6 (C), 113.8
(C), 114.8 (2CH), 114.9 (2CH), 125.2 (C), 126.5 (C),
138.2 (2CH), 139.2 (2CH), 153.4 (CH), 155.6 (CH), 165.8
(C), 166.1 (C), 168.0 (C), 170.9 (C), 194.4 (C), 196.5
(C). Found, %: C 65.93; H 4.50. [M]+ 218. C12H10O4.
Calculated, %: C 66.05; H 4.62.
(E,Z)-3-[(E)-3-Phenylallylidene]tetrahydrofuran-
2,4-dione (XXV). Yield 81 (a), 56% (b). IR spectrum,
cm–1: 1180, 1590 (max), 1610 (max), 1645 sh, 1715,
1770. 1H NMR spectrum (CDCl3), δ, ppm: 4.59 s (1.1H,
CH2) and 4.64 s (0.9H, CH2), 7.42–7.55 m (3Harom
+
2
6
3
H
vinyl), 7.69 d (2H, Harom+Harom, J 7.0 Hz), 7.74 d
3
(0.55H, Hvinyl, J 12.0 Hz) and 7.80 d (0.45H, Hvinyl
,
3J 12.0 Hz), 8.27 d.d and 8.32 d.d [1Hvinyl, 3J1 15.0 (8.27),
15.5 (8.32), 3J2 12.0 Hz]. 13C NMR spectrum (CDCl3),
δ, ppm: 72.1 (CH2), 72.3 (CH2), 115.4 (C), 115.7 (C),
122.8 (CH), 123.2 (CH), 129.3 (4CH), 129.5 (4CH),
132.3 (2CH), 134.7 (C), 134.9 (C), 151.7 (CH), 153.2
(CH), 155.7 (CH), 156.0 (CH), 167.9 (C), 169.3 (C),
195.6 (C), 195.8 (C). Found, %: C 72.80; H 4.61. [M]+
214. C13H10O3. Calculated, %: C 72.89; H 4.71.
(E,Z)-3-(4-Butoxybenzylidene)tetrahydrofuran-
2,4-dione (XXIII). Yield 71% (a). IR spectrum, cm–1:
1175, 1560 (max), 1585 (max), 1615, 1715, 1765. 1H NMR
spectrum (CDCl3), δ, ppm: 1.00 t [3H, O(CH2)3CH3,
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PASHKOVSKII et al.
666
(C). Found, %: C 58.66; H 4.53. [M]+ 306. C15H14O7.
(E,Z)-Methyl 2-{4-[(2,4-dioxodihydrofuran-3(2H)-
ylidene)methyl]phenoxy}acetate (XXXIV). Yield 29%
(d). IR spectrum, cm–1: 1170, 1570, 1590 (max), 1620,
1700, 1745, 1755. H NMR spectrum (CDCl3+CD3OD),
δ, ppm: 3.85 s (3H, CO2CH3), 4.65 s (1.4H, CH2 of
cycle) and 4.76 s (0.6H, CH2 of cycle), 4.83 br.s (2H,
OCH2CO2Me), 7.06 d (2Harom, 3J 8.5 Hz), 7.94 s (0.7H,
Calculated, %: C 58.82; H 4.61.
(E,Z)-Methyl 2-{5-[(2,4-dioxodihydrofuran-
3(2H)-ylidene)methyl]-2-methoxyphenoxy}acetate
(XXXVII). Yield 27% (d). IR spectrum, cm–1: 1300
1
1
(max), 1565, 1605, 1700, 1730, 1745. H NMR spectrum
(CDCl3), δ, ppm: 3.85 s and 3.86 s (3H, CO2CH3), 4.02 s
and 4.03 s (3H, OCH3), 4.60 s (1.4H, CH2 of cycle) and
4.72 s (0.6H, CH2 of cycle), 4.84 s (0.6H, OCH2CO2Me)
and 4.87 s (1.4H, OCH2CO2Me), 7.01 d and 7.02 d (1H,
H3arom, 3J 8.5 Hz), 7.74 br.d (1H, H4arom, 3J 8.5 Hz), 7.88
s and 7.89 s (1H, Hvinyl), 8.73 d (0.7H, H6arom, 4J 1.5 Hz)
and 8.76 d (0.3H, H6arom, 4J 2.0 Hz). 13C NMR spectrum
(CDCl3), δ, ppm: 52.5 (2CH3), 56.4 (2CH3), 65.5 (2CH2),
71.6 (CH2), 72.7 (CH2), 111.5 (2CH), 113.7 (C), 114.0
(C), 116.6 (CH), 117.7 (CH), 125.4 (C), 126.7 (C), 133.9
(CH), 134.9 (CH), 147.1 (C), 147.3 (C), 153.5 (CH),
155.8 (CH), 155.9 (C), 156.2 (C), 168.2 (C), 168.6 (C),
168.7 (C), 170.9 (C), 194.7 (C), 196.4 (C). Found, %:
C 58.62; H 4.55. [M]+ 306. C15H14O7. Calculated, %:
C 58.82; H 4.61.
H
vinyl) and 7.97 s (0.3H, Hvinyl), 8.57 d (2Harom,
3J 8.5 Hz). 13C NMR spectrum (CDCl3+CD3OD), δ,
ppm: 52.7 (2CH3), 65.3 (2CH2), 72.1 (CH2), 73.1 (CH2),
114.5 (C), 114.7 (C), 115.5 (2CH), 115.6 (2CH), 126.2
(C), 127.5 (C), 138.4 (2CH), 139.3 (2CH), 153.7 (CH),
155.7 (CH), 163.9 (C), 164.3 (C), 169.0 (3C), 171.7 (C),
194.8 (C), 197.0 (C). Found, %: C 60.69; H 4.29. [M]+
276. C14H12O6. Calculated, %: C 60.87; H 4.38.
(E,Z)-Methyl 2-{3-[(2,4-dioxodihydrofuran-3(2H)-
ylidene)methyl]phenoxy}acetate (XXXV). Yield 65%
(a). IR spectrum, cm–1: 1170 (max), 1590, 1615, 1715,
1
1775. H NMR spectrum (CDCl3), δ, ppm: 3.84 s and
3.85 s (3H, CO2CH3), 4.64 s (1.4H, CH2 of cycle) and
4.75 s (0.6H, CH2 of cycle), 4.76 s (0.6H, OCH2CO2Me)
and 4.78 s (1.4H, OCH2CO2Me), 7.26–7.31 m (1H,
H4arom), 7.45 t and 7.47 t (1H, H5arom, 3J 8.0 Hz), 7.76 br.d
3-Cinnamoyltetrahydrofuran-2,4-dione (L) was
prepared by procedure [1]. Yield 69%, mp 141–143°C
(from ethyl acetate) (138–140°C [13]).
(1H, H6arom, J 7.5 Hz), 7.96 s and 7.97 s (1H, Hvinyl),
3
8.42 narrow t (0.7H, H2arom, 4J 2.0 Hz) and 8.46 narrow t
(0.3H, H2arom, 4J 2.0 Hz). 13C NMR spectrum (CDCl3), δ,
ppm: 52.4 (2CH3), 65.1 (CH2), 65.2 (CH2), 71.8 (CH2),
72.8 (CH2), 116.9 (CH), 117.2 (C), 117.3 (C), 118.0 (CH),
123.6 (CH), 124.0 (CH), 129.6 (CH), 130.2 (CH), 130.3
(CH), 130.6 (CH), 133.0 (C), 134.0 (C), 153.7 (CH),
156.0 (CH), 158.1 (2C), 168.9 (3C), 169.7 (C), 194.4
(C), 196.0 (C). Found, %: C 60.79; H 4.33. [M]+ 276.
C14H12O6. Calculated, %: C 60.87; H 4.38.
Reduction of 3-arylidenetetronic acids XXII–XXV,
XXXIV–XXXVII and cinnamoyl-tetrahydrofuran-
2,4-dione (L) was performed with triethylsilane in
trifluoroacetic acid (method a) and with sodium cyano-
borohydride in a system TΓΤ–2 N aqueous HCl (method
b) along procedures of reduction of 3-acyltetronic acids
[7].
3-(4-Methoxybenzyl)tetrahydrofuran-2,4-dione
(XXXVIII). Yield 95 (a), 75% (b), mp 173–175°C.
IR spectrum, cm–1: 1605 br (max), 1650 br. sh, 1715,
(E,Z)-Methyl 2-{4-[(2,4-dioxodihydrofuran-3(2H)-
ylidene)methyl]-2-methoxyphenoxy}acetate (XXXVI).
Yield 48% (b). IR spectrum, cm–1: 1165, 1570, 1585,
1610, 1710, 1760, 1770. 1H NMR spectrum (CDCl3 +
CD3OD), δ, ppm: 3.84 s (3H, CO2CH3), 4.01 s (1.05H,
OCH3) and 4.04 s (1.95H, OCH3), 4.64 s (1.3H, CH2 of
cycle) and 4.76 s (0.7H, CH2 of cycle), 4.86 s and
4.87 s (2H, OCH2CO2Me), 6.88 d and 6.89 d (1H,
1
2380–2820 br. H NMR spectrum (CD3OD), δ, ppm:
3.41 s (2H, CH2PhOCH3), 3.73 s (3H, OCH3), 4.63 s (2H,
CH2 of cycle), 6.79 d (2Harom, 3J 8.5 Hz), 7.14 d (2Harom
,
3J 8.5 Hz). 13C NMR spectrum (CD3OD), δ, ppm: 26.9
(CH2), 55.7 (CH3), 68.4 (CH2), 101.4 (C), 114.8 (2CH),
130.2 (2CH), 132.7 (C), 159.6 (C), 175.6 (C), 178.5
(C). Found, %: C 65.39; H 5.45. [M]+ 220. C12H12O4.
Calculated, %: C 65.45; H 5.49.
H6arom 3J 8.5 Hz), 7.75 d.d and 7.77 d.d (1H, H5arom
, ,
3J 8.5, 4J 2.0 Hz), 7.92 s (0.65H, Hvinyl) and 7.94 s (0.35H,
H
(0.35H, H3arom, 4J 2.0 Hz). 13C NMR spectrum (CDCl3 +
CD3OD), δ, ppm: 52.7 (2CH3), 56.3 (2CH3), 65.7 (2CH2),
71.9 (CH2), 72.9 (CH2), 112.5 (2CH), 114.3 (C), 114.5
(C), 116.5 (CH), 117.4 (CH), 126.2 (C), 127.9 (C), 132.4
(CH), 133.4 (CH), 149.4 (2C), 154.0 (CH), 154.1 (2C),
156.2 (CH), 168.5 (3C), 171.3 (C), 194.8 (C), 196.8
4
vinyl), 8.76 d (0.65H, H3arom, J 2.0 Hz) and 8.80 d
3-(4-Butoxybenzyl)tetrahydrofuran-2,4-dione
(XXXIX). Yield 89 (a), 87% (b), mp 166–168°C. IR
spectrum, cm–1: 1600 br (max), 1655 sh, 1710, 2700
1
(2380–2840) br. H NMR spectrum (CDCl3 + CD3OD),
δ, ppm: 0.96 t [3H, O(CH2)3CH3, 3J 7.5 Hz], 1.47 sextet
3
[2H, O(CH2)2CH2CH3, J 7.5 Hz], 1.74 quintet (2H,
OCH2CH2CH2CH3, 3J 7.0 Hz), 3.45 s (2H, CH2PhOBu),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008

HETEROCYCLIC ANALOGS OF PROSTAGLANDINES: IV.
667
3
%: C 60.29; H 4.99. [M]+ 278. C14H14O6. Calculated, %:
C 60.43; H 5.07.
3.92 t [2H, OCH2(CH2)2CH3, J 6.5 Hz], 4.54 s (2H,
CH2 of cycle), 6.80 d (2Harom, 3J 8.5 Hz), 7.19 d (2Harom
,
3J 8.5 Hz). 13C NMR spectrum (CDCl3 + CD3OD), δ,
ppm: 13.9 (CH3), 19.3 (CH2), 26.3 (CH2), 31.4 (CH2),
67.0 (CH2), 67.8 (CH2), 100.9 (C), 114.5 (2CH), 129.4
(2CH), 131.2 (C), 157.6 (C), 173.1 (C), 176.6 (C). Found,
%: C 68.53; H 6.85. [M]+ 262. C15H18O4. Calculated, %:
C 68.68; H 6.92.
Methyl 2-{4-[(2,4-dioxotetrahydrofuran-3-
yl)methyl]-2-methoxyphenoxy}acetate (XLIII). Yield
91% (a), mp 76–79°C. IR spectrum, cm–1: 1230, 1605,
1640 sh, 1650 sh, 1675 br, 1755, 2380–2830 br. 1H NMR
spectrum (CDCl3), δ, ppm: 3.46 s (2H, CH2Ar), 3.72 s
(3H, OCH3), 3.76 s (3H, CO2CH3), 4.47 br.s (2H, CH2
3-(4-Butoxy-3-methoxybenzyl)tetrahydrofuran-
2,4-dione (XL). Yield 84 (a), 93% (b), mp 107–109°C.
IR spectrum, cm–1: 1600 sh, 1610 (max), 1640–1680 br,
of cycle), 4.57 s (2H, OCH2CO2Me), 6.62 br.d (1Harom
,
3J 7.0 Hz), 6.71 br (1Harom), 6.82 br (1Harom). 13C NMR
spectrum (CDCl3), δ, ppm: 26.7 (CH2), 52.4 (CH3), 55.8
(CH3), 66.4 (CH2), 67.9 (CH2), 99.4 (C), 112.6 (CH),
114.3 (CH), 120.4 (CH), 134.3 (C), 145.1 (C), 149.1 (C),
170.3 (C), 176.3 (C), 177.9 (C). Found, %: C 58.22;
H 5.16. [M]+ 308. C15H16O7. Calculated, %: C 58.44;
H 5.23.
1
1720, 2700 (2380–2820) br. H NMR spectrum (CD3OD),
δ, ppm: 0.96 t [3H, O(CH2)3CH3, 3J 7.5 Hz], 1.48 sextet
[2H, O(CH2)2CH2CH3, 3J 7.5 Hz], 1.72 quintet (2H,
3
OCH2CH2CH2CH3, J 7.0 Hz), 3.41 s (2H, CH2Ar),
3.79 s (3H, OCH3), 3.93 t [2H, OCH2(CH2)2CH3,
3J 6.5 Hz], 4.63 s (2H, CH2 of cycle), 6.74 d.d (1H, H6arom
,
Methyl 2-{5-[(2,4-dioxotetrahydrofuran-3-yl)-
methyl]-2-methoxyphenoxy}acetate (XLIV). Yield
97% (a), mp 128–131°C. IR spectrum, cm–1: 1240,
3J 8.0, 4J 2.0 Hz), 6.79 d (1H, H5arom, 3J 8.0 Hz), 6.88 d (1H,
H2arom, 4J 2.0 Hz). 13C NMR spectrum (CD3OD), δ, ppm:
14.2 (CH3), 20.3 (CH2), 27.4 (CH2), 32.5 (CH2), 56.5
(CH3), 68.3 (CH2), 70.2 (CH2), 101.3 (C), 113.9 (CH),
114.9 (CH), 121.6 (CH), 133.7 (C), 148.3 (C), 150.8 (C),
175.6 (C), 178.5 (C). Found, %: C 65.55; H 6.84. [M]+
292. C16H20O5. Calculated, %: C 65.74; H 6.90.
1
1595, 1670 br, 1740, 1765 sh, 2420–2820 br. H NMR
spectrum (CDCl3), δ, ppm: 3.41 s (2H, CH2Ar), 3.78 s
(3H, CO2CH3), 3.80 s (3H, OCH3), 4.58 s (2H, CH2 of
cycle), 4.64 s (2H, OCH2CO2Me), 6.76 m (2Harom), 6.85
d.d (1H, H4arom, 3J 8.5,4J 1.5 Hz), 8.11 br (1H, OH enol).
13C NMR spectrum (CDCl3), δ, ppm: 26.4 (CH2), 52.6
(CH3), 55.9 (CH3), 66.2 (CH2), 67.8 (CH2), 100.8 (C),
112.2 (CH), 114.8 (CH), 122.4 (CH), 131.3 (C), 146.7
(C), 148.0 (C), 170.6 (C), 174.5 (C), 178.3 (C). Found,
%: C 58.31; H 5.19. [M]+ 308. C15H16O7. Calculated, %:
C 58.44; H 5.23.
Methyl 2-{4-[(2,4-dioxotetrahydrofuran-3-yl)-
methyl]phenoxy}acetate (XLI). Yield 89% (a), mp
166–168°C (from MeOH). IR spectrum, cm–1: 1220
(max), 1620 sh, 1650 sh, 1665, 1720, 1750, 2710 (2380–
1
2810) br. H NMR spectrum (CD3OD), δ, ppm: 3.41 s
(2H, CH2Ar), 3.75 s (3H, CO2CH3), 4.63 s (2H, CH2 of
cycle), 4.65 s (2H, OCH2CO2Me), 6.80 d (2Harom
,
3-Cinnamyltetrahydrofuran-2,4-dione (XLV).
Yield 83% (b), mp 153–156°C. IR spectrum, cm–1: 1280,
1455 (max), 1605–1665 br, 1725, 2720 (2380–2840)
br. 1H NMR spectrum (CD3OD), δ, ppm: 3.06 d (2H,
3J 8.5 Hz), 7.15 d (2Harom, 3J 8.5 Hz). 13C NMR spectrum
(CD3OD), δ, ppm: 27.0 (CH2), 52.6 (CH3), 66.2 (CH2),
68.4 (CH2), 101.2 (C), 115.6 (2CH), 130.4 (2CH), 133.8
(C), 157.9 (C), 171.6 (C), 175.7 (C), 178.4 (C). Found,
%: C 60.26; H 5.04. [M]+ 278. C14H14O6. Calculated,
%: C 60.43; H 5.07.
3
CH2CH=CHPh, J 6.5 Hz), 4.65 s (2H, CH2 of cycle),
6.24 d.t (1H, CH2CH=CHPh, 3J 15.5, 6.5 Hz), 6.41 br.d
(1H, CH2CH=CHPh, 3Jtrans 15.5 Hz), 7.16 br.t (1H, H4arom
,
3
5
3
3J 7.5 Hz), 7.25 br.t (2H, Harom + Harom, J 7.5 Hz),
Methyl 2-{3-[(2,4-dioxotetrahydrofuran-3-yl)meth
yl]phenoxy}acetate (XLII). Yield 72 (a), 59% (b), mp
105–110°C (decomp.). IR spectrum, cm–1: 1240 br,
1600 sh, 1620, 1655 sh, 1675 br, 1750, 2380–2820 br.
1H NMR spectrum (CDCl3), δ, ppm: 3.45 s (2H, CH2Ar),
3.77 s (3H, CO2CH3), 4.54 br.s (2H, CH2 of cycle), 4.57 C
(2H, OCH2CO2Me), 6.67 d (1Harom, 3J 7.5 Hz), 6.80 br.s
3
7.32 br.d (2H, H2arom+ H6arom, J 7.5 Hz). 13C NMR
spectrum (CD3OD), δ, ppm: 25.3 (CH2), 68.4 (CH2), 99.4
(C), 127.0 (CH), 127.1 (2CH), 128.1 (CH), 129.5 (2CH),
131.8 (CH), 138.9 (C), 175.9 (C), 178.4 (C). Found, %:
C 72.14; H 5.51. [M]+ 216. C13H12O3. Calculated, %:
C 72.21; H 5.59.
(1H, H2arom), 6.87 d (1Harom , 3J 7.5 Hz), 7.14 t (1H, H5arom
,
3-(3-Phenylpropyl)tetrahydrofuran-2,4-dione
(XLIX). Yield 91 (from L), 79 (from XLV) (a), 88%
(from L) (b), mp 132–133°C (from ethyl acetate). IR
spectrum, cm–1: 1240, 1280, 1605–1665 br (max), 1725,
3J 7.5 Hz). 13C NMR spectrum (CDCl3), δ, ppm: 27.0
(CH2), 52.4 (CH3), 65.1 (CH2), 67.7 (CH2), 100.3 (C),
112.0 (CH), 115.0 (CH), 122.0 (CH), 129.6 (CH), 140.6
(C), 157.7 (C), 170.1 (C), 174.5 (C), 174.6 (C). Found,
1
2725 (2380–2850) br. H NMR spectrum (CD3OD), δ,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008

PASHKOVSKII et al.
668
ppm: 1.78 quintet (2H, CH2CH2CH2Ph, 3J 7.5 Hz), 2.20 t
Methyl 2-{4-[(4-oxo-2-ethoxy-4,5-dihydrofuran-
3-yl)methyl]phenoxy}acetate (LIII). Yield 98%. IR
spectrum, cm–1: 1600 (max), 1690, 1735 sh, 1750. 1H
NMR spectrum (CDCl3), δ, ppm: 1.40 t (3H, OCH2CH3,
3J 7.0 Hz), 3.35 s (2H, CH2Ar), 3.80 s (3H, CO2CH3), 4.42
q (2H, OCH2CH3, 3J 7.0 Hz), 4.57 s (2H, CH2 of cycle),
3
[2H, CH2(CH2)2Ph, J 7.5 Hz], 2.60 t (2H, CH2Ph,
3J 7.5 Hz), 4.56 s (2H, CH2 of cycle), 7.12 t (1H, H4arom
,
3J 7.5 Hz), 7.17d(2H, H2arom+ H6arom, 3J 7.0Hz), 7.23 t (2H,
H3arom + H5arom, 3J 7.5 Hz). 13C NMR spectrum (CD3OD),
δ, ppm: 21.8 (CH2), 30.7 (CH2), 36.6 (CH2), 68.1 (CH2),
101.1 (C), 126.7 (CH), 129.2 (2CH), 129.3 (2CH), 143.4
(C), 175.3 (C), 178.7 (C). Found, %: C 71.45; H 6.44.
[M]+ 218. C13H14O3. Calculated, %: C 71.54; H 6.47.
3
4.60 s (2H, OCH2CO2Me), 6.80 d (2Harom, J 8.5 Hz),
3
7.18 d (2Harom, J 8.5 Hz). 13C (CDCl3), δ, ppm: 14.8
(CH3), 24.7 (CH2), 52.2 (CH3), 65.4 (CH2), 65.9 (CH2),
74.9 (CH2), 94.0 (C), 114.5 (2CH), 129.4 (2CH), 133.7
(C), 156.1 (C), 169.6 (C), 181.6 (C), 195.6 (C). Found,
%: C 62.84; H 5.99. [M]+ 306. C16H18O6. Calculated, %:
C 62.74; H 5.92.
3-(4-Butoxybenzyl)-4-methoxy-2,5-dihydrofuran-
2-one (LI) was obtained from 3-arylalkyltetronic acid
XXXIX by procedure from [1]. Yield 65%. IR spectrum,
cm–1: 1605 sh, 1620, 1675 (max), 1750. 1H NMR
spectrum (CDCl3), δ, ppm: 0.96 t [3H, O(CH2)3CH3,
3J 7.5 Hz], 1.47 sextet [2H, O(CH2)2CH2CH3, 3J 7.5 Hz],
1.74 quintet (2H, OCH2CH2CH2CH3, 3J 7.0 Hz), 3.53 s
(2H, CH2Ar), 3.92 t [2H, OCH2(CH2)2CH3, 3J 6.5 Hz],
3.93 s (3H, OCH3), 4.68 s (2H, CH2 of cycle), 6.80 d
(2Harom, 3J 8.5 Hz), 7.16 d (2Harom, 3J 8.5 Hz). 13C NMR
spectrum (CDCl3), δ, ppm: 13.6 (CH3), 19.0 (CH2), 26.7
(CH2), 31.1 (CH2), 57.4 (CH3), 65.1 (CH2), 67.4 (CH2),
102.9 (C), 114.2 (2CH), 129.0 (2CH), 130.7 (C), 157.5
(C), 172.5 (C), 174.5 (C). Found, %: C 69.49; H 7.38.
[M]+ 276. C16H20O4. Calculated, %: C 69.54; H 7.30.
Methyl 2-{3-[(4-oxo-2-ethoxy-4,5-dihydrofuran-3-
yl)methyl]phenoxy}acetate (LIV). Yield 83%. IR spec-
trum, cm–1: 1600 (max), 1690, 1735 sh, 1750. 1H NMR
spectrum (CDCl3), δ, ppm: 1.40 t (3H, OCH2CH3,
3J 7.0 Hz), 3.39 s (2H, CH2Ar), 3.80 s (3H, CO2CH3),
3
4.42 q (2H, OCH2CH3, J 7.0 Hz), 4.57 s (2H, CH2 of
cycle), 4.61 s (2H, OCH2CO2Me), 6.70 d.d (1Harom
,
,
3J 8.0, 4J 2.5 Hz), 6.83 br (1H, H2arom), 6.90 d (1Harom
3
3J 8.0 Hz), 7.17 t (1H, H5arom, J 8.0 Hz). 13C NMR
spectrum (CDCl3), δ, ppm: 14.8 (CH3), 25.6 (CH2), 52.2
(CH3), 65.4 (CH2), 66.0 (CH2), 75.0 (CH2), 93.5 (C),
112.0 (CH), 114.9 (CH), 121.9 (CH), 129.4 (CH), 142.1
(C), 157.9 (C), 169.5 (C), 181.6 (C), 195.5 (C). Found,
%: C 62.80; H 6.00. [M]+ 306. C16H18O6. Calculated, %:
C 62.74; H 5.92.
3-(4-Butoxybenzyl)-4-(heptylamino)-2,5-dihydro-
furan-2-one (LII) was obtained from methyl enol
ether LI and heptylamine by procedure from [1].
Yield 70%. IR spectrum, cm–1: 1635 br (max), 1730,
3310 br. 1H NMR spectrum (CDCl3), δ, ppm: 0.88 t [3H,
4-(4-Butoxy-3-methoxybenzyl)-5-ethoxy-2,3-
3
dihydrofuran-3-one (LVII). Yield 99%. IR spectrum,
NH(CH2)6CH3, J 7.0 Hz], 0.97 t [3H, O(CH2)3CH3,
3J 7.5 Hz], 1.12 m [2H, NH(CH2)5CH2CH3], 1.18–1.24
cm–1: 1595 sh, 1620 (max), 1700. H NMR spectrum
1
3
m [4H, NH(CH2)3(CH2)2CH2CH3], 1.27 quintet [2H,
(CDCl3), δ, ppm: 0.96 t [3H, O(CH2)3CH3, J 7.5 Hz],
3
3
NH(CH2)2CH2(CH2)3CH3, J 7.0 Hz], 1.37 quintet (2H,
1.41 t (3H, OCH2CH3, J 7.0 Hz), 1.47 sextet [2H,
NHCH2CH2, 3J 7.0 Hz), 1.48 sextet [2H, O(CH2)2CH2CH3,
3J 7.5 Hz], 1.75 quintet [2H, OCH2CH2CH2CH3,
3
O(CH2)2CH2CH3, J 7.5 Hz], 1.80 quintet (2H,
3
OCH2CH2CH2CH3, J 7.0 Hz), 3.35 s (2H, CH2Ar),
3
3J 7.0 Hz], 2.94 q (NHCH2, J 6.5 Hz), 3.48 C (2H,
3.84 s (3H, OCH3), 3.97 t [2H, OCH2(CH2)2CH3,
3J 7.0 Hz], 4.43 q (2H, OCH2CH3, 3J 7.0 Hz), 4.57 s (2H,
CH2 of cycle), 6.76 narrow m (2Harom), 6.85 s (1Harom).
13C NMR spectrum (CDCl3), δ, ppm: 13.9 (CH3), 14.8
(CH3), 19.2 (CH2), 25.2 (CH2), 31.3 (CH2), 56.0 (CH3),
65.9 (CH2), 68.8 (CH2), 74.9 (CH2), 94.2 (C), 112.3 (CH),
112.8 (CH), 120.1 (CH), 133.0 (C), 146.8 (C), 149.2 (C),
181.6 (C), 195.7 (C). Found, %: C 67.51; H 7.63. [M]+
320. C18H24O5. Calculated, %: C 67.48; H 7.55.
3
CH2PhOBu), 3.93 t [2H, OCH2(CH2)2CH3, J 6.5 Hz],
4.19 br (1H, NH), 4.63 s (2H, CH2 of cycle), 6.82 d
(2Harom, 3J 8.5 Hz), 7.14 d (2Harom, 3J 8.5 Hz). 13C NMR
spectrum (CDCl3), δ, ppm: 13.9 (CH3), 14.0 (CH3), 19.2
(CH2), 22.5 (CH2), 26.4 (CH2), 27.6 (CH2), 28.8 (CH2),
30.3 (CH2), 31.4 (CH2), 31.6 (CH2), 44.0 (CH2), 65.4
(CH2), 67.7 (CH2), 92.3 (C), 114.6 (2CH), 129.2 (2CH),
130.6 (C), 157.8 (C), 163.6 (C), 176.3 (C). Found, %:
C 73.39; H 9.27. [M]+ 359. C22H33NO3. Calculated, %:
C 73.50; H 9.25.
4-Cinnamyl-5-ethoxy-2,3-dihydrofuran-3-one
(LIX). Yield 97%. IR spectrum, cm–1: 1605 (max),
1
Synthesis of 4-substituted 5-ethoxy-2,3-dihydro-
furan-3-ones LIII, LIV, LVII, LIX, LX was described
in [1].
1690. H NMR spectrum (CDCl3), δ, ppm: 1.42 t (3H,
OCH2CH3, 3J 7.0 Hz), 3.00 d.d (2H, CH2CH=CHPh,
3J 6.5, 4J 1.0 Hz), 4.45 q (2H, OCH2CH3, 3J 7.0 Hz),
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HETEROCYCLIC ANALOGS OF PROSTAGLANDINES: IV.
669
4.59 s (2H, CH2 of cycle), 6.21 d.t (1H, CH2CH=CHPh,
3J 16.0, 6.5 Hz), 6.40 br.d (1H, CH2CH=CHPh, 3Jtrans
16.0 Hz), 7.18 br.t (1H, H4arom, 3J 7.5 Hz), 7.27 t (2H, H3 +
H5arom, 3J 7.5 Hz), 7.33 br.d (2H, H2+H6arom, 3J 7.5 Hz).
13C NMR spectrum (CDCl3), δ, ppm: 14.8 (CH3), 23.0
(CH2), 65.9 (CH2), 74.9 (CH2), 92.1 (C), 126.1 (2CH),
126.9 (2CH), 128.4 (2CH), 130.2 (CH), 137.5 (C), 181.6
(C), 195.7 (C). Found, %: C 73.84; H 6.65. [M]+ 244.
C15H16O3. Calculated, %: C 73.75; H 6.60.
cm–1: 1535 sh, 1570 br (max), 1590 sh, 1615 sh, 1660,
3080 br, 3320. 1H NMR spectrum (CDCl3), δ, ppm:
0.87 t (3H, CH3, 3J 7.0 Hz), 0.88 t (3H, CH3, 3J 7.0 Hz),
1.15 m (2H, CH2), 1.19–1.33 m (14H, 7CH2), 1.44
3
quintet [2H, C(O)NHCH2CH2, J 7.0 Hz], 1.54 quintet
(2H, NHCH2CH2, 3J 6.5 Hz), 3.25 q (2H, NHCH2, 3J 7.0
3
Hz), 3.32 q [2H, C(O)NHCH2, J 7.0 Hz], 3.47 s (2H,
CH2Ar), 4.41 s [2H, OCH2C(O)NH], 4.55 s (2H, CH2 of
cycle), 5.16 br (1H, NH), 6.64 br [1H, C(O)NH], 6.72 br.d
(1Harom, 3J 8.0 Hz), 6.81 br.s (1H, H2arom), 6.89 d (1Harom
,
4-(3-Phenylpropyl)-5-ethoxy-2,3-dihydrofuran-3-
3J 8.0 Hz), 7.22 t (1H, H5arom, J 8.0 Hz). 13C NMR
spectrum (CDCl3), δ, ppm: 14.1 (2CH3), 22.5 (CH2), 22.6
(CH2), 26.0 (CH2), 26.3 (CH2), 26.8 (CH2), 28.7 (CH2),
28.9 (CH2), 29.6 (CH2), 30.0 (CH2), 31.6 (CH2), 31.7
(CH2), 39.1 (CH2), 41.4 (CH2), 67.2 (CH2), 74.4 (CH2),
90.5 (C), 112.0 (CH), 115.0 (CH), 121.8 (CH), 129.9
(CH), 141.7 (C), 157.6 (C), 168.0 (C), 177.8 (C), 192.6
(C). Found, %: C 70.56; H 9.29. [M]+ 458. C27H42N2O4.
Calculated, %: C 70.71; H 9.23.
3
one (LX). Yield 95%. IR spectrum, cm–1: 1610 br (max),
1
1705. H NMR spectrum (CDCl3), δ, ppm: 1.42 t (3H,
OCH2CH3, 3J 7.0 Hz), 1.78 quintet (2H, CH2CH2CH2Ph,
3
3J 7.5 Hz), 2.15 t [2H, CH2(CH2)2Ph, J 7.5 Hz],
2.61 t (2H, CH2Ph, 3J 7.5 Hz), 4.42 q (2H, OCH2CH3,
3J 7.0 Hz), 4.52 s (2H, CH2 of cycle), 7.15–7.19 m
(3Harom), 7.24–7.27 m (2Harom). 13C NMR spectrum
(CDCl3), δ, ppm: 14.8 (CH3), 19.3 (CH2), 29.7 (CH2),
35.6 (CH2), 65.7 (CH2), 74.7 (CH2), 93.7 (C), 125.6 (CH),
128.2 (2CH), 128.4 (2CH), 142.4 (C), 181.6 (C), 196.3
(C). Found, %: C 73.27; H 7.47. [M]+ 246. C15H18O3.
Calculated, %: C 73.15; H 7.37.
9-Oxa-7-azaprostanoids LVIII, LXI, and LXII were
obtained by procedure from [1].
Methyl 6-[3-(4-butoxy-3-methoxybenzyl)-4-oxo-
4,5-dihydrofuran-2-ylamino]hexanoate (LVIII).
Yield 40%, mp 63–65°C (from ether). IR spectrum,
The reaction of 4-substituted 5-ethoxy-2,3-dihydro-
furan-3-ones XLI and XLII with heptylamine was
carried out by the procedure of the synthesis of 11-oxa-
13-azaprostanoids [1].
1
cm–1: 1530 br, 1575 br, 1615 sh, 1680, 1735. H NMR
spectrum (CDCl3), δ, ppm: 0.97 t (3H, CH3, 3J 7.5 Hz),
1.19 quintet [2H, NH(CH2)2CH2(CH2)2CO2Me,
3J 7.5 Hz], 1.43 quintet (2H, CH2CH2CO2Me, 3J 7.5 Hz),
N-Heptyl-2-{4-[(2-(heptylamino)-4-oxo-4,5-di-
hydrofuran-3-yl)methyl]phenoxy}acetamide (LV).
Yield 58%, mp 140–142°C (from ethyl acetate). IR
spectrum, cm–1: 1515 sh, 1535 sh, 1550 sh, 1580 br
3
1.48 sextet [2H, O(CH2)2CH2CH3, J 7.5 Hz], 1.56
3
quintet (2H, NHCH2CH2, J 7.5 Hz), 1.80 quintet (2H,
OCH2CH2CH2CH3, 3J 7.0 Hz), 2.27 t (2H, CH2CO2Me,
3J 7.5 Hz), 3.22 q (2H, NHCH2, 3J 6.5 Hz), 3.44 s (2H,
CH2Ar), 3.66 s (3H, CO2CH3), 3.82 s (3H, OCH3),
3.97 t [2H, OCH2(CH2)2CH3, 3J 6.5 Hz], 4.52 br.s (2H,
CH2 of cycle), 5.27 br (1H, NH), 6.72–6.78 m (3Harom).
13C NMR spectrum (CDCl3), δ, ppm: 13.9 (CH3), 19.2
(CH2), 24.2 (CH2), 25.7 (CH2), 25.8 (CH2), 29.6 (CH2),
31.2 (CH2), 33.6 (CH2), 40.9 (CH2), 51.6 (CH3), 56.0
(CH3), 68.8 (CH2), 74.2 (CH2), 91.2 (C), 112.1 (CH),
112.9 (CH), 120.0 (CH), 131.8 (C), 147.2 (C), 149.7 (C),
173.9 (C), 177.8 (C), 192.5 (C). Found, %: C 65.78; H 7.92.
[M]+ 419. C23H33NO6. Calculated, %: C 65.85; H 7.93.
1
(max), 1605 sh, 1655, 3065, 3290. H NMR spectrum
(CDCl3), δ, ppm: 0.87 t (3H, CH3, 3J 7.5 Hz), 0.88 t (3H,
CH3, 3J 7.5 Hz), 1.14–1.35 m (16H, 8CH2), 1.44 quintet
[2H, C(O)NHCH2CH2, 3J 7.5 Hz], 1.54 quintet (2H,
NHCH2CH2, 3J 7.0 Hz), 3.24 q (2H, NHCH2, 3J 6.5 Hz),
3.32 q [2H, C(O)NHCH2, 3J 7.0 Hz], 3.43 s (2H, CH2Ar),
4.33 s [2H, OCH2C(O)NH], 4.51 s (2H, CH2 of cycle),
5.42 br (1H, NH), 6.64 br [1H, C(O)NH], 6.79 d (2Harom
,
3J 8.5 Hz), 7.15 d (2Harom, 3J 8.5 Hz). 13C NMR spectrum
(CDCl3), δ, ppm: 14.0 (2CH3), 22.5 (CH2), 22.6 (CH2),
25.1 (CH2), 26.4 (CH2), 26.8 (CH2), 28.8 (CH2), 28.9
(CH2), 29.6 (CH2), 30.0 (CH2), 31.7 (2CH2), 39.1 (CH2),
41.4 (CH2), 67.5 (CH2), 74.3 (CH2), 90.8 (C), 114.8
(2CH), 129.4 (2CH), 133.2 (C), 155.8 (C), 168.1 (C),
177.9 (C), 192.6 (C). Found, %: C 70.67; H 9.25. [M]+
458. C27H42N2O4. Calculated, %: C 70.71; H 9.23.
(Ε)-Methyl 6-(4-oxo-3-cinnamyl-4,5-dihydrofuran
-
2-ylamino)hexanoate (LXI). Yield 49%. IR spectrum,
cm–1: 1500, 1535 sh, 1555 sh, 1580 br (max), 1650, 1680,
1735, 3030 br, 3220 br. 1H NMR spectrum (CDCl3), δ,
ppm: 1.27 quintet [2H, NH(CH2)2CH2(CH2)2––CO2Me,
3J 7.5 Hz], 1.55 m [4H, NHCH2CH2CH2CH2CH2–
CO2Me], 2.20 t (2H, CH2CO2Me, 3J 7.5 Hz), 3.07 d (2H,
N-Heptyl-2-{3-[(2-(heptylamino)-4-oxo-4,5-
dihydrofuran-3-yl)methyl]phenoxy}acetamide (LVI).
Yield 47%, mp 99–101°C (from ether). IR spectrum,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008

PASHKOVSKII et al.
670
3
2. Tolstikov, G.A., Miftakhov, M.S., Lazareva, D.N.,
Pomoinetskii, V.D., and Sidorov, N.N., Prostaglandiny
i ikh analogi v reproduktsii zhivotnykh i cheloveka
(Prostaglandines and Their Analogs in Reproduction of
Animals and Human), Ufa, 1989, 400 p.
CH2CH=CHPh, J 6.5 Hz), 3.32 q (2H, NHCH2,
3J 6.5 Hz), 3.65 s (3H, CO2CH3), 4.53 s (2H, CH2 of
cycle), 6.01 br (1H, NH), 6.15 d.t (1H, CH2CH=CHPh,
3J1trans 15.5, J2 6.5 Hz), 6.43 d (1H, CH2CH=CHPh,
3
3Jtrans 15.5 Hz), 7.19 br.t (1H, H4arom, 3J 7.0 Hz), 7.26–
7.31 m (4Harom). 13C NMR spectrum (CDCl3), δ, ppm:
23.4 (CH2), 24.0 (CH2), 25.8 (CH2), 29.5 (CH2), 33.5
(CH2), 41.0 (CH2), 51.4 (CH3), 74.2 (CH2), 89.1 (C),
125.9 (2CH), 127.1 (CH), 127.5 (CH), 128.4 (2CH), 130.4
(CH), 136.9 (C), 173.8 (C), 178.0 (C), 192.1 (C). Found,
%: C 69.90; H 7.43. [M]+ 343. C20H25NO4. Calculated,
%: C 69.95; H 7.34.
3. Lakhvich, F.A., Pashkovskii, F.S., and Koroleva, E.V.,
Usp. Khim., 1992, vol. 61, p. 456; Sollins, P.W. and Dju-
ric, S.W., Chem. Rev., 1993, vol. 93, p. 1533; Dogné, J.-M.,
de Leval, X., Delarge, J., David, J.-L., and Masereel, B.,
Curr. Med. Chem., 2000, vol. 7, p. 609; Lauchli, R. and
Boland, W., Tetrahedron, 2003, vol. 59, p. 149.
4. Mitsos, C.A., Zografos, A.L., , and Igglessi-Markopou-
lou, O., J. Org. Chem., 2000, vol. 65, p. 5852.
5. Rubinov, D.B., Rubinova, I.L., andAkhrem,A.A., Chem.
Rev., 1999, vol. 99, p. 1047; Kim, T.H., Oh, D.R., Na, H.S.,
and Lee, H.C., Arch. Pharm. Res., 2003, vol. 26, p. 192.
6. Schnell, B. and Kappe, T., Monatsh. Chem., 1998, vol. 129,
p. 871.
7. Pashkovskii, F.S., Katok, Ya.M., Khlebnikova, T.S.,
Koroleva, E.V., and Lakhvich, F.A., Zh. Org. Khim., 2003,
vol. 39, p. 1060.
8. Zimmer, H., Hillstrom, W.W., Schmidt, J.C., See-
muth, P.D., and Vogeli, R., J. Org. Chem., 1978, vol. 43,
p. 1541.
9. Schmidt, D.G. and Zimmer, H., J. Heterocycl. Chem.,
1983, vol. 20, p. 787.
10. Effenberger, F. and Syed, J., Tetrahedron: Asymmetry,
1998, vol. 9, p. 817.
11. Ramachary, D.B. and Barbas, C.F., Chem. Eur. J.,
2004, vol. 10, p. 5323; Simon, C., Constantieux, T., and
Rodriguez, J., Eur. J. Org. Chem., 2004, p. 4957; Koz-
lov, N.G., Gusak, K.N., and Skatetskii, V.V., Zh. Org.
Khim., 2006, vol. 42, p. 119.
Methyl 6-[4-oxo-3-(3-phenylpropyl)-4,5-dihydro-
furan-2-ylamino]hexanoate (LXII). Yield 39%. IR
spectrum, cm–1: 1500, 1535 sh, 1555 sh, 1575 br (max),
1675, 1735, 3030, 3220 br. 1H NMR spectrum (CDCl3),
δ, ppm: 1.33 quintet [2H, NH(CH2)2CH2(CH2)2CO2Me,
3J 7.5 Hz], 1.57 quintet (2H, NHCH2CH2, J 7.0 Hz),
1.63 quintet (2H, CH2CH2CO2Me, J 7.5 Hz), 1.73
quintet (2H, CH2CH2CH2Ph, J 7.5 Hz), 2.15 t [2H,
CH2(CH2)2Ph, J 7.5 Hz], 2.31 t (2H, CH2CO2Me,
3J 7.5 Hz), 2.59 t (2H, CH2Ph, J 7.5 Hz), 3.31 q (2H,
NHCH2, J 6.5 Hz), 3.65 s (3H, CO2CH3), 4.51 br.s
(2H, CH2 of cycle), 6.41 br (1H, NH), 7.15 narrow m
(3Harom), 7.24 t (2H, H3arom + H5arom, 3J 7.5 Hz). 13C NMR
spectrum (CDCl3), δ, ppm: 19.7 (CH2), 24.2 (CH2), 26.0
(CH2), 29.6 (CH2), 30.0 (CH2), 33.7 (CH2), 35.4 (CH2),
41.1 (CH2), 51.6 (CH3), 74.3 (CH2), 92.2 (C), 125.7 (CH),
128.2 (2CH), 128.4 (2CH), 142.3 (C), 174.1 (C), 178.1
(C), 192.4 (C). Found, %: C 69.53; H 7.98. [M]+ 345.
C20H27NO4. Calculated, %: C 69.54; H 7.88.
3
3
3
3
3
3
REFERENCES
12. Beilst. H., vol. 8, p. 60.
13. Baker, W., Grice, K.D., and Jansen,A.B.A., J. Chem. Soc.,
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1. Pashkovskii, F.S., Shchukina, E.M., Gribovskii, M.G., and
Lakhvich, F.A., Zh. Org. Khim., 2006, vol. 42, p. 545.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008