Synthesis of (2-Ethoxy-2-oxoethylthio)methyl Derivatives of Furoic Acids and Attempts of Their Intramolecular Cyclizations under the Conditions of the Claisen Reaction

Article abstract of DOI:10.1134/S1070363220020024

Abstract: Based on reactions of phosphorylated derivatives of halomethylfuroic acid esters with thioglycolic acid ester in the presence of bases, a method for the synthesis of mono-and bisphosphosphorylated esters of (2-ethoxy-2-oxoethylthio)methyl derivatives of furoic acids, containing an ester group in the position adjacent to the sulfide moiety was developed. Obtained compounds are relatively easily metallized with potassium tert-butylate, but intramolecular cyclization proceeds smoothly only in the case of 5-(diethoxyphosphorylmethyl)-2-(ethoxycarbonylmethylthiomethyl)furan-3-carboxylic acid. The resulting 1,3-dicarbonyl derivative of 7H-thiopyrano[3,4-b]furan is hydrolytically unstable, but its enol O-methyl ether is stabile. Alkaline hydrolysis of the latter compound was studied, and it was shown that it proceeds at the ester as well as at the phosphonate group.

Full text of DOI:10.1134/S1070363220020024

ISSN 1070-3632, Russian Journal of General Chemistry, 2020, Vol. 90, No. 2, pp. 166–181. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Obshchei Khimii, 2020, Vol. 90, No. 2, pp. 173–191.
Synthesis of (2-Ethoxy-2-oxoethylthio)methyl Derivatives
of Furoic Acids and Attempts of Their Intramolecular
Cyclizations under the Conditions of the Claisen Reaction
a,
b
L. M. Pevzner * and N. P. Stepanova
a
St. Petersburg Institute of Technology (Technical University), St. Petersburg, 190013 Russia
b
I.I. Mechnikov Northwestern State Medical University, St. Petersburg, 195067 Russia
*
e-mail: pevzner_lm@list.ru
Received September 29, 2019; revised September 29, 2019; accepted October 8, 2019
Abstract—Based on reactions of phosphorylated derivatives of halomethylfuroic acid esters with thioglycolic
acid ester in the presence of bases, a method for the synthesis of mono-and bisphosphosphorylated esters of
(2-ethoxy-2-oxoethylthio)methyl derivatives of furoic acids, containing an ester group in the position adjacent
to the sulfide moiety was developed. Obtained compounds are relatively easily metallized with potassium tert-
butylate, but intramolecular cyclization proceeds smoothly only in the case of 5-(diethoxyphosphorylmethyl)-
2
-(ethoxycarbonylmethylthiomethyl)furan-3-carboxylic acid. The resulting 1,3-dicarbonyl derivative of 7H-
thiopyrano[3,4-b]furan is hydrolytically unstable, but its enol O-methyl ether is stabile. Alkaline hydrolysis of the
latter compound was studied, and it was shown that it proceeds at the ester as well as at the phosphonate group.
Keywords: phosphorylated halomethylfurans, thioglycolic acid esters, alkyl-intramolecular cyclization, 7H-
thiopyrano[3,4-b]furans
DOI: 10.1134/S1070363220020024
Interest to saturated heterocycles, annelated with the
furan ring was developed relatively long ago when trying
to synthesize nucleotides in which one of the phosphorus
acid residues in deoxyribose diphosphate is replaced with
the thiopyran cycle [1]. For constructing of the annelated
heterocyclic system cyclization of the branched-chain
thiocarbohydrate was used, which by itself is hardly
available. Later, more convenient approaches to the
preparation of 7H-thiopyrano[3,4-b]furans, including
acyloin condensation of 3-hydroxytetrahydropyran-4-one
with 1,3-diketones [2] and the Prince reaction between
constant interest to these annelated heterocycles shows
that manifestation of high biological activity is expected
from such structures. Due to that developing of new
methods for constructing them is relevant.
As is known [4], sulfides activated with carbonyl
group, have a noticeable CH-acidity. Therefore, they
can be used in Claisen reactions as methylene compo-
nents. Correspondingly, furoic acid esters acids having
(2-ethoxy-2-oxoethylthio)methyl moiety in the adjacent
position of the ring can be suitable substrates for intramo-
lecular cyclization leading to formation of thiopyran cycle
annelated with the furan one. In this case, ketone and ester
groups allowing to carry out its further functionalization
can be introduced in sulfur-containing heterocycle, and
6
-mercaptohexen-1-ol and aromatic aldehydes [3] were
developed. However, these methods are also quite labori-
ous, and functionalization of the thiopyran cycle while
their use is practically impossible. At the same time the
Scheme 1.
CO Et
CO Et
2
2
HSCH COOEt
2
KOH
(
EtO) OPH C
CH Br
(EtO) OPH C
CH SCH COOEt
2 2
2
2
O
2
2
2
O
2
3
1
66

SYNTHESIS OF (2-ETHOXY-2-OXOETHYLTHIO)METHYL DERIVATIVES
167
Scheme 2.
CO Me
CO Me
2
2
CO Me
2
Py  HCrOCl
CH (COOH)
3
2
2
CH Cl
Py
2
2
O
HOH C
O
O
2
OHC
HOOC
4
6
5
CO Me
CO Me
2
2
MeOH
Py
SOCl2
DMF
O
O
ClOC
MeO
2C
8
7
the furan moiety may have substituents, stable under the
conditions of the Claisen reaction or due to steric reasons
not capable of participating in it. One of such promising
substituents is a phosphonate group.
97% yield as mobile red oil. Next, we tried to synthesize
furylmethyl sulfides having phosphorylated fragments of
more complex structure in the position 5 of the ring. For
this purpose, hydroxymethylfuran 4 was oxidized with
pyridinium chlorochromate in dichloromethane to give
aldehyde 5, which was isolated in 59% yield. The latter
was introduced into the Knovenaegel condensation with
malonic acid in the presence of pyridine (Scheme 2).
Target 3-[4-(methoxycarbonyl)-5-methylfur-2-yl]acrylic
acid 6 was obtained in 33% yield. By treating it with
thionyl chloride in benzene in the presence of the catalytic
amount of DMF the crystalline chloride 7 was obtained
in 79% yield. Methanolysis of the latter in ethyl acetate
in the absence of pyridine led to methyl ester 8 (yield
The aim of this work is to develop methods of syn-
thesis of phosphorylated derivatives of 2-[(2-ethoxy-
2
-oxoethylthio)methyl]-3-furoates, studying their be-
havior under the conditions of intramolecular Claisen
reaction, and investigation of chemical properties of the
products of cyclization.
The first step of the study was investigation of
alkylation of thioglycolic acid ethyl ester 1 with phos-
phorylated dervatives of 2-bromomethyl-3-furoate 2
(
Scheme 1). The reaction of bromide 2 with ester 1 was
carried out at 1 : 1.02 molar ratio in the presence of
equiv of potassium hydroxide in acetone–ethanol
6
7%, Scheme 2).
1
Phosphorylation of the ester 8 was carried out in
mixture at room temperature. To avoid formation of
disulfides, the saturated ethanol solution of potassium
hydroxide was added in one portion to the solution of
reagents in acetone. Target product 3 was obtained in
excess of diethylphosphite in the presence of absolute
ethanol and a small amount of sodium foil (Scheme 3).
The reaction began with the significant evolution of heat,
and its completion required heating at 85°C for 4 h. Be-
Scheme 3.
CO Et
CO Et
2
2
CO Et
CO Et
2
2
HPO(OEt)
2
NBS
8
Na + EtOH
CH Br
AIBN
2
O
O
(
EtO) OP
(EtO) OP
2
2
9
10
CO Et
2
CO Et
2
HSCH CO Et
2
2
KOH + EtOH
O
(
EtO) OP
S
2
EtO C
2
11
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 2 2020

168
PEVZNER, STEPANOVA
Scheme 4.
potassium fluoride in dioxane as well as of sodium ethyl-
ate in absolute ethanol (Scheme 4). In the preparations
CO Et
2
obtained the ratio of aldehyde 5 and hydroxyphosphonate
HPO(OEt)
2
5
12 was (0.7–0.9) : 1 according to H and P NMR spec-
troscopy. We failed to isolate compound 12 pure. Note
that in no case phosphonate-phosphate rearrangement of
hydroxyphosphonate was observed, and its calculated
yield on the converted aldehyde 5 during the reaction in
the presence of sodium ethylate was almot twice lower
than in the presence of potassium fluoride.
1
31
HO
KF–dioxane or
NaOEtꢀEtOH
O
(
EtO) OP
2
1
2
sides addition of phosphite, ester transesterification took
place during the reaction leading to formation of complete
ethyl ester 9 in 53% yield. The signal of the phosphorus
nucleus in the specrum of this compound was observed
at 23.57 ppm, that is, in the region characteristic of the
saturated phosphonates.
Then we tried to brominate the aldehyde 5 with N-
bromosuccinimide according to the procedure [5] with the
aim of obtaining acid bromide 13 and its further conver-
sion to acyl phosphonate (Scheme 5). The reaction was
performed in carbon tetrachloride on boil for 5 h. After
separation of succinimide and distillation of solvent,
acid bromide 13 was obtained in 79% yield. No bromi-
nation of methyl group in the furan ring was observed.
Compound 13 was involved into the Arbuzov reaction
with triethyl phosphite in benzene at room temperature.
However, it turned out that under these conditions diethyl
The bromination of phosphonate 9 was carried out
with N-bromosuccinimide in carbon tetrachloride in the
presence of azobis(isobutyronitrile) on boil. The reaction
proceeded selectively at the methyl group of the furan
ring. Bromide 10 was isolated in 81% yield (Scheme 3).
Its reaction with thioglycolic acid ester 1 was carried out
in a mixture of acetone and ethanol similar to phosphonate
2
. The yield of sulfide 11 was 79%. Signal of phosphorus
nucleus in the spectrum of compound 11 was located at
3.22 ppm, signals of carbon nuclei of sulfur-containing
substituent were observed at 27.32 (SCH CO), 33.52
bromophosphate (δ –1.04 ppm) is formed, and the furan
Р
fragment decomposes.
2
Hydrolysis of acid bromide 13 in the presence of
potassium bicarbonate in aqueous acetone at room tem-
perature led to monoethyl ether 14 which was formed in
2
(
SCH -furan) and 169.95 ppm (C=O).
2
The introduction of unsaturated phosphorus-contain-
26% yield (Scheme 6). By treating it with thionyl chloride
ing fragment to position 5 of the furan ring was supposed
to be carried out by means of Wittig reaction with the
participation of the corresponding furoyl phosphonate.
We tried to synthesize the latter by addition of diethyl
hydrogen phosphite to ester aldehyde 5 and subsequent
oxidation of hydroxyphosphonate. However, it turned
out that the reaction does not complete in the presence of
in 1 : 1.3 molar ratio in the presence of a catalytic amount
of DMF acid chloride 15 was synthesized in 95% yield
(Scheme 6). The latter was reacted with triethyl phosphite
in benzene. The process was accompanied by a slight heat
release. After completion of the exothermic reaction and
3
1
handling for 3 h in the P NMR spectrum of the reaction
mixture signals of acyl phosphonate 16 (δ –2.99 ppm),
Р
Scheme 5.
CO Et
2
NBS
P(OEt)
3
5
BrPO(OEt)
2
AIBN
BrOC
O
1
3
Scheme 6.
CO Et
CO Et
CO Et
2
2
2
SOCl2
P(OEt)
2
(EtO) OP
NaHCO3
2
13
HO C
DMF
O
2
ClOC
O
1
O
15
O
4
16
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 2 2020

SYNTHESIS OF (2-ETHOXY-2-OXOETHYLTHIO)METHYL DERIVATIVES
169
Scheme 7.
CO Et
CO Et
2
2
CO Et
CO Et
2
2
(
Ph) P=CH–CO Et
NBS
3
2
1
6
CH Br
AIBN
2
O
O
(
EtO) OP
(EtO) OP
2
2
1
7
18
Scheme 8.
CO Et
2
CO Et
2
CO Et
2
OH
Na + EtOCHO
+
HO
O
O
O
(
EtO) OPH C
2 2
PO(OEt)
2
PO(OEt)
2
1
9
20a
ꢀꢁɛ
diethyl chlorophosphate (δ –0.52 ppm), and diethyl
20b hydroxyl group proton gives a wide exchange signal
at 10.73 ppm, and signal of the proton at the double bond
appears at 7.53 ppm (JPH = 10.4 Hz).
Р
phosphite (δ 7.57 ppm) were observed. Via washing
P
the reaction mixture with saturated sodium bicarbonate
solution the latter two compounds were removed and acyl
phosphonate 16 was isolated pure in 73% yield.
The resulting mixture of compounds 20a, 20b was
introduced in the Wittig reaction with ethoxycarbonylme-
thylenetriphenylphosphorane similarly to [7]. In resulted
in formation of 4-furyl-4-(diethoxyphosphoryl)but-3-eno-
ate 21 with trans-location of ethoxycarbonylmethyl and
phosphoryl groups against the double bond in 93% yield
(Scheme 9). Its bromination with N-bromosuccinimide
showed that under the reaction conditions destruction of
the molecule occurs.
Acyl phosphonate 16 was involved into the Wittig
reaction with ethoxycarbonylmethylenetriphenylphorane
resulting in formation of phosphorylated furyl acrylate
1
7 having trans-location of phosphonate and ester
groups against the double bond in 63% yield (Scheme 7).
Bromination of the latter with N-bromosuccinimide led
to unstable bromomethyl derivative 18. It was charac-
terized only spectrally and was not involved in further
transformations.
31
In the P NMR spectrum of the reaction mixture six
signals of phosphorus nuclei of comparable intensity
were detected.
Lablity of bromide 18 prompted us to synthesize
a similarly constructed compound having longer un-
saturated phosphorus-containing substituent. The
first stage of synthesis was formylation of 2-methyl-
Thus, it was found that 2-bromethyl derivatives of
furan with unsaturated phosphorus-containing substitu-
ent in the position 5 of the ring are unstable even in the
presence of electron-accepting groups in the furan ring
and in the alkene fragment.
5
-(diethoxyphosphorylmethyl)-3-furoate 19 with ethyl
formate under the conditions of the Claisen reaction. The
reaction was carried out in benzene in the presence of
sodium foil according to the protocol [6]. Derivative of
furylacetic aldehyde was obtained in 77% yield. In chlo-
roform solution it existed as a mixture of cis-(20a) and
trans-enol (20b) forms in 1 : 2.5 molar ratio (Scheme 8).
In the spectrum of cis-enol 20a, signal of proton at the
double bond was observed at 7.73 ppm (JPH = 39.2 Hz),
and the signal of proton of the hydroxyl group was located
at 11.22 ppm. Due to the formation of an intramolecular
hydrogen bond with the oxygen atom of the phosphoryl
group it is narrow and split from phosphorus with the
coupling constant JPH = 12.4 Hz. In the case of trans-enol
Then we tried to synthesize ethoxycarbonylmethy-
lenetiomethyl derivatives of furan, containing several
phosphonate groups in the molecule, as well as esters
Scheme 9.
CO Et
2
CO Et
2
(
Ph) P=CH–CO Et
3
2
2
0a, 20b
O
PO(OEt)
2
2
1
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 2 2020

170
PEVZNER, STEPANOVA
Scheme 10.
CO Et
2
CO Et
CO Et
2
2
ClH C
2
HSCH CO Et
CH O + ZnCl + HCl
2
2
2
2
S
19
KOH
O
O
(
EtO) OPH C
(EtO) OPH C
2
2
2
2
2
3
2
2
Scheme 11.
CO Et
(EtO) OPH C
IH C
CO Et
2
2
2
2
2
NaI·H O
2
P(OEt)
3
22
(
EtO) OPH C
O
(EtO) OPH C
O
2
2
2
2
2
5
26
CO Et
2
CO Et
(
EtO) OPH C
2
2
(
EtO) OPH C
2
2
2
2Et
CO Et
2
NBS
HSCH
KOH
2
CO
S
CH Br
(EtO) OPH C
2 2
(
EtO) OPH C
O
2
O
2
2
2
7
24
of furan-3-carboxylic acid having a sulfide moiety in
the position 4 of the ring. The latter was supposed to be
introduced in the intramolecular ester condensation with
possible formation of the derivatives of 4H-thiopyrano
in acetone at room temperature in the dark. Iodide 25
was isolated in 85% yield as light yellow oil, relatively
stable to the action of light. It was immediately introduced
into the Arbuzov reaction with triethylphosphite. The
liberation of ethyl iodide began at 120°C, the reaction
was completed within 15 min at 145°C. The yield of
bis(phosphonate) 26 was 78%. In the 31P NMR spec-
[3,4-c]furan. Key stage of these syntheses was chloro-
methylation of phosphonate 19. The reaction was carried
out in dichloroethane at phosphonate: paraform : zinc
chloride = 1 : 1.5 : 0.25 molar ratio. Reaction temperature
of 60–65°C was maintained for 3 h. The target product
5
trum of this substance two doublets at 23.29 (P ) and
4
5
27.01 ppm (P ) with the coupling constant J = 19.5 Hz
РР
2
2 was isolated in 91% yield (Scheme 10).
were observed.
Compound 22 was reacted with ethyl thioglycolate.
The bromination of bis(phosphonate) 26 was
carried out with N-bromosuccinimide in carbon tet-
rachloride on boil. The reaction was initiated with
azobis(isobutyronitrile). Bromide 27 was isolated in 81%
yield (Scheme 11). Signal of protons of bromomethyl
group in this compound was observed at 4.69 ppm, and
the signal of the corresponding carbon atom at 25.08 ppm.
The process was carried out in acetone at an equimolar
ratio of reagents at room temperature in the presence
of 1 equiv of saturated solution of potassium hydrox-
ide in ethanol. Sulfide 23 was isolated in 94% yield
(
Scheme 10). Due to steric loading of molecule signals
of protons of the methylene group from the furan–CH2S
fragment formed AB-system with the coupling constant
JAB = 6.4 Hz, and protons of furan–CH Pand SCH CO Et
5
Signals of phosphorus nuclei were located at 22.36 (P )
4
5
and 26.37 ppm (P ), coupling constant J = 18.2 Hz.
2
2
2
PP
fragments each gave two signals with the 1 : 1 intensity
Synthesis of sulfide 24 was carried out at room tem-
perature in acetone at equimolar ratio of bis(phosphonate)
7, ethyl thioglycolate and potassium hydroxide. The
latter was added to the reaction mixture as a saturated
solution in ethanol. The target product was isolated in
86% yield. The appearance of the sulfide group was con-
31
ratio. In P NMR spectrum two signals of equal inten-
sity at 21.72 and 22.69 ppm were also found. Doubling
2
1
3
of signals was also observed in the C NMR spectrum.
Bis(phosphonate) 24 was synthesized according to
Scheme 11. Chloromethylphosphonate 22 was introduced
into the Finkelstein reaction with sodium iodide dihydrate
firmed by signals of methylene groups at 3.23 (SCH CO)
2
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 2 2020

SYNTHESIS OF (2-ETHOXY-2-OXOETHYLTHIO)METHYL DERIVATIVES
171
Scheme 12.
CO Et
CO Et
2
2
ClH C
ClH C
2
P(OEt)3
2
NBS
22
CH Br
CH PO(OEt)
2 2
2
O
O
(
EtO) OPH C
(EtO) OPH C
2
2
2
2
2
9
30
CO Et
2
CO Et
2
HSCH CO Et
2
2
S
CH PO(OEt)
2
2
O
(
EtO) OPH C
2
2
2
8
and 4.08 ppm (SCH -furan). Signals of correspond-
ing carbon atoms nuclei were recorded at 27.82 and
signals of the corresponding carbon atom nuclei were
located at 25.29 and 32.30 ppm. Doublets of phosphorus
2
2
5
6
3
2
3.49 ppm. Doublets of phosphorus nuclei were found at
nuclei were found at 21.35 (P ) and 22.27 ppm (P ), J =
PP
5
4
5
2.82 (P ) and 26.60 ppm (P ), J = 18.2 Hz.
8.3 Hz. Thus, as a result of the above-described work a
fairly wide range of phosphorus-containing derivatives of
furan with the adjacent location of ester and (2-ethoxy-
PP
In the synthesis of bis(phosphonate) 28 the difference
in reactivity of chloromethyl and bromomethyl groups
in the Arbuzov reaction was used. Chloromethylphos-
phonate 22 was brominated at methyl group with N-
bromosuccinimide in carbon tetrachloride on boil in the
2
-oxoethylthio)methyl groups was synthesized. These
compounds were considered by us as suitable objects for
intramolecular ester condensation.
presence of azobis(isobutyronitrile). The target product
We began the study of this reaction starting from com-
pound 3. Condensation was carried out in absolute ben-
zene, a small excess of potassium tert-butylate was used as
the base (Scheme 13).After the reagents were mixed, the
temperature of the reaction mass rose on 10°C. The forma-
tion of friable light yellow precipitate, very hygroscopic
and rapidly spreading on contact with air moisture was
observed.After extraction with water and acidification of
the aqueous phase to pH = 3–4, the released oil was quick-
ly extracted with chloroform, the extract was dried and
1
29 was isolated in 83% yield (Scheme 12). In its H NMR
spectrum bromomethyl group protons gave two signals at
at 4.76 and 4.77 ppm. Doubling of signals was observed
in the case of methylene protons of the ester group (4.37
and 4.38 ppm). Apparently, in this case, due to sterical
obstacles two stable spectroscopically distinguishable
1
3
conformers are formed. Note that in the C NMR spec-
trum, no doubling of signals of the corresponding carbon
atom nuclei was observed.
1
Compound 29 was phosphorylated with triethyl
phosphite under the conditions of the Arbuzov reaction.
Liberation of ethyl bromide began at 125°C, and at 135°C
heating was stopped so as not to involve chloromethyl
group in the reaction. Bis(phosphonate) 30 was isolated
in 92% yield (Scheme 12). Doublets of phosphorus nu-
clei in the spectrum of this compound were located at
evaporated. In the H NMR spectrum of the preparation
obtained signal of protons of the methylene group from
the SCH CO fragment disappeared, and the proton signal
2
the methylene group of the SCH -furan fragment was
2
shifted upfield from 4.08 to 3.33 ppm. The signal the
corresponding carbon nucleus was doubled and observed
at 34.41 and 34.46 ppm. In the 1H NMR spectrum a
broadened signal at 9.46 ppm was characteristic of the
enol form of 1,3-dicarbonyl compound, signals of carbon
atom nuclei at the double bonds were at 136.50 ppm
2
5
6
2
7
1.12 (P ) and 21.31 ppm (P ), coupling constant J =
PP
.8 Hz. Signal of the chloromethyl group protons was
revealed at 4.70 ppm, and the signal of corresponding
carbon atom at 35.62 ppm.
[O=CC(S)=] and 171.26 ppm (=COH). For side chain
Synthesis of sulfide 28 was carried out according to
the above-described standard protocol. The target prod-
uct was isolated in 92% yield. Signals of protons of the
methylene groups of SCH CO and SCH -furan fragments
ester group doubling of the signal of the carbonyl carbon
atom (172.39 and 172.40 ppm) and of carbon nuclei of
the ethyl substituent was observed. Signals of protons and
carbon atom nuclei of the furan fragment and diethoxy-
phosphorylmethyl groups did not undergo significant
2
2
were observed at 3.37 and 3.90 ppm respectively, and
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 2 2020

172
PEVZNER, STEPANOVA
Scheme 13.
HO
O
CO Et
2
S
HCl
KO
O
CO Et
2
(EtO) OPH C
2 2
3
1
t-BuOK
3
S
H CO
CO Et
3
2
(
EtO)2
OPH C
2
CH3I
S
EtO)2
OPH C
2
O
(
3
2
changes. The signal of the phosphorus nucleus was
located at 23.13 ppm.
with some losses. The above-mentioned salt does not react
with methyl iodide. From the data presented it can be seen
that metallization of compound 11 takes place during the
reaction, and the sodium salt formed has linear structure.
At the same time, it remains unknown, which of the CH-
acid centers of the substance 11 takes part in the reaction.
No cyclization was observed also in the reaction of po-
tassium tert-butylate with bis(phosphonate) 24, though
during the reaction there was a noticeable heat evolution,
and the formation of potassium salt was noted.
So, spectral data permit to characterize the compound
synthesized as ethyl 2-(diethoxyphosphorylmethyl)-
4
-hydroxy-7H-thiopyrano [3,4-b]-furan-5-carboxylate
3
1. Yield of the product was 28%. Having discovered
the sensitivity of potassium salt, formed during the
reaction, to moisture and oxygen we decided to carry
out its alkylation directly in the reaction mass to form
significantly more stable enol ether. For this purpose
to the suspension of potassium salt, formed during the
interaction of compound 3 with potassium tert-butylate
in absolute diethyl ether, a slight excess of methyl iodide
was added and the resulting mixture was refluxed with
stirring for 4 h. After separation of the reaction mixture
The reaction of phosphonate 23 with potassium tert-
butylate was also accompanied by heat evolution and
formation of hygroscopic potassium salt. The acidification
of its aqueous solution and the subsequent extraction al-
1
lowed to isolate the preparation whose H NMR spectrum
1
the product 32 was isolated. In its H NMR spectrum the
contained two broad signal at 9.65 and 9.80 ppm, and the
signals of protons of the phosphonomethyl group were
absent. The signals of protons of both methylene groups
bound with sulfur have also disappeared. In the same time,
signal of methoxyl group was observed at 4.16 ppm, and
the signal of corresponding carbon atom was located at
6
1.42 ppm. The downfield broadened signal of the
31
hydroxyl fragment disappeared. Signal of the carbon atom
nucleus of the O–C= thiopyrane ring fragment shifted
upfield to 163.17 ppm, the doubling of signals of the es-
ter group disappeared, spectral characteristics of the rest
structural fragments were without significantly changing.
Yield of the enol methyl ether 32 basing on compound 3
was 84% (Scheme 13).
in the PNMR spectrum, two signals of phosphorus were
observed at 23.28 and 25.38 ppm, what is characteristic
of saturated phosphonates. Singlet at 2.52 ppm in the
1
H NMR spectrum may belong to protons of the methyl
1
3
group at the furan ring. However C NMR spectrum of
the preparation obtained is uninformative, and we failed
to prove the presence of the furan ring in the molecule.
It can be only mentioned that a deep and controversial
restructuring of the molecule involving several CH-acid
centers takes place.
The interaction of phosphorylated sulfide 11 with
potassium tert-butylate was carried out in absolute ether
on boil. In the course of the reaction yellow precipitate of
potassium salt was formed. Under the layer of solvent it
does not change, but in the air it immediately blurs with
the formation of dark red viscous oil. Acidifying of its
aqueous solution permits to obtain starting compound 11
In the case of bis(phosphonates) 24 and 28 treating
with potassium tert-butylate in ether or THF also lead to
formation of highly hygroscopic salts. At acidification
of their aqueous solutions starting compounds were ex-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 2 2020

SYNTHESIS OF (2-ETHOXY-2-OXOETHYLTHIO)METHYL DERIVATIVES
173
clusively formed. While treating these salts with methyl
iodide no C-methylation was observed. Only starting
materials were returned from the reaction mixtures.
sible to obtain a series of compounds of 7H-thiopyrano-
[3,4-b]furan series. However, this method is very depen-
dent on steric loading of substrate and on the presence of
other CH-acid centers in it. Additional functional group
can be introduced in the position 4 of the cyclization
product by means of oxygen-containing linker. Selective
performing of reactions at the ester group and CH-acid
centers is complicated and requires the development of
special methods.
Thus, the possibility of proceeding of intramolecular
cyclization involving the ester and ethoxycarbonyl-
methylthiomethyl groups very much depends on steric
factors and the presence in the molecule of the other
CH-acid centers, though substrate metallization proceeds
relatively easy. When these obstacles are absent, cycliza-
tion eagerly takes place, and hydrolytically stable enol
ether can be obtained in 84% yield. Using of function-
lyzed halides may allow you to introduce linker-mediated
functional groups in the position 4 of 7H-thiopyrano-
EXPERIMENTAL
1H, 13C, and 31Р NMR spectra were recorded on a
1
Bruker ASCENDTM-400 spectrometer [400.13 ( H),
[3,4-b]furan skeleton.
31
13
1
61.97 ( P), 100.16 ( C). Melting points were measured
It was previously shown that phosphonocarbocarb-
on a Boёtius apparatus.
oxylates of the furan series are selectively hydrolyzed
with potassium hydroxide in ethanol at the ester group
Ethyl [(2-ethoxy-2-oxoethylthio)methyl]-5-
(
diethoxyphosphorylmethyl)-3-furoate (3). To a
solution of 6.72 g (17.5 mmol) of ethyl 2-bromomethyl-
-(diethoxyphosphorylmethyl)-3-furoate and 2.0 mL
18.2 mmol) of ethyl thioglycolate in 45 mL of acetone
[8]. We tried to use this method for hydrolysis of an ester
group in compound 32. It turned out that in this case no
5
(
high selectivity was observed. Even in presence of an
1
excess of alkali in the H NMR spectrum of the prepara-
the solution of 1.00 g (17.8 mmol) of potassium hydroxide
in 10 mL of ethanol was added under vigorous stirring.
Temperature of the reaction mixture rose to 36°C. The
resulting mixture was stirred for 3 h and left overnight.
On the next day it was evaporated to dryness, treated
with 30 mL of water and extracted with diethyl ether (3×
20 mL). The extract was washed with 15 mL of water,
15 mL of brine and dried over sodium sulfate. The fil-
trate was evaporated, the residue was kept in vacuum
(1 mmHg) at room temperature for 1 h.Yield 7.18 g (97%),
tion isolated signals of both ester and phosphonate groups
were observed. This fact greatly narrows the possibily of
performing transformations of the carboxyl group.
In the molecule of compound 32 there are two CH-acid
centers at the methylene groups bound with phosphorus
and sulfur atoms. We tried to carry out their formylation
according to Claisen using ethyl formate and sodium
foil. The reaction was carried out in benzene at a molar
ratio of phosphonate 32 : sodium : formate = 1 : 1.2 : 2.
Dissolution of sodium foil in the reaction mixture took
place in 3–4 h with a noticeable evolution of heat.
However, after water extraction and acidification, only
starting material was isolated. An attempt to convert the
enol salt into the hydrolytically stable enol ether via al-
kylation with methyl iodide was also unsuccessful. The
only phosphorus-containing substance isolated from the
reaction mixture was compound 32.
red oil. 1H NMR spectrum (CDCl ), δ, ppm: 1.18–1.25 m
3
(12H, CH -ethyl), 3.13 d (2H, CH Р, J = 20.8 Hz), 3.24 s
3
2
PH
(2H, ОC–CH S), 4.03 s (2H, furan–CH S), 4.02–4.05 m
2
2
(4H, CH ОР), 4.17–4.22 m (4H, CH ОC), 6.46 s (1H,
2
2
H4-furan). 13C NMR spectrum (CDCl ), δ , ppm: 14.05
3
C
(
CH -ester), 14.19 (CH -ester), 16.33 d (CH -phospho-
3 3 3
3
1
nate, J =5.6 Hz), 26.54 d (CH Р, J = 142.8 Hz),
PC
2
PC
2
7.34 (ОC–CH S), 33.61 (furan–CH S), 60.38 (CH О-
2
2
2
2
So, the product of formylation of phosphonate 32
quickly hydrolyzes in the aquatic environment, and its
sodium salt does not react with methyl iodide. Because
such behavior is not characteristic of phosphorylated
derivatives of furylacetic aldehydes [9], we can propose
that in the case under consideration the methylene group
bound with sulfur is involved in the reaction.
ester), 61.31(CH О-ester), 62.43 d (CH ОР, J
6.6 Hz), 109.15 d (H -furan, J = 7.2 Hz), 115.99
(H -furan), 145.40 d (H -furan, J = 9.2 Hz), 156.84 d
=
2
2
PC
4
3
PC
3
5
2
PC
2
4
(H -furan, J =2.6 Hz), 163.05 (CО-furan), 169.84
PC
3
1
(CО–CH ). Р NMR spectrum (CDCl ), δ , ppm: 22.07.
2
3
Р
Methyl 2-methyl-5-formyl-3-furoate (5). To the
solution of 5.16 g (30 mmol) of methyl 2-methyl-
5-(hydroxymethyl)-3-furoate 4 in 120 mL of methylene
chloride 9.80 g (45 mmol) of pyridinium chlorochromate
was added. The resulting mixture was stirred for 5 h and
Thus, using the intramolecular Claisen reaction
starting from phosphonomethylated serivative of
2-(ethoxycarbonylmethylthiomethyl)-3-furoate it is pos-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 2 2020

174
PEVZNER, STEPANOVA
left overnight. On the next day the solution was decanted
and diluted with 120 mL of diethyl ether. The precipitate
of chromium salts was filtered off, the filtrate was washed
with 50 mLof water and dried with calcium chloride. Sol-
vent was distilled off, the remaining oil gradually crystal-
methanol and 0.6 mL (8 mmol) of pyridine in 10 mL
of ethyl acetate 1.38 g (6 mmol) of acid chloride 7 was
added. The resulting mixture was stirred at room tempera-
ture for 9 h and left overnight. On the next day pyridine
hydrochloride was filtered off, the filtrate was washed
with 5 mL of 5% hydrochloric acid, 5 mL of water,
5 mL of saturated sodium bicarbonate solution and dried
over calcium chloride. The solution was filtered through
a thin layer of silica gel and evaporated. The residue
was triturated with hexane, the crystals formed were
lized when standing. Yield 3.68 g (59%), yellow crystals,
1
mp 48°C. H NMR spectrum (CDCl ), δ, ppm: 2.68 s (3H,
3
4
CH -furan), 3.86 s (3H, CH О), 7.46 s (1H, H -furan),
.55 s (1H, CHО). C NMR spectrum (CDCl ), δ , ppm:
3
3
13
9
1
1
1
3 C
4
4.31 (CH -furan), 51.90 (CH О), 116.21 (C -furan),
3
3
3
5
2
22.43 (C -furan), 150.37 (C -furan), 163.00 (C -furan),
filtered off. Yield 0.91 g (67%), light brown powder, mp.
64.81 (CО-ester), 177.19 (CО-aldehyde).
1
1
02–103°C. H NMR spectrum (CDCl ), δ, ppm: 2.63 s
3
trans-3-[4-(Methoxycarbonyl)-5-methyl-fur-2-yl]-
acrylic acid (6). The mixture of 3.68 g (22 mmol)
of aldehyde 5, 2.30 g (22 mmol) of malonic acid and
(
6
3H, CH -furan), 3.79 s (3H, CH О), 3.84 s (3H, CH О),
3 3 3
3
.30 d (1H, =CH–CО, JHH = 15.8 Hz), 6.83 s (1H, H -
13
furan), 7.35 d (1H, =CH-furan, JHH = 15.8 Hz). C NMR
spectrum (CDCl ), δ , ppm: 14.05 (CH -furan), 51.55
1
1
1
.1 mL (13 mmol) of pyridine was stirred for 4 h at
00°C. Then the reaction mixture was dissolved in
5 mL of 10% aqueous ammonia, the solution was
3
C
3
3
4
(CH О), 51.73(CH О), 115.16 (C -furan), 115.84 (C -
3 3
furan), 115.92 (=CH-furan), 130.48 (=CH–CО), 148.61
washed with 5 mL of ethyl acetate and acidified with
hydrochloric acid. The oil released was extracted with
methylene chloride (2×15 mL), the extract was dried
over sodium sulfate and evaporated. The residue was
2
5
(
C -furan), 161.54 (C -furan), 163.68 (furan–C=О),
1
67.23 (=CH–CО).
Ethyl 3-(diethoxyphosphoryl)-3-[4-(ethoxy-
carbonyl)-5-methylfur-2-yl]propanoate (9). To the
mixture of 1.85 g (8.2 mmol) of acrylate 8 and 3 mL
crystallized from ethyl acetate–hexane (1 : 4). Yield
1
1
.54 g (33%), mp 167–168°C (decomp.). H NMR spec-
(20.3 mmol) of diethyl hydrogen phosphite 0.7 mL of
trum (DMSO-d ), δ, ppm: 2.59 s (3H, CH -furan), 3.77 s
6
3
absolute ethanol and 0.1 g of sodium foil were added
with vigorous stirring. Light yellow reaction mass in the
course of 30 s turned dark red, the temperature rose up to
70°C.After the completion of heat evolution the reaction
mixture was stirred for 4 h at 80°C, neutralized with acetic
acid, dissolved in 20 mL of ethyl acetate, washed with
5 mL of water, 5 mL of NaCl solution and dried over
sodium sulfate. After removing of solvent low-boiling
products (up to 60°C, 1 mmHg) were distilled off from the
(
3H, CH О), 6.17 d (1H, =CH–CО, J = 15.6 Hz), 7.17
3 HH
3
s (1H, H -furan), 7.36 d (1H, =CH-furan, J = 15.6 Hz),
1
δ , ppm: 14.19 (CH -furan), 52.02 (CH О), 115.66 (C -
furan), 115.71 (C -furan), 117.31 (=CH-furan), 130.56
HH
13
2.47 br.s (1H, CООH). C NMR spectrum (DMSO-d ),
6
3
C
3
3
4
2
5
(
(
=CH–CО), 148.97 (C -furan), 161.60 (C -futan), 163.40
furan–C=О), 167.52 (=CH–CО).
trans-3-[4-(Methoxycarbonyl)-5-methylfur-2-yl]-
acryloyl chloride (7). The mixture of 1.54 g (7.3 mmol)
of the acid 6, 1 mL (14 mmol) of thionyl chloride and
3
1
residue. Yield of compound 9 1.69 g (53%), light brown
1
syrup. H NMR spectrum (CDCl ), δ, ppm: 1.15–1.34 m
drops of DMF was refluxed for 5 h with stirring in
5 mLof benzene. The solvent was distilled of on a rotary
3
(
12H, CH ), 2.50 br.s (3H, CH -furan), 2.79–3.00 m (2H,
3 3
evaporator, the residue was triturated with hexane. Yield
CH2–C=О), 3.72 d.d.d (1H, Р–CH, JHH = 10.2 Hz, 4.8 Hz;
J = 22.4 Hz), 3.97–4.15 m (6H, CH ОC, CH ОР), 4.21 q
1
1
.33 g (79%) of acid chloride 7, mp 102°C. H NMR
РH
2
2
3
spectrum (CDCl ), δ, ppm: 2.67 s (3H, CH -furan), 3.87 s
(2H, CH ОC, J = 7.0 Hz), 6.45 d (0.5H, H -furan, J
=
C
3
3
2
HH
РH
3.6 Hz), 6.46 d (0.5H, H -furam, J = 3.6 Hz). 13
3
(
3H, CH О), 6.50 d (1H, =CH–CО, J 15.2 Hz), 7.07 s
3
HH
РH
3
13
(1H, H -furan), 7.49 d (1H, =CH-furan, J 15.2 Hz). C
NMR spectrum (CDCl ), δ , ppm: 13.71 (CH -furan),
HH
3 C 3
NMR spectrum (CDCl ), δ , ppm: 14.25 (CH -furan),
14.06 (CH -ester), 14.30 (CH -ester), 16.30 d (CH -
3 3 3
3
C
4
3
3
3
5
1.77 (CH О), 116.81 (C -furan), 119.41 (C -furan),
phosphonate, J = 5.6 Hz), 16.32 (CH -phosphonate,
3
РH
3
2
3
119.88 (=CH-furan), 135.10 (=CH–CО), 147.53 (C -
JРH = 5.8 Hz), 33.18 (CH –C=О), 34.27 d (Р–CH,
J =144.0Hz),60.01(CH ОC),60.97(CH ОC),62.64d(
CH ОР, J = 6.9 Hz), 62.81 d (CH ОР, J = 6.9 Hz),
108.69 d (C -furan, J = 7.8 Hz), 114.53 d (C -furan,
2
5
furan), 163.17 (C -furan), 163.48 (furan–C=О), 165.57
1
РC
2
2
(=CH–CО).
2
2
2
РC
3
2
РC
3
4
Methyl trans-3-[4-(methoxycarbonyl)-5-methylfur-
РC
4
2
2
2
-yl]acrylate (8). To a solution of 0.5 mL (12 mmol) of
J = 2.6 Hz), 146.98 d (C -furan, J = 9.2 Hz), 158.60 d
РC РC
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 2 2020

SYNTHESIS OF (2-ETHOXY-2-OXOETHYLTHIO)METHYL DERIVATIVES
175
5
4
(
(
C -furan, J = 2.4 Hz), 163.82 (furan–C=О), 170.55 d
δ, ppm: 1.20 t (3H, CH -ester, J = 7.2 Hz), 1.24–1.34
3 HH
РC
C=О, 3JРC = 18.0 Hz). Р NMR spectrum (CDCl ), δ ,
31
m (12H, CH -ester, CH -phosphonate), 2.84–3.03 m
3
Р
3 3
ppm: 23.57.
(2H, CH –C=О), 3.30 s (2H, О=C–CH S), 3.79 s (2H,
2 2
furan–CH S), 3.80 d.d.d (1H, Р–CH, J = 10.6 Hz,
Ethyl 3-(diethoxyphosphoryl)-3-[4-(ethoxy-
carbonyl)-5-bromomethylfur-2-yl]propanoate (10).
To a solution of 1.69 g (4.3 mmol) of phosphonate 9 in
2
HH
5
.0 Hz; JРH = 22.8 Hz), 4.01–4.21 m (6H, CH ОC,
2
CH ОР), 4.25 q (2H, CH ОC, J = Hz), 6.53 d (1H,
2
2
HH
H -furan, J = 3.6 Hz). 13C NMR spectrum (CDCl3),
3
РH
3
0 mL of carbon tetrachloride 0.90 g (5.0 mmol) of N-
δ , ppm: 14.10 (CH -ester), 14.13 (CH -ester), 14.25
C
3
3
bromosuccinimide and 0.2 g of azobis(isobutyronitrile)
was added with stirring. The reaction mixture was re-
fluxed at vigorous stirring for 6 h, then 30 mL of hexane
was added, and the mixture formed was left overnight.
Succinimide was filtered off, the solvents were removed,
and the residue was kept in vacuum (1 mmHg) for 1 h at
3
(
CH -ester), 16.40 d (CH -phosphonate, J = 5.8 Hz),
3 3 РC
2
7.32 (О=C–CH S), 33.08 br.s (CH –C=О), 33.52 (furan–
2 2
1
CH S), 34.44 d (Р–CH, J = 143.5 Hz), 60.48 (CH ОC),
2
РC
2
2
61.08 (CH ОC), 61.40 (CH ОC), 62.75 d (CH ОР, J =
2 2 2 РC
2
7
.0 Hz), 62.90 d (CH ОР, J = 6.9 Hz), 108.95 d
2
РC
3
3
4
4
(
C -furan, J = 7.3 Hz), 115.84 d (C -furan, J
=
РC
РC
room temperature. Yield 1.63 g (81%), yellowish brown
2
2
3
.1 Hz), 148.71 d (C -furan, J = 9.1 Hz), 157.13 d
РC
1
syrup. H NMR spectrum (CDCl ), δ, ppm: 1.20 t (3H,
3
5
4
(C -furan, J = 2.9 Hz), 163.10 (furan–C=О), 169.95
РC
CH -ester, J = 7.2 Hz), 1.27 t (3H, CH -ester, J
=
3
HH
3
HH
3
31
(C=О-thioacetate), 170.46 d (C=О, J = 17.7 Hz). Р
РC
7
3
1
.0 Hz), 1.29–1.36 m (6H, CH -phosphonate), 2.86–
3
NMR spectrum (CDCl ), δ , ppm: 23.22.
3
Р
.06 m (2H, CH –C=О), 3.79 d.d.d (1H, Р–CH, J
=
2
HH
Reaction of aldehyde 5 with diethyl phosphite. a.
In the presence of anhydrous potassium fluoride. To the
solution of 1.62 g (8.9 mmol) of aldehyde 5 and 1.3 mL
0.6 Hz, 4.8 Hz; J = 23.2 Hz), 3.02–4.12 m (6H, CH ОC,
РH
2
CH ОР), 4.30 q (2H, CH ОC, J = 7.0 Hz), 4.46 d
2
2
HH
(
1
1H, CH Br, J = 11.0 Hz), 4.79 d (1H, CH Br, J
=
2
HH
2
HH
(10.1 mmol) of diethyl hydrogen phosphite in 25 mL of
3
1.0 Hz), 6.56 d (0.5 H, H -furan, J = 3.6 Hz), 6.57
РH
13
dioxane 3 g of freshly finely ground potassium fluoride
was added, and reaction mixture was heated for 16 h
at 100°C under vigorous stirring. After that, potassium
fluoride was filtered off, washed with ethyl acetate, and
combined organic phases were evaporated. The residue
was dissolved in 40 mL of ethyl acetate, washed with
3
d (0.5 H, H -фураH, J = 3.6 Hz). C NMR spectrum
РH
(
CDCl ), δ , ppm: 14.11 (CH -ester), 14.32 (CH -
3 C 3 3
3
ester), 16.41 d (CH -phosphonate, J = 5.8 Hz), 23.41
(
3
РH
3
CH Br), 32.99 d (CH –C=О, J = 0.9 Hz), 34.55 d
2 2 РC
1
(Р–CH, J =143.3Hz), 60.81(CH ОC), 61.17(CH ОC),
РC
2
2
2
6
2
2.94 d (CH ОР, J = 6.8 Hz), 63.12 d (CH ОР,
2 РC 2
1
0 mL of water and dried over sulfate sodium. Solvent
was distilled off, and the residue was kept in a vacuum
1 mmHg) for 1 h at room temperature. 1.81 g of a mixture
3
3
J = 7.0 Hz), 109.49 d (C -furan, J = 7.3 Hz), 117.17 d
РC
4
РC
4
2
2
(
9
(
C -furan, J = 3.1 Hz), 146.95 d (C -furan, J
.0 Hz), 154.63 d (C -furan, J = 2.8 Hz), 162.57
furan–C=О), 170.38 d (C=О, 3J = 18.1 Hz). Р NMR
=
РC
РC
(
5
4
РC
of aldehyde 5 and hydroxyphosphonate 12 in 0.7 : 1 ratio
was obtained. The yield of compound 12 calculated on the
31
РC
spectrum (CDCl ), δ , ppm: 22.72.
3
Р
1
reacted aldehyde 5 was 65% according to H NMR data.
Ethyl 3-(diethoxyphosphoryl)-3-[4-(ethoxy-
carbonyl)-5-[(2-ethoxy-2-oxoethylthio)methyl]fur-2-
yl]propanoate (11). To the solution of 2.25 g (4.8 mmol)
of bromide 10 in 30 mL of acetone 0.7 mL (6.4 mmol)
of ethyl thioglycolate and saturated solution of 0.30 g
(
4-Ethoxycarbonyl-5-methylfur-2-yl)(diethoxy-
1
phosphoryl) methanol (12). H NMR spectrum (CDCl ),
δ, ppm: 1.29–1.39 m (9H, CH -ester, CH -phosphonate),
.58 s (3H, CH -furan), 4.15–4.21 m (4H, CH ОР), 4.28 q
2H, CH ОC, J = 7.2 Hz), 4.94 d (1H, Р–HC–О,
3
3
3
2
(
3
2
2 HH
(5.4 mmol) of potassium hydroxide in ethanol was added
3
13
JРH = 14.0 Hz), 6.76 d (1H, H -furan, J = 2.4 Hz). C
РH
with stirring. The reaction mixture was stirred for 4 h at
room temperature and left overnight. On the next day
the precipitate was removed, the filtrate was evaporated
and the residue was dissolved in 40 mL of ethyl acetate,
washed with 10 mLof a 5% solution of sodium carbonate,
then with water (2 ×10 mL) and dried over sodium sulfate.
Solvent was removed, and the residue was kept in vacuum
NMR spectrum (CDCl ), δ , ppm: 14.13 (CH -furan),
3
C
3
3
1
6
4.33 (CH -ester), 16.33 d (CH -phosphonate, J
=
3
3
РC
3
.5 Hz), 16.39 d (CH -phosphonate, J = 6.6 Hz),
3
РC
60.19 (CH ОC), 63.42 d (CH ОР, 2J = 7.1 Hz), 63.59 d
2
2
РC
2
1
(CH ОР, J =5.1Hz),64.43d(Р–HC–О, J =164.6Hz),
2
РC
РC
3
3
4
110.29 d (H -furan, J = 6.4 Hz), 114.59 d (H -furan,
РC
4
2
2
JРC = 1.1 Hz), 148.08 d (H -furan, J = 7.3 Hz),
РC
5
31
(
(
1 mmHg) for 1 h at room temperature. Yield 1.94 g
159.51 br.s (H -furan), 163.78 (C=О). Р NMR spectrum
(CDCl ), δ , ppm: 18.76.
1
79%), light brown syrup. H NMR spectrum (CDCl ),
3
3
Р
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176
PEVZNER, STEPANOVA
b. In presence of sodium ethylate. To the mixture of
.22 g (12 mmol) of aldehyde 5 and 4 mL (31 mmol) of
diethyl hydrogen phosphite 1 mLof absolute ethanol and
.1 g of sodium foil was added with stirring. Temperature
CООH). 13C NMR spectrum (CDCl ), δ , ppm: 14.24
3 C
2
(CH -furan), 14.30 (CH -ester), 60.80 (CH ОC), 116.22
3 3 2
3
4
2
(C -furan), 120.90 (C -furan), 141.35 (C -furan), 162.77
5
0
(C -furan), 162.80 (C=О-ester), 163.91 (C=О-acid).
of the reaction mixture rose to 71°C.After complete evo-
lution of heat the reaction mixture was stirred for 2 h at
4
-(Ethoxycarbonyl)-5-methyl-2-furoyl chloride
15). To the suspension of 1.47 g (5.8 mmol) of acid 14 in
0 mL of benzene 0.7 mL (9.6 mmol) of thionyl chloride
(
2
8
0–85°C. Ratio of intensities of phosphonate and diethyl
hydrogen phosphite signals in 31P NMR spectrum was
: 5. It did not change during heating for 8 h. No forma-
and 2 drops of DMF was added with stirring. The reac-
tion mixture was refluxed with stirring for 6 h, and then
evaporated. The residue was kept in a vacuum (1 mmHg)
for 1 h at room temperature. Yield 1.52 g (95%), yellow
1
tion of phosphates was observed. The reaction mass was
neutralized with acetic acid, diluted with 40 mL of ethyl
acetate, washed with water (2×15 mL) and dried over
sodium sulfate. The solvent was distilled off, the residue
was kept in vacuum (1 mmHg) for 1 h at room tempera-
ture. A mixture of aldehyde 5 and hydroxyphosphonate
1
syrup. H NMR spectrum (CDCl ), δ, ppm: 1.39 t (3H,
3
CH -ester, J = 7.0 Hz), 2.72 s (3H, CH -furan), 4.35 q
3
HH
3
3
(
13
2H, CH О-ester, J = 7.0 Hz), 7.74 C (1H, H -furan).
C NMR spectrum (CDCl ), δ , ppm: 14.28 (CH -furan),
4.54 (CH -ester), 60.10 (CH ОC), 117.13 (C -furan),
3 2
25.65 (C -furan), 143.59 (C -furan), 155.18 (C -furan),
2
HH
3
C
3
4
1
2 in 0.9 : 1 ratio, 1.70 g, was obtained. The yield of
1
1
1
compound 12 calculated on the reacted aldehyde 5 was
3
2
5
1
3
9% according to H NMR data.
62.08 (C=О-ester), 166.32 (Cl–C=О).
4
-(Ethoxycarbonyl)-5-methyl-2-furoyl bromide
Diethyl 4-(ethoxycarbonyl)-5-methyl-2-furo-
(13). To the solution of 2.73 g (15 mmol) of aldehyde 5
yl phosphonate (16). To the solution of 1.65 g
in 50 mL of carbon tetrachloride 3.03 g (17 mmol) of N-
bromosuccinimide and 0.20 g of azobis(isobutyronitrile)
was added with stirring. The reaction mixture was refluxed
with stirring for 4 h until no crystals of N-bromosuccin-
imide remained and left overnight for crystallization.
On the next day succinimide was filtered off, the filtrate
was evaporated, and the residue was kept in vacuum
(
7.6 mmol) of acid chloride 15 in 15 mLof benzene 1.4 mL
(8.2 mmol) of triethylphosphite was added with stirring
in one portion. Temperature of the reaction mixture rose
from 25 up to 30°C. The resulting mixture was stirred for
5 h, washed with saturated solution of sodium bicarbonate
in water (2×8 mL) and dried over sodium sulfate. Benzene
was distilled off and the residue was kept in a vacuum
(1 mmHg) for 1 h at room temperature. Yield 1.77 g
(
1 mmHg) for 1 hour at room temperature. Yield 3.10 g
1
1
(
79%), red syrup. H NMR spectrum (CDCl ), δ, ppm:
(73%), light brown syrup. H NMR spectrum (CDCl ),
3
3
1
.38 t (3H, CH -ester, J = 7.2 Hz), 2.68 s (3H, CH3-
δ, ppm:1.30–1.40 m (9H, CH -phosphonate, CH -ester),
3
HH
3
3
furan), 4.34 q (2H, CH О-ester, J = 7.2 Hz), 7.76 s (1H,
2.71s(3H, CH -furan), 4.27d.q(4H, CH ОР, J =7.0Hz,
2
HH
3 2 HH
3
13
H -furan). C NMR spectrum (CDCl ), δ , ppm: 14.20
JРH = 14.8 Hz), 4.32 q (2H, CH О-ester, J = 7.2 Hz),
2 HH
3
C
3
13
(
(
(
CH -furan), 14.28 (CH -ester), 61.14 (CH ОC), 119.12
7.71 s (1H, H -furan). C NMR spectrum (CDCl ), δ ,
3
3
2
3 C
3
4
2
C -furan), 125.73 (C -furan), 149.88 (C -furan), 160.96
ppm: 14.29 (CH -furan), 14.42 (CH -ester), 16.13 d (CH -
3 3 3
5
3
C -furan), 161.69 (C=О-ester), 166.62 (Br–C=О).
phosphonate, J = 6.7 Hz), 16.34 d (CH -phosphonate,
РC 3
3JРC = 5.7 Hz), 60.91 (CH ОC), 64.36 d (CH ОР, J
.1 Hz), 116.94 (C -furan), 126.47 (C -furan), 149.62 d
2
=
4
-(Ethoxycarbonyl)-5-methyl-2-furoic acid (14).
To the solution of 2.74 g (10.5 mmol) of acid bromide
3 in 30 mL of acetone the saturated solution of 2.30 g
22.8 mmol) of potassium bicarbonate in water was
2
2
РC
4
3
7
(
2
2
C -furan, J = 91.1 Hz), 162.40 (C=О-ester), 166.12
1
(
РC
5
1
(
3
C -furan), 184.76 d (C=О-phosphonate, J = 190.0 Hz).
Р NMR spectrum (CDCl ), δ , ppm: –2.99.
РC
1
added. The reaction was stirred for 12 h at room tem-
perature, then acetone was distilled off, the residue was
suspended in 8 mL water and washed with 5 mL of ethyl
acetate. Water layer was acidified with concentrated hy-
drochloric acid to pH = 2, the precipitate was filtered off
3
Р
Ethyl 3-(diethoxyphosphoryl)-3-[4-(ethoxy-
carbonyl)-5-methylfur-2-yl]acrylate (17). To the solu-
tion of 2.41 g (7.6 mmol) of furoyl phosphonate 16 in
15 mL of benzene 2.80 g (8.0 mmol) of ethoxycarbo-
nylmethylenetriphenylphosphorane was added with stir-
ring. The resulting mixture was refluxed with stirring for
10 h. Thereafter the hot mixture was diluted with 40 mL
of hexane and left overnight. On the next day triphen-
1
and dried on air. Yield 0.54 g (26%), mp 137–138°C. H
NMR spectrum (CDCl ), δ, ppm: 1.39 t (3H, CH -ester,
3
3
JHH = 7.2 Hz), 2.71 s (3H, CH -furan), 4.34 q (2H, CH О-
3
2
3
ester, JHH = 7.2 Hz), 7.58 s (1H, H -furan), 9.95 br.s (1H,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 2 2020

SYNTHESIS OF (2-ETHOXY-2-OXOETHYLTHIO)METHYL DERIVATIVES
177
ylphosphine oxide was filtered off, and the filtrate was
washed with 5% hydrochloric acid (2×10 mL), 10 mL of
water and dried over sodium sulfate. Solvents were dis-
tilled off, and the residue was kept in vacuum (1 mmHg)
for 1 h at room temperature. Yield 1.86 g (63%), a very
tions of the Claisen reaction. To the solution of 5.00 g
(16.4 mmol) of ethyl 2-methyl-5-(diethoxyphosphoryl-
methyl)-3-furoate 19 and 2.7 mL (33.4 mmol) of ethyl
formate in 50 mL of benzene 0.50 g (22 meq) of sodium
foil was added under intense stirring. The reaction mix-
ture was stirred for 4 h until sodium has dissolved and
left overnight. On the next day the mixture formed was
extracted with water (2×20 mL), the aqueous extract
was washed with 10 mL of ethyl acetate, acidified with
formic acid until pH = 2–3 and then extracted with chlo-
roform (2×20 mL). The extract was washed with 10 mL
of brine and dried over sodium sulfate. Chloroform was
removed on a rotary evaporator, the residue was kept
in a vacuum (1 mmHg) for 1 h at room temperature.
Yield 4.20 g (77%) of a mixture of isomeric Z-20a and
E-20b enols of (diethoxyphosphoryl)(4-ethoxycarbonyl-
5-methylfur-2-yl) acetic aldehyde in 1 : 2.5 ratio, light
1
thick yellow syrup. H NMR spectrun (CDCl ), δ, ppm:
3
1
.30–1.35 m (12H, CH -phosphonate, CH -ester), 2.56 s
3 3
(
3H, CH -furan), 4.08–4.21 m (4H, CH ОC), 4.27 d.q
3
2
(
4H, CH ОР, J = 7.0 Hz, JРH = 14.0 Hz), 6.74 d (1H,
2
HH
3
13
HC=, JРH = 23.6 Hz), 7.08 s (1H, H -furan). C NMR
spectrum (CDCl ), δ , ppm: 13.42 (CH -furan), 14.10
3
C
3
(
CH -acrylate), 14.34 (CH -furoate), 16.28 d (CH -phos-
3 3 3
3
phonate, J = 6.3 Hz), 60.38 (CH ОC-acrylate), 61.31
РC
2
2
(CH ОC-furoate), 63.00 d (CH ОР, J = 5.4 Hz), 114.77
2 2 РC
3
4
1
(
1
C -furan), 115.70 (C -furan), 126.63 d (=CР, J
=
РC
2
77.8 Hz), 130.03 d (=CH, J = 6.6 Hz), 145.03 d
РC
2
2
5
(
(
C -furan, J = 19.7 Hz), 160.27 (C -furan), 163.41
РC
3
1
C=О-furoate), 166.04 d (C=О-acrylate, J = 26.6 Hz).
red syrup. H NMR spectrum (CDCl ), δ, ppm: common
РC
3
3
1
Р NMR spectrum (CDCl ), δ , ppm: 13.90.
signals: 1.28–1.35 m (9H, CH -ester, CH -phosphonate),
3
Р
3
3
4
7
.02–4.18 m (4H, CH ОР), 4.27 q (4H, CH ОC, J
=
Ethyl 3-(diethoxyphosphoryl)-3-[4-(ethoxy-
2
2
HH
3
.2 Hz); 20а: 2.54 s (3H, CH -furan), 6.35 s (1H, H -
carbonyl)-5-(bromomethyl) fur-2-yl]acrylate (18). To
the solution of 1.43 g (3.7 mmol) of acrylate 17 in 25 mL
of carbon tetrachloride 0.70 g of N-bromosuccinimide
and 0.2 g of azobis(isobutironitrile) was added with
stirring. The reaction mixture was refluxed with stirring
for 4 h until the disappearance of N-bromosuccinimide.
Then succinimide was filtered off, carbon tetrachloride
was removed, and the residue was kept in a vacuum
3
furan), 7.73 d (1H, =CH–О, JРH = 39.2 Hz), 11.22 d (1H,
ОH, J = 12.4 Hz); 20b: 2.57 s (3H, CH -furan), 6.79 s
(1H, H -furan), 7.53 d (1H, =CH–О, JРH = 10.4 Hz), 10.74
br.s (1H, ОH). 13C NMR spectrum (CDCl3), δC, ppm:
20а: 13.72 (CH3-furan), 14.33 (CH3-ester), 16.08 d (CH3-
phosphonate, JРC = 6.2 Hz), 60.19 (CH2ОC), 62.83 d
(CH2ОР, JРC = 4.5 Hz), 91.38 d (=C–Р, JРC = 178.5 Hz),
105.61 d (C -furan JРC = 1.2 Hz), 114.90 (C -furan),
145.90 d (C -furan, JРC = 16.6 Hz), 157.47 (C -furan),
161.72 d (=C–О, 2JРC = 2.1 Hz), 164.02 (C=О); 20b:
13.78 (CH -furan), 14.33 (CH -ester), 16.13 d (CH -phos-
phonate, J = 6.5 Hz), 60.16 (CH ОC), 62.45 d (CH ОР,
2JРC = 4.9 Hz), 92.78 d (=C–Р, J = 198.8 Hz), 109.15
d (C -furan, J = 6.3 Hz), 114.73 (C -furan), 145.46 d
РC
(C -furan, J = 8.3 Hz), 157.10 (C -furan), 158.03 d
(=C–О, 2JРC = 20.7 Hz), 164.19 (C=О). Р NMR spec-
РH
3
3
3
2
1
3
3
4
(
1
1 mmHg) for 1 h at room temperature. Crude bromide
7, 1.56 g, was obtained as dark brown syrup eagerly
2
2
4
releasing hydrogen bromide. In the course of 2–3 h the
1
preparation became brittle, non-melting resin. H NMR
3
3
3
3
spectrum (CDCl ), δ, ppm: 1.31–1.39 m (12H, CH -
3
3
РC 2 2
1
phosphonate, CH -ester), 4.09–4.21 m (4H, CH ОC),
3
2
РC
3
3
4
4
4
7
.37 d.q (4H, CH ОР, J = 7.2 Hz, JРH = 14.4 Hz),
2
HH
2
2
4
.76 s (2H, CH Br), 6.85 d (1H, HC=, J = 23.2 Hz),
2
РH
РC
3
13
31
.10 s (1H, H -furan). C NMR spectrum (CDCl ), δ ,
3
C
ppm: 14.11 (CH -acrylate), 14.25 (CH -furoate), 16.30 d
trum (CDCl ), δ , ppm: 21.21 (20а), 20.26 (20b).
3
3
3
Р
3
(
(
(
1
1
1
1
CH -phosphonate, J = 6.0 Hz), 20.66 (CH Br), 61.06
3 РC 2
Ethyl 4-(diethoxyphosphoryl)-4-(4-ethoxycarbon-
yl-5-methylfur-2-yl)but-3-enoate (21). To the solution
of 3.90 g (11.7 mmol) of a mixture of compounds 20a,
20b in 20 mL of benzene 4.50 g (12.9 mmol) of ethoxy-
carbonylmethylenetriphenylphosphorane was added with
stirring. The mixture formed was refluxed with stirring
for 10 h. After that hot solution was diluted with stirring
with 60 mLof hexane and stirring was continued until the
formation of crystals. On the next day triphenylphosphine
oxide was filtered off, the filtrate was evaporated, the
CH ОC-acrylate), 61.78 (CH ОC-furoate), 63.21 d
2
2
2
3
3
CH ОР, J = 5.6 Hz), 114.62 d (C -furan, J = 1.9 Hz),
2
РC
4
РC
1
17.80 (C -furan), 124.85 d (=CР, J = 170.2 Hz),
29.82 d (=CH, 2JРC = 8.4 Hz), 145.62 d (C -furan, J
8.7 Hz), 155.99 (C -furan), 162.23 (C=О-furoate),
66.75 d (C=О-arylate, 3JРC = 28.6 Hz). 31Р NMR
РC
2
2
=
РC
5
spectrum(CDCl ), δ , ppm: 13.08.
3
Р
Formylation of ethyl 2-methyl-5-(diethoxy-
phosphorylmethyl)-3-furoate (19) under the condi-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 2 2020

178
PEVZNER, STEPANOVA
residue was kept in a vacuum (1 mmHg) for 1 h at room
temperature. Yield 4.39 g (93%), yellow syrup. H NMR
To the solution of 2.23 g (6.3 mmol) of chloride 22 in
50 mL of acetone 0.7 mL (6.4 mmol) of ethyl thioglyco-
late and saturated solution of 0.4 g (7 mmol) of potassium
hydroxide in ethanol was added with stirring at room
temperature. The mixture formed was stirred for 8 h at
room temperature and left overnight. On the next day
the precipitate was filtered off, acetone was removed,
and the residue was dissolved in 30 mL of ethyl acetate.
The solution obtained was washed with 10 mL of water,
10 mL of brine and dried over sodium sulfate. Ethyl
acetate was distilled off, the residue was kept in vacuum
(1 mmHg) for 1 h at room temperature.Yield 2.58 g (94%),
1
spectrum (CDCl ), δ, ppm: 1.25 t (3H, CH -aliphatic
3
3
ester, JHH = 7.2 Hz), 1.30 t (6H, CH -phosphonate, J
=
3
HH
7
.2 Hz), 1.32 t (3H, CH -furoate, J = 7.2 Hz), 2.58 s
3
HH
(
CH -furan), 3.60 d.d (CH –CH=, J = 7.2 Hz, JРH
=
3 2 HH
3
.6 Hz), 4.04–4.16 m (CH ОР), 4.15 q (3H, CH ОC-
2 2
aliphatic, JHH = 7.2 Hz), 4.27 q (3H, CH ОC-furoate, J
=
=
2
HH
3
7
.2 Hz), 6.87 s (1H, H -furan), 6.92 d.q (1H, HC=, J
HH
7
.2 Hz, JРH = 23.2 Hz). 13C NMR spectrum (CDCl3),
δ , ppm: 13.92 (CH -furan), 14.17 (CH -aliphatic ester),
C
3
3
3
1
5
4.33 (CH -furoate), 16.24 d (CH -phosphonate, J
.3 Hz), 35.81 d (CH –CH=, J = 18.8 Hz), 60.28
=
3
3
РC
3
1
light yellow syrup. H NMR spectrum (CDCl ), δ, ppm:
2
РC
3
(
CH О-furan), 61.08 (CH О-aliphatic), 62.47 d (CH ОР,
1.23–1.36 m (12H, CH -ester, CH -phosphonate), 2.50 d
2
2
2
3
3
2
3
3
J
= 5.2 Hz), 112.75 d (C -furan, J = 1.8 Hz), 115.11
(1.5H, CH -furan, J = 1.6 Hz), 2.51 d (1.5H, CH -furan,
РC
4
РC
3 РH 3
1
(
C -furan), 122.16 d (Р–C=, J = 182.3 Hz), 137.95 d
JРH = 2.0 Hz), 3.08 s (1H, S–CH –C=O), 3.21 d (1H,
РC
2
2
2
2
(HC=, J = 7.8 Hz), 146.61 d (C -furan, J = 22.0 Hz),
CH Р, J = 20.4 Hz), 3.28 s (1H, S–CH –C=O), 3.29 d
РC
РC
2
РH
2
4
1
59.27 (C -furan), 163.35 (furan–C=О), 170.23 (C=О,
(1H, CH Р, J = 20.4 Hz), 3.63 d (1H, furan–CH S,
2 РH A
31
aliphatic). Р NMR spectrum (CDCl ), δ , ppm: 15.61.
JAB = 6.4 Hz), 3.66 d (1H, furan–CH S, J = 6.4 Hz),
3
Р
В
AB
13
4
.03–4.32 m (8H, CH ОC, CH ОР). C NMR spectrum
Ethyl 2-methyl-4-chloromethyl-5-(diethoxy-
2
2
(
1
5
CDCl ), δ , ppm: 14.08 (CH -furan), 14.09 (CH -furan),
phosphorylmethyl)-3-furoate (22). To the solution of
3 C 3 3
3
4.20 br.s (CH -ester), 16.31 d (CH -phosphonate, J
=
2
.92 g (9.6 mmol) of phosphonate 19 in 50 mL of di-
chloroethane 0.60 g (20 mmol) of paraformaldehyde and
.40 g (3 mmol) of finely pulverized anhydrous zinc
3
3
РC
3
.9 Hz), 16.34 d (CH -phosphonate, J = 5.9 Hz),
3
РC
1
1
0
24.64 d (CH2Р, JРC = 142.4 Hz), 25.09 d (CH2Р, JРC =
142.4 Hz), 25.35 (S–CH2–C=O), 31.85 (furan–CH2S),
32.28 (furan–CH2S), 60.12 (CH2О-ester), 60.29 (CH2О-
ester), 61.29 (CH2О-ester), 61.44 (CH2О-ester), 62.33 d
(CH2ОР, JРC = 6.6 Hz), 62.53 d (CH2ОР, JРC = 6.6 Hz),
113.10 d (C -furan, JРC = 2.4 Hz), 118.60 d (C -furan,
3
chloride was added with stirring. The reaction mixture
was saturated with hydrogen chloride, heated with stir-
ring to 60–65°C and kept at this temperature for 3 h
passing a small flow of hydrogen chloride through the
mixture to maintain saturation conditions. After that, the
mixture formed was washed with water (2×20 mL) and
dried over sodium sulfate. Dichloroethane was distilled
off, the residue was kept in vacuum (1 mmHg) for 1 h
2
2
3
4
4
5
2
JРC = 9.4 Hz), 142.33 d (C -furan, JРC = 13.0 Hz),
2
4
159.34 d (C -furan, J = 2.5 Hz), 163.85 (furan–C=О),
170.87 (C=О-aliphatic). Р NMR spectrum (CDCl ), δ ,
РC
31
3
Р
at room temperature. Yield 3.09 g (91%), light brown
ppm: 21.72, 22.69, intensity ratio 1 : 1.
1
syrup. H NMR spectrum (CDCl ), δ, ppm: 1.27 t (6H,
3
Ethyl 2-methyl-4-iodomethyl-5-(diethoxy-
phosphorylmethyl)-3-furoate (25). To the solution of
3.3 g (17.7 mmol) of sodium iodide dihydrate in 40 mLof
acetone 3.02 g (8.6 mmol) of chloride 22 was added. The
resulting mixture was left for 12 h at room temperature
in the dark. After that, it was poured in the solution of
4 g of sodium sulfite in 80 mLof water, the precipitated oil
was extracted with chloroform (3×20 mL), washed with
water, then with brine, and dried over sodium sulfate at
room temperature in the dark. Chloroform was distilled
off, the residue was kept in a vacuum (1 mmHg) for
1 h at room temperature. Yield 3.25 g (85%), light yel-
CH -phosphonate, J = 7.0 Hz), 1.33 t (3H, CH -ester,
3
HH
3
JHH = 7.0 Hz), 2.50 s (3H, CH -furan), 3.21 d (2H, CH Р,
3
2
JРH = 20.4 Hz), 4.06 d.q (4H, CH ОР, J = 7.0 Hz,
2
HH
JРH = 13.6 Hz), 4.22 d (2H, CH ОC, J = 7.0 Hz), 4.69
2
HH
s (2H, CH Cl). 13C NMR spectrum (CDCl ), δ , ppm:
2
3
C
1
4.08 (CH -furan), 14.17 (CH -ester), 16.32 d (CH -
3 3 3
3
1
phosphonate, J = 5.7 Hz), 25.11 d (CH Р, J =
РC
2
РC
1
43.0 Hz), 35.88 (CH Cl), 60.26 (CH О-ester), 62.60 d
2 2
2
3
4
(CH ОР, J = 6.5 Hz), 112.75 d (C -furan, J = 2.4 Hz),
2
РC
4
РC
3
5
1
19.31 d (C -furan, J = 8.8 Hz), 143.32 d (C -furan,
РC
2
2
31
JРC = 12.5 Hz), 159.35 (C -furan), 163.46 (C=О). Р
NMR spectrum (CDCl ), δ , ppm: 21.95.
1
3
Р
low oil. H NMR spectrum (CDCl ), δ, ppm: 1.30 t (6H,
3
Ethyl 2-methyl-4-[(2-ethoxy-2-oxoethylthio)-
methyl]-5-(diethoxyphosphorylmethyl)-3-furoate (23).
CH -phosphonate, J = 7.2 Hz), 1.40 t (3H, CH -ester,
3
HH
3
JHH = 7.2 Hz), 2.52 s (3H, CH -furan), 3.16 d (2H, CH Р,
3
2
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 2 2020

SYNTHESIS OF (2-ETHOXY-2-OXOETHYLTHIO)METHYL DERIVATIVES
179
5
JРH = 20.8 Hz), 4.10 d.q (4H, CH ОР, J = 7.2 Hz, JРH
=
2.0Hz), 3.39d.d(2H, C H Р, J 5 =21.2Hz, J 5 =1.6Hz),
2
HH
2
Р H
Р H
1
4.8 Hz), 4.35 q (2H, CH ОC, J = 7.2 Hz), 4.55 s
3.93–4.07 m (8H, CH ОР), 4.28 q (2H, CH ОC, J
=
2
HH
2
2
HH
13
13
(2H, CH I). C NMR spectrum (CDCl ), δ , ppm: –5.03
7.2 Hz), 4.69 s (2H, CH Br). C NMR spectrum (CDCl ),
2
3
C
2
3
(
CH I), 14.12 (CH -furan), 14.30 (CH -ester), 16.39 d
δ , ppm: 14.10 (CH -ester), 16.30 d (CH -phosphonate,
C 3 3
2
3
3
3
1
3
3
(CH -phosphonate, J = 5.9 Hz), 25.59 d (CH Р, J
=
=
J = 6.0 Hz), 16.35 d (CH -phosphonate, J = 6.1 Hz),
РC 3 РC
3
РC
2
РC
2
1
1
6
(
43.4 Hz), 60.34 (CH О-ester), 62.54 d (CH ОР, J
21.16 br.d (CH Р, J 5 = 138.8 Hz), 25.08 (CH Br),
2 Р C 2
2
3
2
РC
4
1
4
.6 Hz), 112.45 d (C -furan, J = 2.9 Hz), 120.83 d
25.22 d.d (CH Р, J 5 = 141.5 Hz, J 5 = 1.7 Hz), 60.73
2 Р C Р C
РC
4
3
5
2
2
C -furan, J = 9.0 Hz), 142.19 d (C -furan, J
=
(CH О-ester), 62.07 d (CH ОР, J = 6.8 Hz), 62.54 d
2 2 РC
(CH ОР, J = 6.7 Hz), 113.97 d.d (C -furan, J 5 =
2 РC Р C
10.6 Hz, J 5 = 8.6 Hz), 116.17 d.d (C -furan, J 5 =
Р C Р C
РC
РC
2
4
2
4
2
1
2.8 Hz), 159.44 d (C -furan, J = 2.4 Hz), 163.57
РC
31
3
3
3
(C=О). Р NMR spectrum (CDCl ), δ , ppm: 20.80.
3
Р
4
5
2
3
1
1
2
.2 Hz, J 5 = 3.2 Hz), 142.30 d.d (C -furan, J 5 =
Ethyl 2-methyl-4,5-bis(diethoxyphosphoryl-
Р C Р C
3
2
4
2.1Hz, J 5 =9.0Hz),154.67d(C -furan, J 5 =3.5Hz),
methyl)-3-furoate (26). The mixture of 3.25 g (7.3 mmol)
of iodide 25 and 2 mL (11.5 mmol) of triethyl phosphite
was heated under stirring. At 120°C liberation of ethyl
iodide began. It completed in 15 min in the temperature
range up to 150°C. The reaction mixture was heated for
extra 5 min to 150°C, and then diethyl ethyl phosphonate
was distilled off at 55–60°C (1 mmHg). The residue was
bis(phosphonate) 26, yield 2.59 g (78%), brown syrup. H
NMR spectrum (CDCl ), δ, ppm: 1.16–1.30 m (15H, CH -
phosphonate, CH -ester), 2.45 s (3H, CH -furan), 3.28
d.d (2H, C H Р, J 5 = 20.2 Hz, J 5 = 2.2 Hz), 3.35 d.d
Р C
Р C
3
1
62.69 (C=О). Р NMR spectrum (CDCl ), δ , ppm:
3
Р
5
5
4 5
2.36 d (Р , J = 18.2 Hz), 26.37 d (Р , J = 18.2 Hz).
РР
РР
Ethyl [(2-ethoxy-2-oxoethylthio)methyl]-4,5-
bis(diethoxyphosphorylmethyl)-3-furoate (24). To
the solution of 3.73 g (7.0 mmol) of bromide 27 in
50 mL of acetone 0.8 mL (7.3 mmol) of ethyl thioglyco-
late and then the saturated solution of 0.4 g (7.1 mmol) of
potassium hydroxide in ethanol was added with vigorous
stirring. The mixture formed was stirred for 5 h at room
temperature and left overnight. On the next day the pre-
cipitate was filtered off, and the filtrate was evaporated to
dryness. The residue was dissolved in 40 mL of chloro-
form, washed with 15 mLof water and dried over sodium
sulfate.After that, chloroforms was distilled off, the resi-
due was kept in vacuum (1 mmHg) for 1 h at room tem-
1
3
3
3
3
4
2
Р H
Р H
5
(
2H, C H Р, J 5 = 21.2 Hz, J 5 = 2.2 Hz), 3.92–4.04 m
2 Р H Р H
13
(8H,CH ОР),4.21q(2H,CH ОC,J =7.2Hz). CNMR
2 2 HH
spectrum (CDCl ), δ , ppm: 14.20 (CH -furan), 14.31
3
C
3
3
(CH -ester), 16.29 d (CH -phosphonate, J = 6.0 Hz),
3
3
РC
1
4
2
1.23 d.d (CH Р, J 5 = 143.4 Hz, J 5 = 1.4 Hz), 24.92
2 Р C Р C
1
4
d.d (CH Р, J 5 = 141.8 Hz, J 5 = 1.8 Hz), 59.95
1
2
Р C
Р C
perature. Yield 3.45 g (86%), yellowish brown syrup. H
2
(CH О-ester), 61.80 d (CH ОР, J = 6.7 Hz), 62.17 d
2 2 РC
NMR spectrum (CDCl ), δ, ppm: 1.17–1.32 m (18H, CH -
3
3
2
4
2
(
1
3
CH ОР, J = 6.6 Hz), 112.71 d.d (C -furan, J 5 =
2 РC Р C
phosphonate, CH -ester), 3.23 s (2H, SCH –CО), 3.38 d.d
3 2
3
3
3
0.6 Hz, J 5 = 9.1 Hz), 113.66 d.d (C -furan, J 5 =
4
Р C
Р C
(2H, C H Р, J 5 = 20.4 Hz, J 5 = 2.0 Hz), 3.42 d.d
2 Р H Р H
(2H, C H Р, J 5 = 21.2 Hz, J 5 = 1.2 Hz), 3.92–4.07 m
2 Р H Р H
4
5
2
.0 Hz, J 5 = 3.0 Hz), 142.19 d.d (C -furan, J 5 = 12.3
5
Р C
Р C
3
2
4
Hz, J 5 = 9.5 Hz), 159.44 d (C -furan, J = 2.7 Hz,
1
2
Р C
РC
(8H, CH ОР), 4.08 s (2H, furan–CH S), 4.12 q (2H,
2 2
CH ОC, J = 7.0 Hz), 4.24 q (2H, CH ОC, J = 7.2 Hz).
2 HH 2 HH
3
1
63.99 (C=О). Р NMR spectrum (CDCl ), δ , ppm:
3 Р
5
5
4 5
5.30 d (Р , J = 19.5 Hz), 27.01 d (Р , J = 19.5 Hz).
13
РР
РР
C NMR spectrum (CDCl ), δ , ppm: 14.09 (CH -ester),
3 C 3
3
Ethyl 2-bromomethyl-4,5-bis(diethoxyphos-
phorylmethyl)-3-furoate (27). To the solution of 2.52 g
5.6 mmol) of compound 26 in 50 mLof carbon tetrachlo-
14.12 (CH -ester), 16.30 d (CH -phosphonate, J
4.4Hz),16.35d(CH -phosphonate, J =5.3Hz),21.27d.d
=
3
3
3
РC
3
РC
1
4
(
(CH Р, J 5 = 138.8 Hz, J 5 = 1.6 Hz), 25.12 br.d (CH Р,
2 Р C Р C 2
1
ride 1.1 g (6.2 mmol) of N-bromosuccinimide and 0.3 g
of azobis(isobutyronitrile) was added with stirring. The
reaction mixture was refluxed with stirring for 5 h until
the disappearance of N-bromosuccinimide precipitate and
left overnight. On the next day, succinimide was filtered
off, solvent was removed, and the residue was kept in a
J 5 = 141.7 Hz), 27.83 (CH ОC), 33.49 (furan–CH S),
Р C 2 2
60.43 (CH О-ester), 61.33 (CH О-ester), 61.93 d (CH ОР,
2
2
2
2JРC = 5.0 Hz), 62.36 d (CH ОР, J = 6.9 Hz), 62.44 d
2
2
РC
2
4
2
(CH ОР, J = 6.9 Hz), 113.14 d.d (C -furan, J 5 =
2
РC
Р C
3
3
3
10.0 Hz, J 5 = 8.9 Hz), 115.00 d.d (C -furan, J 5 =
Р C
Р C
4
5
2
2.7 Hz, J 5 = 2.7 Hz), 144.05 d.d (C -furan, J 5 =
Р C
Р C
3
2
4
vacuum (1 mmHg) for 1 h at room temperature. Yield
2
9.6 Hz, J 5 = 9.6 Hz), 154.67 d (C -furan, J 5 =
Р C
Р C
31
1
.40 g (81%), yellowish brown glass. H NMR spectrum
3.0 Hz), 163.24 (C=О-furan), 169.86 (C=О-sulfide). Р
NMR spectrum (CDCl ), δ , ppm: 22.82 d (Р , J
18.5 Hz), 26.60 d (Р4, 5JРР = 18.5 Hz).
5
5
(CDCl ), δ, ppm: 1.17–1.30 m (15H, CH -phosphonate,
=
3
3
3
Р
РР
4
CH -ester), 3.34 d.d (2H, C H Р, J 5 = 20.4 Hz, J 5 =
3
2
Р H
Р H
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 2 2020

180
PEVZNER, STEPANOVA
4
31
Ethyl 2-bromomethyl-4-chloromethyl-5-(diethoxy-
phosphorylmethyl)-3-furoate (29). To the solution of
.46 g (4.1 mmol) of chloride 22 in 30 mL of carbon
2.3 Hz), 162.87 d (C=О, J 2 = 2.8 Hz). Р NMR spec-
Р C
2
6
trum (CDCl ), δ , ppm.: 21.12 d (Р , J = 7.8 Hz), 21.31 d
3
Р
РР
5
6
1
(Р , J = 7.8 Hz).
РР
tetrachloride 0.82 g (4.6 mmol) of N-bromosuccinimide
and 0.2 g azobis(isobutyronitrile) was added with stir-
ring. The reaction mixture was refluxed with stirring for
Ethyl 2,5-bis(diethoxyphosphorylmethyl)-4-[(2-
ethoxy-2-oxoethylthio)methyl]-3-furoate (28). To the
solution of 2.05 g (4.2 mmol) of bis(phosphonate) 30
and 0.6 mL (5.5 mmol) of ethyl thioglycolate in 25 mL
of acetone the saturated solution of 0.3 g (5.4 mmol) of
potassium hydroxide in ethanol was added with stirring in
one portion. The resulting mixture was stirred for 4 h and
left overnight. On the next day the precipitate was filtered
off, the filtrate was evaporated, the residue was dissolved
in 30 mL of chloroform, washed with 10 mL of water,
10 mLof brine and dried over sodium sulfate. Solvent was
removed, and the residue was kept in vacuum (1 mmHg)
for 1 h at room temperature. Yield 2.06 g (92%), light
4
h until the disappearance of N-bromosuccinimide and
left overnight. On the next day succinimide precipitate
was filtered off, carbon tetrachloride was distilled, and
the residue was kept in a vacuum (1 mmHg) for 1 h at
room temperature. Yield 1.48 g (83%), yellowish brown
1
syrup. H NMR spectrum (CDCl ), δ, ppm: 1.32 t (6H,
3
CH -phosphonate, J = 7.0 Hz), 1.41 t (3H, CH -ester,
3
HH
3
JHH = 7.0 Hz), 3.32 d (2H, CH Р, J = 21.2 Hz), 4.12 d.q
2
РH
(
4H, CH ОР, J = 7.0 Hz, JРH = 14.0 Hz), 4.37 q (1H,
2 HH
CH ОC, J = 7.0 Hz), 4.38 q (1H, CH ОC, JHH = 7.0 Hz),
2
HH
2
4
.73 s (2H, CH Cl), 4.76 s (1H, CH Br), 4.77 s
1
2
2
brown viscous oil. H NMR spectrum (CDCl ), δ, ppm:
3
13
(1H, CH Br). C NMR spectrum (CDCl ), δ , ppm: 14.13
2 3 C
1.24–1.35 m (18H, CH -phosphonate, CH -ester), 3.34 d
3
3
3
(CH -ester), 16.43 d (CH -phosphonate, J = 5.8 Hz),
5
3
3
РC
(2H, CH Р , J = 20.8 Hz), 3.37 s (2H, S–CH –C=O),
2 РH 2
1
2
5.17 (CH Br), 25.51 d (CH Р, J = 142.6 Hz), 35.26
2
2
2
РC
3.66 d (2H, CH Р , J = 22.4 Hz), 3.90 s (2H, S–CH2-
2 РH
2
(CH Cl), 61.09 (CH О-ester), 62.98 d (CH ОР, J
=
4
2
2
2
РC
furan), 4.00–4.21 m (8H, CH ОР), 4.23–4.32 m (4H,
2
3
4
6.5 Hz), 115.23 d (C -furan, J = 2.4 Hz), 120.27 d (C -
13
РC
CH ОC). C NMR spectrum (CDCl ), δ , ppm: 14.13
2 3 C
3
5
2
furan, J = 8.7 Hz), 146.10 d (C -furan, J = 13.5 Hz),
3
РC
РC
(CH -ester), 16.36 d (CH -phosphonate, J = 6.2 Hz),
3 3 РC
2
4
1
55.46 d (C -furan, J = 2.9 Hz), 162.28 (C=О). 31
Р
3
РC
16.40 d (CH -phosphonate, J = 6.9 Hz), 24.83 d (CH Р,
3 РC 2
NMR spectrum (CDCl ), δ , ppm: 21.29.
1J = 142.5 Hz), 25.29 (S–CH –C=O), 26.82 d (CH Р,
3
Р
РC 2 2
1
Ethyl 2,5-bis(diethoxyphosphoryl)methyl)-4-chlo-
romethyl-3-furoate (30). The mixture of 2.09 g
JРC = 138.5 Hz), 32.30 (S–CH2-furan), 61.33 (CH2О-
ester), 61.67 (CH2О-ester), 62.31 d (CH2ОР, JРC =
.4 Hz), 62.37 d (CH ОР, J = 6.1 Hz), 62.39 d (CH ОР,
J = 6.5 Hz), 115.11 d.d (C -furan, J 2 = 8.2 Hz, J 5 =
2
2
6
2
(4.8 mmol) of halide 29 and 2 mL (11.5 mmol) of tri-
2
РC
3
2
3
4
ethyl phosphite was heated with stirring. Evolution of
ethyl bromide proceeded in the range of 125–135°C and
completed within 10 min. After that volatile substances
boiling up to 60°C (1 mmHg) were distilled from the
reaction mixture. The residue was the target product 30,
РC
Р C
Р C
4
3
4
2
1
1
1
.7Hz),118.95d.d(C -furan, J 5 =9.3Hz, J 5 =2.6Hz),
Р C Р C
5
2
4
44.08 d.d (C -furan, J 5 = 12.5 Hz, J 2 = 2.4 Hz),
52.58 d.d (C -furan, J 2 = 13.2 Hz, J 5 = 2.3 Hz),
63.33 br.s (C=О-furan), 170.79 (C=О-sulfide). Р NMR
Р C
Р C
2
2
4
Р C
Р C
31
2
6
1
spectrum (CDCl ), δ , ppm: 21.35 d (Р , J = 8.3 Hz),
yield 2.18 g (92%), light brown syrup. H NMR spectrum
CDCl ), δ, ppm: 1.21–1.34 m (15H, CH -phosphonate,
3 Р РР
5
6
2
2.27 d (Р , J = 8.3 Hz).
РР
(
3
3
5
CH -ester), 3.24 d (2H, CH Р , J = 20.0 Hz), 3.65 d
Ethyl 2-(diethoxyphosphorylmethyl)-4-hyd-
3
2
РH
2
(2H, CH Р , J = 21.6 Hz), 3.96–3.26 m (8H, CH ОР),
roxy-7H-thiopyrano[3,4-b]furan-5-carboxylate (31).
To the solution of 4.94 g (12 mmol) of sulfide 3 in 40 mL
of anhydrous benzene 1.5 g (13 mmol) of potassium tert-
butylate was added with stirring. Temperature of the reac-
tion mixture rose to 36°C, the formation of friable light
yellow precipitate was observed. Stirring was continued
for 6 h, and then the reaction mixture was left overnight.
On the next day it was extracted with water (2×15 mL),
the extract was washed with 8 mL of ethyl acetate and
acidified to pH = 3–4 with formic acid. The oil formed
was extracted with chloroform (3×15 mL), washed with
water, then with brine and dried over sodium sulfate. The
2
РH
2
4
.31 q (2H, CH ОC, J = 7.2 Hz), 4.70 s (2H, CH Cl).
2 HH 2
13
C NMR spectrum (CDCl ), δ , ppm: 14.10 (CH -ester),
3
C
3
3
1
6.30 d (CH -phosphonate, J = 5.4 Hz), 16.35 d
3
РC
3
1
(CH -phosphonate, J = 5.0 Hz), 26.70 d (CH Р, J
=
3
РC
2
РC
1
1
39.5 Hz), 26.90 d (CH Р, J = 138.6 Hz), 35.62
2 РC
(
(
6
2
2
2
CH Cl), 60.13 (CH О-ester), 60.64 (CH О-ester), 62.41 d
2 2 2
2
2
CH ОР, J = 5.9 Hz), 62.60 d (CH ОР, J
=
РC
2
РC
2
3
3
4
.6 Hz), 114.70 d.d (C -furan, J 2 = 8.0 Hz, J 5 =
Р C Р C
4
3
4
.4 Hz), 119.56 d.d (C -furan, J 5 = 8.4 Hz, J 5 =
Р C
Р C
5
2
4
.4 Hz), 144.97 d.d (C -furan, J 5 = 11.8 Hz, J 2 =
Р C
Р C
2
2
4
.2 Hz), 152.69 d.d (C -furan, J 2 = 13.2 Hz, J 5 =
Р C
Р C
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 2 2020

SYNTHESIS OF (2-ETHOXY-2-OXOETHYLTHIO)METHYL DERIVATIVES
181
4JРC = 2.9 Hz), 163.17 (=C -О), 169.95 (C=О-ester). Р
4
31
solvent was distilled off, the residue was kept in a vacuum
(
(
1 mmHg) for 1 h at room temperature. Yield 1.21 g
NMR spectrum (CDCl ), δ , ppm: 22.19.
3
Р
1
28%), light brown oil. H NMR spectrum (CDCl ), δ,
3
FUNDING
ppm.: 1.23–1.34 m (9H, CH -phosphonate, CH -ester),
3
3
3
.12 d (2H, CH Р, J = 21.2 Hz), 3.33 s (2H, S–CH2),
2 РH
The work was carried out within the frames of the basic
part of the state project of the Ministry of Education and Sci-
ence of Russia no. 4.5554.2017/8.9 using the equipment of the
engineering center of the St. Petersburg State Technological
Institute (Technical University).
4.11 d.q (4H, CH ОР, J = 7.0 Hz, JРH = 14.0 Hz), 4.27 q
2
HH
13
(2H, CH ОC, J = 7.2 Hz), 9.46 br.s (1H, ОH). C NMR
2 HH
spectrum (CDCl ), δ , ppm: 14.17 (CH -ester), 14.23
3
C
3
3
(CH -ester), 16.33 d (CH -phosphonate, J = 5.9 Hz),
3 3 РC
1
2
6.47 d (CH Р, J = 143.0 Hz), 34.41 (S–CH ), 34.46
2 РC 2
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
REFERENCES
(S–CH ), 60.42 (CH О-ester), 60.58 (CH О-ester), 63.22
2 2 2
2
3
3
d (CH ОР, J = 7.0 Hz), 109.74 d (C -furan, J =
2
РC
РC
β
5
8
.4 Hz), 115.71 (C -nodal furan), 136.50 [S–C (C=О)],
2
2
α
1
53.87 d (C -furan, J = 12.3 Hz), 157.86 (C -nodal
РC
α
4
furan), 157.97 (C -nodal furan), 171.26 (=C -ОH), 172.39
1
. Kawai, K., Chin, J., andJust, G., Nucleosides, Nucleotides,
990, vol. 9, p. 1045.
(
C=О-ester), 172.40 (C=О-ester). 31Р NMR spectrum
(CDCl ), δ , ppm: 23.13.
1
3
Р
https://doi.org/10.1080/07328319008046061
2
. Subba Reddy, B.V., Venkateswarlu, A., Borkar, P.,
Yadav, J.S., Sridhar, B., and Gree, R., J. Org. Chem.,
Ethyl 2-(diethoxyphosphorylmethyl)-4-me-
thoxy-7H-thiopyrano[3,4-b]furan-5-carboxylate (32).
To the solution of 2.36 g (5.8 mmol) of sulfide 3 in 40 mL
of absolute diethyl ether 0.8 g (7 mmol) of potassium tert-
butylate was added with stirring. The resulting mixture
was refluxed with stirring for 3 h, then 0.5 mL (8 mmol)
of methyl iodide was added, and refluxing was contin-
ued for extra 4 h. Then the reaction mixture was washed
with 10 mL of water and dried over sodium sulfate.
Solvent was distilled off, the residue was kept in vacuum
2
014, vol. 79, p. 2716.
https://doi.org/10.1021/jo402832t
. Schickmous, B. and Christoffers, J., Eur. J. Org. Chem.,
3
4
2
014, no. 20, p. 4410.
https://doi.org/10.1002/ejoc201402388
. Kudo, N., Yoneda, A., Sato, K., Honma, T., and Sugai, T.,
Chem. Pharm. Bull., 2000, vol. 28, no. 4, p. 509.
https://doi.org/10.1248/cpb.48.509
5. Williams, D.R., Klingler, F.D., Allen, E.E., and Lichten-
thaler, F.D., Tetrahedron Lett., 1988, vol. 29, p. 5087.
https://doi.org/10.1016/s0040-4039(00)80686-3
(
(
1 mmHg) for 1 h at room temperature. Yield 1.82 g
1
84%), light yellow oil. H NMR spectrum (CDCl ), δ,
3
6
7
8
. Pevzner, L.M., Russ. J. Gen. Chem., 2012, vol. 82, no. 12,
ppm: 1.21–1.36 m (9H, CH -phosphonate, CH -ester),
3
3
p. 1938.
3
4
(
.20 d (2H, CH Р, J = 20.8 Hz), 3.31 s (2H, S–CH2),
2 РH
https://doi.org/10.1134/S1070363212120067
. Pevzner, L.M., Russ. J. Gen. Chem., 2017, vol. 87, no. 7,
p. 1516.
.11 d.q (4H, CH ОР, J = 7.2 Hz, JРH = 14.8 Hz), 4.16 s
2
HH
13
3H, CH О), 4.27 q (2H, CH ОC, J = 7.2 Hz). C NMR
3 2 HH
spectrum (CDCl ), δ , ppm: 14.10 (CH -ester), 14.24
3
C
3
3
https://doi.org/10.1134/S107036321707012Х
. Pevzner, L.M., Russ. J. Gen. Chem., 2011, vol. 81, no. 1,
p. 56.
(
2
(
6
CH -ester), 16.37 d (CH -phosphonate, J = 5.9 Hz),
3 3 РC
1
6.54 d (CH Р, J = 143.0 Hz), 34.18 (S–CH ), 60.47
2 РC 2
CH О-ester), 61.42 (CH -О), 62.52 d (CH ОР, J
.6 Hz), 109.23 d (C -furan, J = 7.4 Hz), 116.06 d (C -
nodal furan, J = 3.1 Hz), 136.65 [S–C (C=О)], 145.43 d
2
=
β
2
3
2
РC
https://doi.org/10.1134/S1070363211010099
3
3
РC
9. Pevzner, L.M., Russ. J. Gen. Chem., 2012, vol. 82, no. 12,
p. 1938.
4
5
РC
2
2
α
(
C -furan, J = 9.3 Hz), 156.90 d (C -nodal furan,
https://doi.org/10.1134/S107036321212006
РC
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 2 2020