Synthesis and selected reactions of 4-(Diethoxyphosphorylmethyl)-3-furoic acid

Article abstract of DOI:10.1134/S1070363212030073

Reduction of 4-(ethoxycarbonyl)-3-furoyl chloride with sodium borohydride in dioxane-DMF mixture leads to an ethyl 4-hydroxymethylfuran-3-carboxylate. The treatment of the latter with thionyl chloride at boiling yields the corresponding chloromethyl derivative. The obtained chloride reacts with one equivalent of sodium iodide in acetone at room temperature to form iodomethylfuran. Halomethylfurans synthesized are phosphorylated with sodium diethyl phosphite and triethyl phosphite to give ethyl 4- (diethoxyphosphorylmethyl)- 3-carboxylate. The hydrolysis of this substance with one equivalent of potassium hydroxide in ethanol gives the corresponding furoic acid. Treating this substance in succession with ethyl chloroformate and sodium azide yields furoyl azide which while heating in toluene undergoes rearrangement to phosphorus-containing 3- furylisocyanate. Heating the latter with a mixture of acetic acid and acetic anhydride gives N-[4- (diethoxyphosphorylmethyl) furyl-3]acetamide. 4-(Diethoxyphosphorylmethyl)-3- furoic acid reacts with thionyl chloride to form the corresponding furoyl chloride. Its reduction with sodium borohydride in dioxane-DMF mixture leads to the phosphorylated 3-furylmethanol. Aminomethylation of its acetate with dimethylmethyleneiminium chloride in acetonitrile does not proceed at the ring. Instead of that the unstable ester of 3-(dimethylamino) propionic acid and the phosphorylated 3-furylmethanol are formed. In slightly basic medium free Mannich base decomposed to give the starting acetate. Pleiades Publishing, Ltd., 2012.

Full text of DOI:10.1134/S1070363212030073

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ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 3, pp. 404–412. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © L. M. Pevzner, 2012, published in Zhurnal Obshchei Khimii, 2012, Vol. 82, No. 3, pp. 411–419.
Synthesis and Selected Reactions
of 4-(Diethoxyphosphorylmethyl)-3-furoic Acid
L. M. Pevzner
All-Russian Scientific and Research Institute of Hydrolysis of Plant Materials,
pr. Kalinina 13, St. Petersburg, 198099 Russia
Received September 26, 2011
Abstract—Reduction of 4-(ethoxycarbonyl)-3-furoyl chloride with sodium borohydride in dioxane–DMF
mixture leads to an ethyl 4-hydroxymethylfuran-3-carboxylate. The treatment of the latter with thionyl chloride
at boiling yields the corresponding chloromethyl derivative. The obtained chloride reacts with one equivalent of
sodium iodide in acetone at room temperature to form iodomethylfuran. Halomethylfurans synthesized are
phosphorylated with sodium diethyl phosphite and triethyl phosphite to give ethyl 4-(diethoxyphosphoryl-
methyl)-3-carboxylate. The hydrolysis of this substance with one equivalent of potassium hydroxide in ethanol
gives the corresponding furoic acid. Treating this substance in succession with ethyl chloroformate and sodium
azide yields furoyl azide which while heating in toluene undergoes rearrangement to phosphorus-containing 3-
furylisocyanate. Heating the latter with a mixture of acetic acid and acetic anhydride gives N-[4-(di-
ethoxyphosphorylmethyl)furyl-3]acetamide. 4-(Diethoxyphosphorylmethyl)-3-furoic acid reacts with thionyl
chloride to form the corresponding furoyl chloride. Its reduction with sodium borohydride in dioxane–DMF
mixture leads to the phosphorylated 3-furylmethanol. Aminomethylation of its acetate with dimethyl-
methyleneiminium chloride in acetonitrile does not proceed at the ring. Instead of that the unstable ester of 3-(di-
methylamino)propionic acid and the phosphorylated 3-furylmethanol are formed. In slightly basic medium free
Mannich base decomposed to give the starting acetate.
DOI: 10.1134/S1070363212030073
3,4-Bisfunctionalized derivatives of furan with
unoccupied positions 2 and 5 of the ring still remain
the most difficultly available compounds in the furan
series. At the same time just the compounds with such
type of substitution are structural fragments of natural
bioregulators. For example, biosynthesis of cellulose
and callose is regulated with the derivatives of 3-
furylmethanol [1]. 3-Mono- and 3,4-disubstituted furyl
fragments are present in quinolizidine alkaloids of
nufaridine series [2] and in the terpenoids of sea
organisms [3]. In connection with that the development
of strategy for the synthesis of 3-substituted furans
containing pharmacophore phosphoryl group in the
position 4 of the ring seems actual and promising.
One of the versions to solve this problem may be
the transformation of functions in the series of
compounds synthesized from the relatively available
dialkyl 3,4-furyldicarboxylates I.
By selective hydrolysis of diethyl ester Ia
according to the procedure [4] we have prepared
monoester II. Treating the latter with thionyl chloride
in benzene in the presence of DMF gave furoyl
chloride III.
HOOC
COOC2H5
ClOC
COOC2H5
C2H5OOC
COOC2H5
SOCl2
(1) KOH
(2) HCl
O
O
O
II
III
Ia
For the reduction of this substance to alcohol we
used the recently developed procedure [5]. The
reaction was carried out in dioxane–DMF mixture at
80–85°C. Sodium borohydride was used as the
reducing agent. After decomposition of the reaction
mixture with diluted acetic acid and extraction with
404

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SYNTHESIS AND SELECTED REACTIONS
405
ICH2
COOC2H5
benzene the target alcohol IV was isolated by a
vacuum distillation in 69% yield. Details of the
procedure and spectral characteristics of the product
are presented in Experimental.
NaI
V
O
VII
1
HOCH2
COOC2H5
a colorless oil which crystallizes at 6–7°C. In its H
NMR spectrum the singlet of iodomethyl group
protons is observed at 4.50 ppm, while the signal of
chloromethyl group protons in starting compound V is
located at 4.68 ppm. Signals of the other protons in the
compounds under consideration are practically
identical.
NaBH4
III
O
IV
Compound IV was boiled with thionyl chloride in
benzene in the presence of DMF to form chloride V.
The alternative procedure using thionyl chloride and
pyridine common in the furan series did not provide a
sufficient conversion of alcohol to chloride. Yield of
compound V was 78%, bp 76°C (1 mm Hg).
The phosphorylation of iodide VII was carried out
with small excess of triethyl phosphite (1.2 mol/mol).
While mixing the reagents at room temperature the
formation of crystals belonging probably to quasiphos-
phonium salt was observed. Its decomposition with the
liberation of ethyl iodide began only at heating the
reaction mixture above 110°C, and the reaction
completed at 155°C. In the course of the vacuum
distillation of reaction mixture a considerable amount
of diethyl ethylphosphonate was collected, and the
target product VI was obtained in 39% yield. The still
contained significant amount of non-melting and
insoluble polymer formed evidently in the course of
thermal decomposition of the iodide.
ClCH2
COOC2H5
SOCl2
IV
O
V
The phosphorylation of chloride V was carried out
with sodium diethyl phosphite under the conditions of
the Michaelis–Becker reaction in benzene at 80°C in
the course of 18 h. It occurred that besides nucleophilic
substitution sodium diethyl phosphite took part in
some other unestablished transformations. Due to that
at the complete consumption of the phosphorylating
agent the conversion of chloride V was 60%, and the
yield of phosphonate VI was 50% calculated on the
consumed chloromethyl derivative. The reaction mix-
ture was separated by vacuum distillation collecting
the fractions with bp 75–78°C (1 mm Hg) and 156°C
(1 mm Hg). The details of the experiment and spectral
characteristics of phosphonate VI are presented in
Experimental.
The hydrolysis of the carboxylic ester group of
phosphonate VI was carried out with 1 mol of
potassium hydroxide in ethanol according to the
procedure [6]. Yield of the acid VIII was 82%, white
crystals with mp 101-102oC. Details of the procedure
and spectral characteristics of the products are
presented in Experimental.
HOOC
CH2PO(OC2H5)2
KOH
HCl
(C2H5O)2OPCH2
COOC2H5
VI
NaPO(OC2H5)2
O
V
VIII
O
VI
Hence, phosphorus-containing 3-furoic acid VIII
occurred to be a relatively available substance which
can be exposed to further transformations. First of all
it should involve the carboxy group because it opens
a pathway to a series of 3-functionalyzed 4-di-
ethoxyphosphorylmethylfurans. As it was mentioned
above, these compounds are promising from the
point of view of the search for the biologically active
structures.
Low reactivity of chloride V in phosphorylation
compelled us to look for a more active alkylating
agent. It was found that under the conditions of
Finkelstein reaction compound V undergoes a
quantitative exchange of chlorine for iodine in the
course of one day under the action of sodium iodide
dihydrate in acetone at room temperature in the
absence of light.
First direction we studied was the conversion of
Similarly to the other iodomethylfurans compound
acid VIII to acylazide IX.
VII easily liberates iodine at elevated temperature. It is
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406
PEVZNER
The latter compound is interesting from two points
product. The detailed description of the process and
spectral characteristics of the product are given in
Experimental.
of view. First of all, the azide-based synthesis of
amides is considered the best for conserving the optical
purity while acylation of chiral amines [7]. Thus the
natural amino acids and peptides can be modified by
introduction of pharmacophoric phosphorus-containing
furyl fragment without the distortion of their structure.
Another interesting pathway is the introduction of
azide IX in Curtius rearrangement leading to the
corresponding phosphorus-containing isocyanate [6],
the starting substance for preparing 3-acylaminofurans.
After refluxing the solution of azide IX in toluene
for 3 h NMR spectra of the isolated preparation show
1
striking changes. In the H NMR spectrum the signal
of PCH2 protons undergoes upfield shift by 0.44 ppm,
and the signals of the furan ring protons, by 0.20 ppm
(H5) and 0.66 ppm (H2). The latter two signals overlap
and form one broadened signal at 7.44 ppm. Hence, the
character of spectral changes shows that electron-
donating substituent appears in the position 3 of the
furan ring. Analogous changes we observed recently
while investigating Curtius rearrangement of the other
(diethoxyphosphorylmethyl)furoyl azides [6]. In the
13C NMR spectrum of compound under consideration
the signals of carbon atoms of diethoxyphosphopyl-
methyl group are located on their usual places, the
signal of C4 atom is shifted from 115.37 ppm (2JCP
7.5 Hz) to 112.85 ppm (2JCP 7.6 Hz), the signal of C3
carbon atom practically does not shift (119.35 ppm in
azide, 119.90 ppm in the product), but the coupling
constant increases from 4.5 to 6.5 Hz. The signal of C5
carbon atom shifts from 143.64 to 139.53 ppm, and
2JCP increases from 6.8 to 11.7 Hz. The signal of C2
atom also shifts from 149.58 ppm to 141.22 ppm. The
signal of the catbonyl carbon atom of the product is
observed at 124.74 ppm characteristic of the
isocyanate group [9]. Hence, the mentioned spectral
alterations show that in the course of heating azide IX
rearranges to isocyanate X.
The synthesis of acylazide IX was carried out
according to the procedure [6] including the formation
of mixed anhydride of the furoic and carbonic acids
and treating it with sodium azide.
VIII
(2) NaN3
(1) C2H5OCOCl, N(C2H5)3
(C2H5O)2OPCH2
CON3
O
IХ
Compound IX is a light brown oil stable at room
temperature and soluble in common organic solvents.
Its iH NMR spectrum contains the signals of
diethoxyphosporylmethyl group and the furan ring
protons. Their position is almost the same as in the
ester VI and the acid VIII. A specific spectral feature
of the azide IX is the high value of the remote
coupling constant between the phosphorus nucleus and
the H5 proton of the furan ring (4JPH 4 Hz) and also the
revealing of coupling between H2 and H5 protons of
the furan ring (JHH ~ 1Hz). The chemical shift of
phosphorus in this substance is 25.392 ppm which is
characteristic of furylmethylphosphonates. Chemical
shifts of carbon atoms in 13C NMR spectrum of ester
VI, acid VIII, and azide IX do not differ significantly,
but the remote JPC constants in the azide are larger and
C
N
CH2PO(OC2H5)2
O
IХ
O
Х
The obtained isocyanate is a viscous light brown oil
soluble in chloroform and aromatic hydrocarbons. The
detailed description of compound X is given in
Experimental.
Heating isocyanate X with a mixture of acetic acid
and acetic anhydride in dioxane for 4 h leads to the
formation of acetamide XI.
are resolved better. For example, in the ester VI 2JPC
4
is
3
3
6.4 Hz, JPC
3
3.9 Hz, and JPC
5
is not observed. In the
azide IX the values of these constants are 7.5, 4.5, and
6.8 Hz respectively.
CH3CONH
(CH3CO)2O
CH2PO(OC2H5)2
1
In the H NMR spectrum of azide IX signals of
impurities at 7.17–7.24 and 7.41–7.44 ppm are present.
We failed to remove these admixtures using methods
which do not cause the destruction of the target
Х
CH3COOH
O
ХI
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SYNTHESIS AND SELECTED REACTIONS
407
1
(C2H5O)2OPCH2
COCl
In the H NMR spectrum of this product signals of
diethoxyphosphorylmethyl group protons are located
on their usual place, a singlet of acetamide methyl
group is observed at 2.17 ppm, and the furan ring
protons give signals at 7.20 ppm (H5, JPH 4 Hz) and
7.29 ppm (H2). The broad signal of the NH proton is
observed at 8.10 ppm. Details of the experiment and
spectral characteristics of the product XI are given in
Experimental.
SOCl2
VIII
O
ХII
O
C2H5O
P
O
H2C
C
O
Amide XI is rather labile. In a free state it is a
glass-like mass which does not change at room
temperature for a week, but in ethyl acetate and
ethanol solutions it decomposes with the formation of
nonstudied products.
O
The reduction of acid chloride XII with sodium
borohydride in DMF–dioxane mixture at 80°C accord-
ing to the procedure [5] leads to phosphorylated 3-
furylmethanol XIII. The admixture of carboxan-
hydride does not affect the reaction. Alcohol XIII is an
oil stable at room temperature but decomposing in the
course of vacuum distillation. Similarly to the
previously studied cases [5] the phosphorus-containing
fragment does not react with the reducing agent.
Another interesting direction of transformations of
acid VIII includes the synthesis of acid chloride and
its reduction to the corresponding 3-furylmethanol.
This pathway is important because by this procedure it
is possible to prepare the phosphorylated analog of
aglycone, the regulator of biosynthesis of cellulose in
higher plants [1].
(C2H5O)2OPCH2
CH2OH
NaBH4
ХII
The synthesis of acid chloride XII was carried out
by treating acid VIII with thionyl chloride in benzene
in the presence of DMF according to the procedure [5]
at 80°C for 4 h. The obtained substance is a light
brown oil soluble in hydrocarbons and chlorinated
hydrocarbons. In the 13C NMR spectrum the carbon
atoms of compound XII give signals at 115.247 ppm
(C4), 123.466 ppm (C3), 144.292 ppm (C5), 153.674
(C2), and 165.285 ppm (COCl). Besides, one more set
of signals with significantly weaker intensity including
four singlets at 118.368 ppm (C3), 142.826 ppm (C5),
146.930 ppm (C2), and 150.499 ppm (C=O) was
observed. Considering the shift of the carbonyl carbon
atom [8] these signals may be attributed to the
O
ХIII
(C2H5)2OPCH2
CH2OCOCH3
CH3COCl
C5H5N
O
ХIV
Compound XIII has two weak electron-acceptor
substituents in the positions 3 and 4 of the furan ring
while two highly reactive positions 2 and 5 are not
occupied. In connection with that it was interesting
from the theoretical and the practical point of view to
establish in which position will enter the substituent in
such compounds in the course of electrophilic
substitution reactions. The signal of H2 and H5 protons
are well distinguishable spectroscopically, and the first
of them is a doublet with JPH 4.4 Hz. Due to that it is
easy to establish the reaction site.
1
anhydride of acid VIII. H NMR spectrum contains
only one set of signals of the corresponding protons.
Evidently, the chemical shifts of protons in acid
chloride and in the anhydride are the same.
Acid chloride XII may be distilled in a vacuum [bp
145–146 (1 mm Hg)], but in the course of distillation a
decomposition takes place, and the preparation
obtained contains more admixtures than that isolated
directly from the reaction mixture.
As a model reaction we have chosen amino-methyla-
tion by dimethylmethyleneimmonium chloride which
we previously studied rather thoroughly on the other
phosphorus-containing derivatives of furan [9, 10]. In
its course a tertiary amine salt is formed which can be
easily separated from the non-polar starting substance
and reliably identified by the signals of the methyl and
methylene groups adjacent to the nitrogen atom.
No traces of cyclization with the formation of
oxaphosphorine heterocycle characteristic of 2,3-
disubstituted (diethoxyphosphorylmethyl)furoyl chlo-
rides [5] were found.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 3 2012