Synthesis of isomeric bromo(diethoxyphosphorylmethyl)furans

Article abstract of DOI:10.1134/S1070363209030050

Series of the previously unknown bromo(diethoxyphosphorylmethyl)furans including four of six possible regioisomers is synthesized. The target products were obtained by bromination of the corresponding (diethoxyphosphorylmethyl) furans or by a four-step sy

Full text of DOI:10.1134/S1070363209030050

ISSN 1070-3632, Russian Journal of General Chemistry, 2009, Vol. 79, No. 3, pp. 362–372. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © L.M. Pevzner, 2009, published in Zhurnal Obshchei Khimii, 2009, Vol. 79, No. 3, pp. 372–382.
Synthesis of Isomeric Bromo(diethoxyphosphorylmethyl)furans
L. M. Pevzner
Russian Scientific and Research Institute of Hydrolysis of Plant Materials,
pr. Kalinina 13, Saint-Petersburg, 198099 Russia
Received November 5, 2008
Abstract―Series of the previously unknown bromo(diethoxyphosphorylmethyl)furans including four of six
possible regioisomers is synthesized. The target products were obtained by bromination of the corresponding
(diethoxyphosphorylmethyl)furans or by a four-step synthesis including bromination of isomeric methyl-furan-
carboxylates, reduction of the products formed to the corresponding alcohols, substitution of hydroxy group
with halogen and phosphorylation by the Michaelis–Becker reaction. It was established for the first fime that
in the course of bromination of alkyl carboxylates and phosphonates of the furan series under the typical
conditions of electrophilic reaction (Br2 + 10% molar of AlCl3, chloroform) the substituent enters not only into
the heteroring, but also into the side chain. In the case of 5-methyl-2-(diethoxyphosphorylmethyl)furan only the
last reaction pathway is observed. It is shown that bromo(chloromethyl)furans react with sodium diethyl
phosphite not only according to the Michaelis–Becker scheme leading to phosphonates, but also by the
pathway of debromination of the furan ring. The last unexpected reaction may acquire a practical use for
removing a substituent protecting the α-position of the furan ring under mild conditions.
DOI: 10.1134/S1070363209030050
H3C
Subaqueous fauna and flora are the abundant
sources of biologically active compounds with the
R
H3C
H3C
structure resembling that of the substances found on
the dry land, but distinguished by the presence of the
furan rings instead of the carbocyclic or heterocyclic
fragments present in the overland analogs. For example,
furanosesquiterpenoids of sponges have the unsatur-
ated side chain analogous to that of tocotrienes found
in the wheat bran, rice, and the Hevea latex, but
instead of the chroman ring these marine products
contain 3-furyl radical [1, 2].
D
C
CH2
O
Y
X
A
B
CH3
X
This trend probably reflects the general tendency in
the structure of the bioregulators of marine organisms.
Formation of furoterpene structures was developed
in the course of total synthesis of pallescensines A and
E [5, 6]. Its key stage is the condensation of (diethoxyphos-
phorylmethyl)furan or the phosphonium salt of similar
structure with the derivatives of formylcyclohexane
under the conditions of the Wittig–Horner reaction.
H3C
CH2
CH
C
R
n
O
CH3
CH3
HO
H
3C
CH3
O
CH2
H3C
O
CH2
C
O
CH
n
H3C
The carbon skeleton of a series of polycyclic
triterpenoids isolated from sponges [3, 4] resembles
the steroid one, but the place of cyclopentane fragment
D is occupied by the furan ring.
H3C
CH3
CH3
CH3
Pallescensine А
Pallescensine Е
362

363
SYNTHESIS OF ISOMERIC BROMO(DIETHOXYPHOSPHORYLMETHYL)FURANS
From the point of view of the search for new
biologically active compounds introduction of
substituents in the furan ring of such substances
presents a great interest. One of the very attractive
substituents is bromine because it is found that the
bromine-containing terpenoids of marine organisms
exhibit an expressed antitumor activity [1].
dioxane dibromide [6]. 2-Furoic acid was brominated
with bromine in the presence of red phosphorus [7],
and its esters, with bromine without a catalyst [5]. The
monobromination of furfural in the position 5 was
carried out with bromine in the presence of sulfur and
hydroquinone in boiling dichloroethane [8]. A selec-
tive 4,5-dibromination of furfural, alkyl 2-furoates, and
acetylfuran was attained in the reaction with bromine
in AlCl3 medium [9,10]. Studies of bromination of
furans were in general completed to the end of
nineteen seventies and afterwards this problem was not
specially tackled.
At the same time the simplest (dialkoxyphospho-
rylmethyl)furans containing the bromine atom in the
ring are not studied at all and no synthetic approaches
to them are developed.
The aim of this work is the investigation of
pathways to the synthesis of such structures.
The data mentioned show that the range of
brominating systems is not wide. While deciding upon
the conditions of bromination of (dialkoxyphospho-
rylmethyl)furans it should be considered that the
substituent present is a weak acceptor and somewhat
deactivated the furan ring for the electrophilic
substitution reactions. Besides, under the action of
hydrogen bromide dealkylation can proceed leading to
the formation of alkyl bromide and the hydroxy group
on phosphorus. That is why it seems the most reason-
able to carry out the bromination with the elementary
bromine in chloroform in the presence of pyridine.
Phosphonates I–IV were chosen as substrates.
Two most evident routes can be principally sug-
gested. One of them is bromination of phosphono-
methylated furans under the electrophilic substitution
conditions, while another one includes phosphorylation
of the corresponding bromo(halomethyl)furans accord-
ing to the Michaelis–Becker reaction. In the course of
our work both approaches were tested.
The electrophilic bromination of furans was studied
incompletely mainly by the example of 2-substituted
compounds. Furan and its homologs were brominated
with bromine in the presence of such hydrogen
bromide acceptors as pyridine and DMF [5], or with
CH2PO(OC2H5)2 CH3
CH2PO(OC2H5)2
O
O
I
II
CH2PO(OC2H5)2
CH2PO(OC2H5)2
CH3
CH3
III
O
O
IV
Each of these compounds has only one position
most active in the electrophilic substitution reactions.
At the same time the effect of α- and β-phos-
phonomethyl group on the course of bromination in
different positions of the ring might be traced.
phonate at δP 21.5 ppm and a minor signal of diethyl
hydrogen phosphate at δP 10.9 ppm showing that the
oxidative cleavage of P–C bond took place. Yield of
bromophosphonate V was evaluated at 69%.
Br2
I
The bromination of phosphonate II was carried out
in chloroform in the presence of 1 mol of pyridine at
25°C. Reaction proceeded with the heat evolution, and
the bromine was consumed practically in the moment
of addition. The workup of the reaction mixture gave
crude bromophosphonate V as a mobile dark oil. The
substance obtained contained no starting compound.
Its 31P NMR spectrum contained a signal of phos-
Br
CH2PO(OC2H5)2
C5H5N
O
V
The substance isolated from the reaction mixture
was distilled in a vacuum with partial decomposition,
but the distillate with bp 128°C (1 mm Рп) was a
spectroscopically pure phosphonate V.
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364
PEVZNER
The reaction of phosphonate II with bromine was
BrCH2
CH3
CH2PO(OC2H5)2
carried out analogously. The coloration with bromine
quickly disappeared in the course of the process, but
analysis of the reaction products showed that no
substitution in the furan ring took place. 31P NMR
spectrum contained the signal of diethyl hydrogen
phosphate at δP 10.975, and a signal with δP –79.910 ppm
attributed by us to bromophosphate. The treatment of
the reaction mixture permitted recovering 23% of the
starting phosphonate II, and to obtain a mixture of the
products of oxidative dephosphorylation of the initial
substance which we failed to separate and identify.
Br2
O
II
AlCl3
CH2Br + phosphonates
O
Reaction of phosphonate II with bromine was
carried out in chloroform at room temperature in the
presence of pyridine. Under these conditions bromine
was completely consumed, but a large amount of the
starting compound remained in the reaction mixture.
1H NMR spectrum of the isolated mixture of sub-
stances contained intense signals in the range 2.5–
4.0 ppm related to the aliphatic compounds. In 31P
NMR spectrum of this preparation the signals with δP
27.903, 24.675, 23.556, and 21.471 ppm characteristic
of the aliphatic phosphonates were observed. The
signals of phosphates at δP 0.868 and 0.471 ppm and of
bromophosphate at δP –72.881 ppm were also
identified. Minor signals with δ 6.282 ppm in 1H NMR
spectrum and with δP 25.161 ppm in 31P NMR
spectrum were attributed to the bromination product
VIII (for pure compound VIII signal of the ring
proton H4 appeared at δ 6.157 ppm and the signal of
phosphorus was observed at δP 25.418, see below).
Hence, in the case of phosphonate III the main
pathway of the reaction with bromine is the opening of
the furan ring without the cleavage of P–C bond.
Oxidative dephosphorylation and bromination of the
furan ring become the side pathways.
With the purpose to turn the reaction of
phosphonate II with bromine to the pathway of
electrophilic substitution we used aluminum chloride
as catalyst in an amount of 6 mol %. The consumption
of bromine in the course of the reaction started at 10°C
and occurred just after the addition of each new
1
portion of the reagent. H NMR spectrum of reaction
mixture permitted the identification of the starting
phosphonate II, bromomethylphosphonate VI [1H
NMR spectrum, δ, ppm: 3.213 d (CH2P, JHP 21.6 Hz),
4.393 s (CH2Br), 6.150 s (H3-furan), 6.256 s (H4-
furan), δP 19.888 ppm], and 5-methyl-2-bromomethyl-
furan VII [1H NMR spectrum, δ, ppm: 2.307 s (CH3-
furan), 4.468 s (CH2Br), 5.917 s (H4-furan), 6.250 s
(H3-furan)]. Bromomethyl derivatives were removed
by treating the reaction mixture with triethylamine, and
37% of starting phosphonate II was recovered from the
residue. Crystals of the salt obtained in the course of
the workup of the reaction mixture were identified
spectroscopically as the triethylammonium salt with an
inorganic anion. It had no clear melting point, and
most probably it was a mixture. The elimination of
triethylammonium salts from the quarternary ammo-
nium ones is characteristic of furans [11] and may be
considered an indirect evidence of their formation, and
hence of the presence of bromomethyl compounds in
the mixture under investigation.
CH2PO(OC2H5)2
CH2PO(OC2H5)2
Br
CH3
CH3
Br
O
O
VIII
IX
Reaction of phosphonate IV with bromine was
carried out analogously to the previous case. In H
NMR spectrum of the obtained mixture of products the
1
were identified starting phosphonate IV, bromide IX
[1H NMR spectrum δ 6.033 ppm (H4-furan), P NMR
31
31P NMR spectrum of the reaction mixture besides
the above-mentioned signals contains also the signals
of phosphates with δP 12.020, 10.849, and 0.457 ppm.
spectrum, δP 24.664 ppm. Bromide IX obtained
1
according to the Michaelis–Becker reaction, H NMR
spectrum δ 6.040 ppm (H4-furan), 31P NMR spectrum
δP 24.671 ppm (see below)]. In the range 2.5–4.0 ppm
numerous signals of aliphatic protons belonging to
nonidentified compounds were observed. 31P NMR
spectrum contained also the signals of phosphates with
δP 6.758 and 0.14 ppm.
Hence, it was established that the reaction of
phosphonate II with bromine under typical conditions
of the aromatic electrophilic substitution proceeds
according to two pathways exclusively in the side
chain.
Hence, reaction of phosphonate with bromine
proceeds also according to several pathways including
At the same time no substitution in the furan ring
was established.
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365
SYNTHESIS OF ISOMERIC BROMO(DIETHOXYPHOSPHORYLMETHYL)FURANS
bromination of the furan ring, its cleavage, and rupture
of the P–C bond.
Ratio of the reaction products depended on
temperature, and at 40–42°C it was 0.8:1 (conversion
79%, overall yield 54%), at 51–52°C it is 1.7:1
(conversion 78%, overall yield 55%) at 55–56°C it was
2.1:1 (conversion 78%, overall yield 58%), and at 64-
65°C it decreased to 0.7:1 (conversion 72%, overall
yield 37%). Bromomethyl compound XIV was
removed by treating the reaction mixture with
triethylamine.
The data presented shows that only bromophos-
phonate V may be prepared by direct bromination of
phosphonate I.
Second approach to the synthesis of bromophos-
phonates includes the preparation of halomethylfurans
brominated in the ring and their subsequent
phosphorylation under the conditions of the Michaelis–
Becker reaction.
Bromination of the ester XI in the presence of small
amount of the aluminum chloride in chloroform
proceeded at room temperature to form single product
XV in 71% yield.
2-Chloromethyl-4-bromofuran, the only known
compound series, was obtained by the four-step syn-
thesis from 4,5-dibromo-2-furaldehyde [12].
COOC2H5
Synthesis of isomeric bromo(chloromethyl)furans
was planned to include bromination of the correspond-
ing alkyl furoates, the reduction of the compounds
obtained to alcohols, and substitution of hydroxy
groups with chlorine.
Br2
Br
CH3
XV
XI
AlCl3
O
Bromination of compound XII proceeded under the
analogous conditions to form the products of
substitution in the ring and in the side chain, the
product ratio being 1.00:0.22. The overall yield
reached 89%. Bromomethyl derivative XVII was
removed by treating the mixture obtained with tri-
ethylamine.
COOC2H5
CH3
COOC2H5
CH3
XI
O
O
X
COOC2H5
COOC2H5
Br
CH3
O
Br2
AlCl3
XII
CH3
XII
O
XVI
Bromination of the esters X–XII with bromine in
chloroform according to the procedure used for alkyl
2-furoates [6] showed that conversion of the esters XI,
XII was not high, and compound X did not react at all.
In connection with that we tried to use the AlCl3
catalyst in the amount up to 10% mol.
COOC2H5
+ BrCH2
O
XVII
It proved that the reaction of compound X with
bromine under these conditions began at 40°C and led
to the formation of two products XIII, XIV.
Hence, it was shown that the reaction of alkyl
furoates with bromine under the typical conditions of
electrophilic substitution was directed in the ring as
well as in the side chain. The extent of the last pathway
increases with the decrease in the activity of the
participating position of the ring in the electrophilic
substitution reactions.
Br
Br2
COOC2H5
X
CH3
AlCl3
O
XII
The formation of bromomethyl derivatives is
understandable within the framework of existing
knowledge on the reactions of furans with electro-
philes. As known, compounds of the furan series react
according to two mechanisms [13]. The first one
BrCH
COOC2H5
+
2
O
XIV
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366
PEVZNER
resembles electrophilic substitution in the aromatic
ring, while the second one includes formation and
subsequent decomposition of the adduct by the posi-
tions 2 and 5 of the ring. In the case of monosub-
stituted furans the same products are formed, while in
the case of polysubstituted substances it is necessary to
analyse the preferred direction of decomposition of the
intermediate adduct of alkyl methylfuroates with
bromine.
In the case of ester X adduct XVIII was formed.
The elimination of bromide ion in this case must
proceed from the position 5 because the electronic
density on the Br5 atom is higher than on the Br2 one
exposed to the effect of the ethoxycarbonyl group. The
intermediate XIX formed is stabilized by the system of
conjugated bonds and is capable of further stabilization
by the transfer of bromine in the side chain with the
restoration of heteroaromatic structure.
CH3
Br
COOC2H5
COOC2H5
−HBr
CH2
XIV
O
O
Br
XVIII
Br
XIX
Considering this scheme in the case of the ester XI
it may be suggested that the elimination of bromide ion
takes place from the position 2 with the subsequent
deprotonation of the position 5, though most probably
the reaction proceeds according to the usual scheme of
electrophilic substitution including the formation of σ-
complex. At least the energetic advantages of the
reaction proceeding according to the addition-
elimination pathway are not evident.
Reduction of the brominated esters XIII, XV, XVI
to alcohols was carried out with lithium aluminum
hydride in ether.
Bromide XIII was reduced to form two alcohols
XXII, XXIII. At 10°C their ratio was 1:0.2.
Br
LiAlH4
XIII
CH2OH
CH3
O
COOC2H5
XXII
Br
CH3
−HBr
XV
CH3
CH2OH
+
O
Br
H
O
In the case of ester XII adduct XX should eliminate
the bromide ion from the position 5 having the highest
electronic density, and in the intermediate XXII two
C=C bonds will be conjugated with the carbonyl group
of the ester fragment. Moderate yield of compound
XVII in this case is connected evidently with the high
activity of the position 2 in the electrophilic
substitution.
XXIII
Analogously the reduction of bromide XV led to
products XXIV, XXV. At 36°C their ratio is 1:0.65,
and at 10°C it decreases to 1:0.1.
CH2OH
CH2OH
LiAlH4
Br
+
XV
O
O
CH3
CH3
XXIV
XXV
COOC2H5
Bromide XVI reacts with lithium aluminum
hydride to give the mixture of alcohols XXVI, XXVII.
At 36°C their ratio is 1.00:1.45, and at 10°C it is equal
to 1.00:1.12.
Br
H
O
Br
CH3
XX
The brominated alcohols are stable at 0°C for
several days, but heating in a vacuum (1 mm Hg)
causes their polymerization at the temperatures below
their boiling points.
COOC2H5
H
−HBr
CH2
XVII
O
Br
Comparison of ratio of the brominated and
debrominated products shows that stronger electron-
XXI
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367
SYNTHESIS OF ISOMERIC BROMO(DIETHOXYPHOSPHORYLMETHYL)FURANS
CH2OH
CH2OH
LiAlH4
XVI
+
CH3
CH3
O
O
Br
XXVI
XXVII
according to the typical procedure [12]. Due to the
high lability of the obtained mixtures of brominated
and debrominated hydroxymethylfurans it was in-
possible to obtain pure substances, so firther trans-
formations were carried out using the products isolated
directly from the reaction mixtures. It turned out, that
bromo(chloromethyl)furans XXXI–XXXIII are signif-
icantly more stable than the corresponding alcohols.
They can be purified by vacuum distillation what
permitted to prepare spectroscopically pure bromide
XXXII and the mixtures consisting of compounds
XXXI, XXVIII in the 1:0.3 ratio and of products
XXXIII, XXX in the 1:0.12 ratio. Details of the
process are given in the Experimental.
acceptor effect of the ester group and the furan ring
oxygen on bromine corresponds to the higher yield of
debrominated alcohol. That is why it can be stated that
just the ester undergoes the debromination, and the
ratio of the rates of the debromination and reduction of
the ester group mainly determines the ratio of the
reaction products. This conclusion agrees also with the
existing concepts on the debromination of aromatic
systems under the action of lithium aluminum hydride
in a nucleophilic substitution reaction [14, 15].
Substutition of hydroxy group with halogen in the
alcohols synthesized was carried out with thionyl
chloride in the presence of pyridine at 10–20°C
CH2Cl
CH2Cl
X
X
CH3
X = H (XXX)
CH2Cl
O
O
O
CH3
X
CH3
X = H (XXVIII)
X = Br (XXXI)
X = H (XXIX)
X = Br (XXXII)
X = Br (XXXIII)
Phosphorylation of bromo(halomethyl)furans syn-
thesized was carried out under the conditions of the
Michaelis–Becker reaction in benzene at 80°C accord-
ing to the typical procedure [16]. The starting
substrates were the mixtures of chlorides obtained,
therefore in all cases the material balance of the reac-
tions was checked considering the data on phosphoryla-
tion of the individual chloromethylfurans XXVIII–XXX.
Phosphorylation of the mixture of compounds
XXXI, XXVIII led to the formation of a mixture of
phosphonates XXXIV, II in 1:0.13 ratio.
Br
NaPO(OC2H5)2
XXXI + XXVIII
CH2PO(OC2H5)2 + II
O
CH3
XXXIV
Yield of bromophosphonate XXXIV was 84%, and
the product II was formed in 39% yield. At the same
time phosphorylation of pure chloride XXVIII under
the analogous conditions permitted to obtain phos-
phonate II in 72% yield [16]. Such decrease in the
yield arises probably from the higher rate of the
reaction of bromo(chloromethyl)furan XXXI with
sodium diethyl phosphite as compared to the
compound XXVIII. Due to that the concentration of
phosphorylating agent quickly decreases, and the
solution obtained has low content of chlorome-
thylfuran XXVIII as well as of sodium diethyl
phosphite. Under these conditions the latter substrate
reacts slowly.
Reaction of bromo(chloromethyl)furan XXXII with
sodium diethyl phosphite was carried out analogously.
Distillation of the reaction mixture in a vacuum
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368
PEVZNER
yielded chloride XXIX with bp 32–34°C (1 mm Hg)
and a fraction with bp 136–138°C (1 mm Hg) con-
sisting of bromophosphonate VIII with a small
admixture of phosphonate III.
CH2PO(OC2H5)2
NaPO(OC2H5)2
XXXII
Br
+ XXIX + III
O
CH3
VIII
Yield of chloromethylfuran XXIX was 16%, of
phosphonate VIII, 49%, and the yield of phosphonate
III was evaluated at 2–3%. Composition of the reac-
tion products shows that besides phosphorylation
according to the Michaelis–Becker scheme the
halogenophilic attack of phosphite anion on the
bromine atom in the furan ring leading to reduction of
compound XXXII to chloromethylfuran XXIX takes
place. The latter in its turn is phosphorylated with
sodium diethyl phosphite, but this reaction proceeds
slower than the phosphorylation of bromide. Forma-
tion of phosphonate III by debromination of phos-
phonate VIII seems hardly probable.
Michaelis–Becker reaction. The side process is the
halogenophilic attack of bromine atom in α-position of
the furan ring leading to its substitution with hydrogen.
The halogenophilic attack of phosphate anion takes
place when the bromine atom carries the effective
positive charge. In the case under consideration
substituents present in the furan ring are weak
acceptors, and the main contribution to the polarization
of bromine is provided by oxygen of the furan ring. It
is particularly valuable because under the conditions
excluding the other reaction pathways mild reduction
of 2-bromofurans can be carried out. Protecting of
position 2 in the furan ring by means of bromination
and subsequent debromination is used in the synthesis
of 3-substituted furans, but the existing debromination
procedures by zinc in the acetic acid at boiling [10,
17], or with butyllithium [18] are applicable only to a
narrow range of compounds.
The reaction of a mixture of chloromethylfurans
XXXIII with sodium diethyl phosphite was carried out
analogously. 1H NMR spectrum of the reaction
mixture taken after removing the solvent permitted
establishing that it is a mixture of phosphonates IX, IV
in 1:0.5 ratio. After distillation in a vacuum the
mixture obtained consisted of the same products in
1:0.7 molar ratio due to the stronger decomposition of
phosphonate IX. Evaluation of the material balance of
this process showed that the greater part of
phosphonate IV was formed not from the starting
chloride XXXI, but through debromination of
bromofurans XXXIII, IX. The data obtained do not
permit to conclude which of these compounds is the
main precursor of phosphonate IV.
Cases of the halogenophilic attack in the furan
series were observed recently and sufficiently
thoroughly studied [19, 20]. All of them concerned the
compounds with a bromine atom in the α-position of
the side chain. Depending on the substrate structure
either formation of the P–C bond or reduction of the
bromine-containing group was observed. Our new data
show that these reactions may proceed independently
with the participation of different reaction centers. The
halogenophilic attack is directed on the bromine atom
bound with the heteroaromatic ring whose influence is
creating the effective positive charge.
XXXIII + XXX
NaPO(OC2H5)2
EXPERIMENTAL
CH2PO(OC2H5)2
1H NMR spectra were taken on a Bruker DPX-400
spectrometer (400.131 MHz), and 31P NMR spectra on
a Bruker AC-200 device (80.014 MHz 31P) in deutero-
chloroform.
CH3
+ IV
O
Br
IX
Bromination of phosphonates I–IV (general
procedure). To a solution of 0.01 mol of phosphonate
I–IV and 0.01 mol of pyridine in 30 ml of chloroform
a solution of 0.01 mol of bromine in 5 ml of chloro-
Hence, it was established that bromo(chloromethyl)-
furans react with sodium diethyl phosphite according
to two pathways. The main one is the formation of
phosphonates according to the classical scheme of the
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369
SYNTHESIS OF ISOMERIC BROMO(DIETHOXYPHOSPHORYLMETHYL)FURANS
form was added dropwise with stirring at room
temperature. After the complete addition of bromine
the reaction mixture was kept at room temperature for
1 h, shaken with a mixture of 5 g of ice and 10 ml of
water, washed with 5% HCl cooled to 0°C, with the
cooled water solution of sodium bicarbonate, and then
dried over calcium chloride. The oil-like residue
obtained after removing the solvent was analyzed by
spectral methods.
formed were filtered off, and the filtrate was distilled
in a vacuum to give 1.07 g (30%) of phosphonate II,
bp 102°C (1 mm Hg). The crystals were ground with
acetone, treated with ethyl acetate, filtered, and dried.
1
Yield 1.03 g, mp 230–250°C. H NMR spectrum
(DMSO-d6), δ, ppm: 1.170 t (CH3), 3.100 q (CH2N+),
8.260 br.s (NH+).
Bromination of esters (X-XII) (general
procedure). To a solution of ester in chloroform alu-
minum chloride was added and the mixture was stirred
for 10–15 min until homogenization. After that a
solution of bromine in chloroform was added dropwise
with stirring at the desired temperature, and the
reaction mixture was maintained for the given time.
Then in was poured on a mixture of water with ice.
Organic layer was separated, washed with water, dried
over CaCl2, solvent was removed, and the residue was
distilled in a vacuum.
5-Bromo-2-(diethoxyphosphorylmethyl)furan (V).
Yield of undistilled phosphonate V 69%. Distillation
of 1.94 g of the crude product in a vacuum gave 0.64 g
1
of light brown oil with bp 128°C (1 mm Hg). H and
1
31P NMR spectra of both products were identical. H
NMR spectrum, δ, ppm: 1.226 t (CH3-ethyl, JHH
7.6 Hz), 3.129 d (CH2P, JHP 21.2 Hz), 4.017 m
(CH2OP, JHH 7.5 Hz, JHP 15.2 Hz), 6.151 s (H3+H4-
furan, overlapping), δP 21.527 ppm.
31
Bromination of phosphonate (II). P NMR spec-
Ethyl 4-bromo-5-methylfuran-2-carboxylate (XIII).
A solution of 14.5 g of the ester XII in 150 ml of
chloroform containing 1.3 g of AlCl3 was brominated
with a solution of 5 ml of bromine in 10 ml of
chloroform. The mixture obtained was maintained for
2 h. Distillation of the reaction mixture gave 3.2 g of
the starting ester and 9.9 g of a fraction with bp 95-
112°C (1 mm Hg) consisting of a mixture of bromides
XIII, XIV in 2.58:1 ratio. The substance obtained was
dissolved in 100 ml of benzene, treated with 2.5 ml of
triethylamine, and left overnight. On the next day the
liquid phase was decanted from crystals, washed with
diluted HCl, dried over CaCl2, and distilled in a
vacuum to give 4.0 g of bromide XIII, bp 80°C (1 mm
trum of the obtained product, δP, ppm: 23.740
(phosphonate II), 10.975 (diethyl hydrogen phos-
phate), –79.910 (probably bromophosphate). Recovery
1
of phosphonate II 23%, H NMR spectrum, δ, ppm:
1.223 t (CH3-ethyl), 2.159 s (CH3-furan), 3.150 d
(CH2P, JHP 20.4 Hz), 4.007 m (CH2OP), 5.824 s (H4-
furan), 6.025 (H3-furan).
Bromination of phosphonate (II) in the presence
of aluminum chloride. Bromination of a mixture of
2.9 g of phosphonate II, 100 mg of AlCl3 and 35 ml of
chloroform with a solution of 0.7 ml of bromine in
5 ml of chloroform at 15–20°C followed by
decomposition of reaction mixture with a mixture of
water with ice, washing with water, with sodium
bicarbonate solution, drying over calcium chloride, and
removing the solvent in a vacuum gave 2.49 g of
brown viscous oil. 1H NMR spectrum, δ, ppm:
phosphonate II: 2.159 s (CH3-furan), 3.150 d (CH2P,
JHP 20.4 Hz), 5.801 s (H4-furan), 6.023 s (H3-furan), δP
23.118 ppm; bromomethylphosphonate VI: 3.213 d
(CH2P, JHP 21.6 Hz), 4.393 s (CH2Br), 6.150 s (H3-
furan), 6.256 s (H4-furan), δP 19.888; 5-methyl-2-
bromomethylfuran VII: 2.307 s (CH3-furan, 4.468 s
(CH2Br), 5.917 s (H4-furan), 6.250 s (H3-furan);
common signals of ester groups: 1.223 m (CH3-ethyl),
4.000 m (CH2OP). 31P NMR spectrum of phosphates,
δP, ppm: 12.020, 10.889, –0.457.
1
Hg). H NMR spectrum, δ, ppm: 1.293 t (CH3-ethyl),
2.303 s (CH3-furan), 4.286 q (CH2OOC), 7.036 (H4-
furan).
Ethyl 5-bromomethylfuran-2-carboxylate (XIV).
1H NMR spectrum, δ, ppm: 1.293 t (CH3-ethyl), 4.286
q (CH2OOC), 4.456 s (CH2Br), 6.463 d (H4-furan, JHH
3.6 Hz), 7.066 d (H3-furan, JHH 3.6 Hz).
Ethyl 2-methyl-5-bromofuran-3-carboxylate (XV).
A solution of 12.2 g of the ester XI in 100 ml of
chloroform containing 1.2 g of AlCl3 was brominated
with a solution of 4.4 ml of bromine in 10 ml of
chloroform at 20–23°C with the subsequent keeping
for 15 min. Vacuum distillation gave 13.2 g (71%) of
1
bromide XV with bp 70–71°C (1 mm Hg). H NMR
The substance obtained was dissolved in 30 ml of
benzene, 3 ml of triethylamine was added, and the
resulting mixture was left overnight. The crystals
spectrum, δ, ppm: 1.289 t (CH3-ethyl), 2.511 s (CH3-
furan), 4.237 q (CH2OOC), 6.511 s (H4-furan).
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PEVZNER
Reduction of bromide (XVI). To a suspension of
1.1 g of lithium aluminum hydride in 70 ml of
anhydrous ether a solution of 7.1 g of bromide XVI in
20 ml of anhydrous ether was added. A mixture of 2-
bromo-5-methyl-3-hydroxymethylfuran XXVI and 5-
methyl-3-hydroxymethylfuran XXVII in the 1:1.12
Ethyl 2-bromo-5-methylfuran-3-carboxylate (XVI).
A solution of 41 g of the ester XII in 150 ml of
chloroform containing 3.2 g of AlCl3 was brominated
with a solution of 14.4 ml of bromine in 30 ml of
chloroform at 20°C. The distillation of the reaction
mixture in a vacuum gave 55.3 g of the fraction with
bp 92°C (1 mm Hg) consisting of bromide XVI and
bromomethylfuran XVII in 1.0:0.22 molar ratio. The
mixture obtained was dissolved in 150 ml of benzene,
6.5 ml of triethylamine was added, and the resulting
mixture was stirred for 1 h and left overnight. On the
next day benzene solution was decanted from the
crystals, washed with diluted hydrochloric acid, with
water, dried over CaCl2, and distilled in a vacuum to
give 33.5 g of bromide XVI with bp 85°C (1 mm Hg).
1H NMR spectrum, δ, ppm: 1.229 t (CH3-ethyl), 2.241
s (CH3-furan), 4.254 t (CH2OOC), 6.035 s (H4-furan).
1
ratio, 3.6 g, was obtained. H NMR spectrum, δ, ppm:
2-bromo-5-methyl-3-hydroxymethylfuran
XXVI:
2.238 s (CH3-furan), 4.343 s (CH2O). 6.071 s (H4-
furan); 5-methyl-3-hydroxymethylfuran XXVII: 2.238
s (CH3-furan), 4.427 s (CH2O), 5.898 s (H4-furan),
7.211 s (H2-furan).
Reaction of hydroxymethylfurans with thionyl
chloride (general procedure). To a mixture of alcohol
and pyridine in anhydrous ether a solution of thionyl
chloride in ether was added dropwise with stirring at
5–10°C. The mixture obtained was stirred for 4 h at
10-15°C, pyridinium chloride was filtered off, ether
was removed, and the residue was distilled in a
vacuum.
Reduction of alkyl bromofurancarboxylates
(general procedure). To a suspension of lithium
aluminum hydride in the anhydrous ether a solution of
alkyl bromofurancarboxylate in the anhydrous ether
was added dropwise with stirring at 10°C. The mixture
obtained was stirred for 2 h at 10°C and left overnight.
On the next day the reaction mixture was treated with
an excess ethyl acetate, and then with the saturated
NH4Cl solution until the separation of phases. Organic
phase was decanted, dried over CaCl2, and evaporated
in a vacuum.
Reaction of a mixture of alcohols (XXII,XXIII)
with thionyl chlorode. Treating a solution of 2.5 g of
a mixture of alcohols XXII, XXIII (1:0.2) and 1.2 ml
of pyridine in 100 ml of anhydrous ether with a
solution of 1.1 ml of thionyl chloride in 10 ml of ether
yielded 1.6 g of a mixture of chlorides XXXI, XXVII
1
in 1:0.3 molar ratio, bp 51°C (1 mm Hg). H NMR
spectrum, δ, ppm: 4-bromo-5-methyl-2-chloromethyl-
furan XXXI: 2.286 s (CH3-furan), 4.482 s (CH2Cl),
6.309 s (H3-furan); 5-methyl-2-chloromethylfuran
XXVII: 2.286 s (CH3-furan), 4.538 s (CH3Cl), 5.911 d
(H4-furan, JHH 2.0 Hz), 6.921 d (H3-furan, JHH 2.0 Hz).
Reduction of bromide (XIII). To a suspension of
0.7 g of lithium aluminum hydride in 50 ml of ether a
solution of 4 g of bromide XIII in 15 ml of ether was
added. A mixture of alcohols XXII, XXIII, 2.5 g, in
the 5:1 ratio was obtained. 1H NMR spectrum, δ, ppm:
2-hydroxymethyl-4-bromo-5-methylfuran XXII: 2.240
s (CH3-furan), 4.458 (CH2O), 6.207 s (H3-furan); 2-
hydroxymethyl-5-methylfuran XXIII: 2.240 s (CH3-
furan), 4.458 s (CH2OH), 5.685 s (H4-furan), 6.133 s
(H3-furan).
Reaction of a mixture of alcohols (XXIV,XXV)
with thionyl chloride. Treating a solution of 4.0 g of a
mixture of alcohols XXIV, XXV (1:0.1) and 1.8 ml of
pyridine in 50 ml of anhydrous ether with a solution of
1.5 ml of thionyl chloride in 5 ml of ether yielded 2.9 g
of 2-methyl-5-bromo-3-(chloromethyl)furan XXXII,
Reduction of bromide (XV). To a suspension of
0.9 g of lithium aluminum hydride in 70 ml of ether a
solution of 5 g of bromide XV in 15 ml of anhydrous
ether was added. 2-Methyl-5-bromo-3-hydroxymethyl-
furan XXIV, 4.0 g, with a small admixture of 2-
1
bp 49–51°C (1 mm Hg). H NMR spectrum, δ, ppm:
2.261 s (CH3-furan), 4.349 s (CH2Cl), 6.250 s (H4-
furan).
Reaction of a mixture of alcohols (XXVI, XXVII)
with thionyl chloride. Treating a solution of 5.8 g of a
mixture of alcohols XXVI, XXVII (1:1.12) and 4.6 ml
of pyridine in 100 ml of ether with a solution of 3.9 ml
of thionyl chloride in 10 ml of ether yielded 1.4 g of a
mixture of chlorides XXXIII,XXX in 1:0.12 molar
ratio, bp 53°C (1 mm Hg). 1H NMR spectrum, δ, ppm:
1
methyl-3-hydroxymethylfuran XXV was obtained. H
NMR spectrum, δ, ppm: 2-methyl-5-bromo-3-
hydroxymethylfuran XXIV: 2.228 s (CH3-furan),
2.608 br.s (OH), 4.347 br.s (CH2O), 6.241 s (H4-
furan); 2-methyl-3-hydroxymethylfuran XXV: 2.239 s
(CH3-furan), 4.403 s (CH2O), 6.323 s (H4-furan), 7.211
s (H3-furan).
2-bromo-5-methyl-3-(chloromethyl)furan
XXXIII:
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371
SYNTHESIS OF ISOMERIC BROMO(DIETHOXYPHOSPHORYLMETHYL)FURANS
2.240 s (CH3-furan), 4.315 s (CH2Cl), 6.023 s (H4-
furan); 5-methyl-3-(chloromethyl)furan XXX: 2.249 s
(CH3-furan), 4.425 s (CH2Cl), 6.423 s (H4-furan),
7.420 s (H2-furan).
of diethyl hydrogen phosphite, and 1.4 g of a mixture
of chlorides XXXIII, XXX (1:0.12 molar ratio) gave a
mixture of phosphonates IX, IV in 1:0.5 molar ratio.
Reaction time 14 h. Distillation in a vacuum gave 0.6 g
of a mixture of these compounds with bp 117-120°C/1
1
General procedure of phosphorylation with
sodium diethyl phosphite. To a solution of sodium
diethyl phosphite in benzene an appropriate substrate
was added in one portion at 80°C, and the mixture
obtained was refluxed with stirring for the desired
time. Precipitate of the inorganic salt was removed on
a centrifuge, benzene was distilled off, and the residue
was distilled in a vacuum.
mm, ratio of phosphonates IX, IV 1:0.7. H NMR
spectrum, δ, ppm: 2-bromo-5-methyl-3-(diethoxyphos-
phorylmethyl)furan IX: 1.247 m (CH3-ethyl), 2.177 s
(CH3-furan), 2.763 d (CH2P, JHP 21.2 Hz), 4.022 m
(CH2OP), 6.040 s (H4-furan), δP 24.671 ppm; 5-
methyl-3-(diethoxyphosphorylmethyl)furan IV: 1.247
m (CH3-ethyl), 2.126 s (CH3-furan), 2.816 d (CH2P,
JHP 21.2 Hz), 4.022 m (CH2OP), 5.928 s (H4-furan),
7.124 (H2-furan), δP 26.048 ppm.
Phosphorylation of a mixture of chlorides
(XXXI, XXVIII). Reaction of 0.2 g of sodium, 1.6 ml
of diethyl hydrogen phosphite, and 1.5 g of a mixture
of chlorides XXXI, XXVIII (1:0.3) gave 1.9 g of a
mixture of phosphonates XXXIV, II in 1:0.13 molar
ratio, bp 134°C (1mm Hg), reaction time 6 h. 1H NMR
spectrum, δ, ppm: 5-methyl-4-bromo-2-(diethoxyphos-
phorylmethyl)furan XXXIV: 1.237 m (CH3-ethyl),
2.165 s (CH3-furan), 3.083 d (CH3P, JHP 20.6 Hz),
4.027 m (CH2OP), 6.118 s (H3-furan), δP 21.846 ppm;
5-methyl-2-(diethoxyphosphorylmethyl)furan II: 1.237
m (CH3-ethyl), 2.127 s (CH3-furan), 3.083 d (CH2P,
JHP 20.6 Hz), 4.027 m (CH2OP), 5.927 s (H4-furan),
6.018 s (H3-furan), δP 22.735 ppm.
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of 0.32 g of sodium, 2.2 ml of diethyl hydrogen
phosphite, and 2.0 g of chloromethylfuran XXXII in
45 ml of benzene gave 0.3 g (16%) of 2-methyl-3-
(chloromethyl)furan XXIX with bp 32–34°C (1 mm
Hg), and 2.1 g (~49%) of phosphonate VIII containing
small admixture of phosphonate III, bp 136–138°C
(1 mm Hg). Reaction time 16 h. 1H NMR spectrum, δ,
ppm: 2-methyl-3-(chloromethyl)furan XXIX: 2.200 s
(CH3-furan), 4.231 s (CH2Cl), 6.240 s (H4-furan),
7.148 s (H5-furan); 2-methyl-5-bromo-3-(diethoxy-
phosphorylmethyl)furan VIII: 1.271 t (CH3-ethyl, JHH
7.2 Hz), 2.159 d (CH3-furan, JHH 3.2 Hz), 2.731 d
(CH2P, JHP 19.6 Hz), 3.818 m (CH2OP, JHH 7.2 Hz, JHP
14.4 Hz), 6.157 s (H4-furan), δP 24.458 ppm; 2-methyl-
3-(diethoxyphosphorylmethyl)furan III: 1.217 t (CH3-
ethyl, JHH 7 Hz), 2.191 br.s (CH3-furan), 2.828 d
(CH2P, JHP 20 Hz), 3.818 m (CH2OP, JHH 7.2 Hz, JHP
14.4 Hz), 6.284 s (H4-furan), 7.182 s (H5-furan), δP
26.248 ppm.
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