Synthesis of 2-functionalized 4-(diethoxyphosphorylmethyl)-5-(1-bromoalkyl) furans and their reactions with amines

Article abstract of DOI:10.1007/s11176-005-0317-8

Phosphorylation of esters and nitriles of 4-chloromethyl-5-alkylfuran-2- carboxylic acids with triethyl phosphite yields the corresponding phosphonates. These compounds are brominated with N-bromosuccinimide in carbon tetrachloride at the α-position of the alkyl radical. The resulting 2-(1-bromoethyl)-, 2-(1-bromopropyl)-, and 2-(1-bromoisobutyl)furans react with secondary amines following the scheme of nucleophilic substitution. The dehydrobromination product was isolated only in the reaction of ethyl 4-(diethoxyphosphorylmethyl)- 5-(1-bromoisopropyl)furan-2-carboxylate with triethylamine, but its yield was low. The reactions of bromo phosphonates with lithium carbonate in DMF result in their decomposition. 2005 Pleiades Publishing, Inc.

Full text of DOI:10.1007/s11176-005-0317-8

Russian Journal of General Chemistry, Vol. 75, No. 5, 2005, pp. 774 781. Translated from Zhurnal Obshchei Khimii, Vol. 75, No. 5, 2005,
pp. 820 828.
Original Russian Text Copyright
2005 by Pevzner.
Synthesis of 2-Functionalized 4-(Diethoxyphosphorylmethyl)-
5-(1-bromoalkyl)furans and Their Reactions with Amines
L. M. Pevzner
Russian Research Institute of Hydrolysis of Vegetable Materials, St. Petersburg, Russia
Received August 31, 2004
Abstract Phosphorylation of esters and nitriles of 4-chloromethyl-5-alkylfuran-2-carboxylic acids with
triethyl phosphite yields the corresponding phosphonates. These compounds are brominated with N-bromo-
succinimide in carbon tetrachloride at the -position of the alkyl radical. The resulting 2-(1-bromoethyl)-,
2-(1-bromopropyl)-, and 2-(1-bromoisobutyl)furans react with secondary amines following the scheme of
nucleophilic substitution. The dehydrobromination product was isolated only in the reaction of ethyl 4-(di-
ethoxyphosphorylmethyl)-5-(1-bromoisopropyl)furan-2-carboxylate with triethylamine, but its yield was low.
The reactions of bromo phosphonates with lithium carbonate in DMF result in their decomposition.
Esters and nitriles of 5-(1-bromoalkyl)furan-2-
carboxylic acids react with phosphorus nucleophiles
along two pathways with the formation of alkenes and
phosphorylation products [1]. In the presence of a
strong acceptor in the furan ring, nucleophilic substi-
tution is preferred, and accumulation of -donors such
as methyl groups in the side chain facilitates the
elimination of hydrogen bromide. This study was
aimed to introduce an additional substituent with
weak electron-acceptor properties, diethoxyphospho-
rylmethyl group, into the furan ring, to examine the
direction of bromination of the resulting phosphorus-
containing derivatives of 5-alkylfuran-2-carboxylic
acids, and to carry out the reactions of the resulting
bromo derivatives with secondary amines. Based on
the previously established effect of substituents, it
could be expected that the main direction of the
process should be the alkylation of amines leading to
phosphorus-containing derivatives of amino acids of
the furan series.
Alkyl 5-alkylfuran-2-carboxylates I III were
chosen as the starting substances. They were chloro-
methylated with paraform in the presence of zinc
chloride in dichloroethane. In all the three cases, the
reaction proceeded with a considerable heat evolution,
and the substituent entered 4-position of the furan
ring.
ClCH2
CH2O + HCl
ZnCl2
R
COOCH3
IV VI
R
COOCH3
I III
O
O
R = C2H5 (I, IV), n-C3H7 (II, V), (CH3)2CHCH2 (III, VI).
It was unexpectedly found that ethyl esters of the
corresponding acids are extremely difficult to chloro-
methylate even at elevated temperatures (35 40 C).
ClCH2
R
CN
O
Chloromethylated nitriles VII IX were obtained by
the following sequence of reactions.
VII IX
R = C2H5 (VII), n-C3H7 (VIII), (CH3)2CHCH2 (IX).
The chlorine atom was substituted with acetoxy
group by treatment with sodium acetate in a mixture
of acetic acid and acetic anhydride boiling in the
range 125 130 C. Hydrolysis of acetates X XIII with
aqueous sodium hydroxide yielded the corresponding
1070-3632/05/7505-0774 2005 Pleiades Publishing, Inc.

SYNTHESIS OF 2-FUNCTIONALIZED 4-(DIETHOXYPHOSPHORYLMETHYL)-...
775
CH3COOCH2
HOCH2
R
CH3COONa
NaOH
IV VI
COOH
R
COOCH3
O
O
X XII
ClCH2
ClCH2
NH4OH
SOCl2
SOCl2
VII IX
R
CONH2
Na2CO3
R
COCl
XIII XV
R = C2H5 (X, XIII, XVI), n-C3H7 (XI, XIV, XVII), (CH3)2CHCH2 (XII, XV, XVIII).
O
O
XVI XVIII
hydroxy acids which were isolated as syrups. These
diisobutyronitrile as initiator. The reaction completion
compounds without special purification were brought was judged from the absence of crystals of N-bromo-
into the reaction with 4 equiv of thionyl chloride in
benzene. After refluxing for several hours and distilla-
tion in a vacuum, acid chlorides XIII XV were
obtained. These compounds were treated with
ammonia at 0 10 C to obtain the corresponding
amides XVI XVIII. The chloromethyl group does
not react under these conditions. The dehydration of
amides to nitriles was carried out with thionyl chlo-
ride in toluene. Intermediate imidoyl chlorides under
these conditions are dehydrochlorinated very slowly;
therefore, after several hours of heating, the reaction
mixture was treated with an excess of aqueous sodium
carbonate. The previously developed procedure of de-
hydrochlorination of amides with phosphorus penta-
chloride [2] appeared to be inefficient.
succinimide on the bottom of the reaction vessel. The
reaction time was about 1.5 h.
(C2H5O)2OPCH2
NBS
XIX XXIV
RCH
Br
X
O
XXV XXX
R = CH3, X = COOC2H5 (XXV), CN (XXVI); R = C2H5,
X = COOCH3 (XXVII), CN (XXVIII); R = (CH3)2CH,
X = COOCH3 (XXIX), CN (XXX).
Bromo derivatives XXV XXX are viscous oils
with the color from yellow to orange. They cannot be
distilled in a vacuum and gradually polymerize when
stored as crude products, but solutions of these com-
pounds in CCl4 and aromatic hydrocarbons are stable.
In this study, we tried to involve these bromides in
further transformations immediately after isolation.
4-Chloromethylfurans IV IX were phosphorylated
by the Arbuzov reaction with triethyl phosphite at
150 190 C in the course of 2 2.5 h.
(C2H5O)2OPCH2
1
The H NMR spectra of these compounds show
P(OC2H5)3
IV IX
that the bromination occurs at the -position of the
alkyl radical and does not involve the methylene
group at phosphorus. The signal of the corresponding
proton lies in the range 4.8 5.2 ppm, and in the
series Et Pr i-Bu it regularly shifts upfield. No
remote coupling between the phosphorus atom and
the -proton in the side chain was observed in any
case.
R
X
O
XIX XXIV
R = C2H5, X = COOCH3 (XIX), CN (XX); R = n-C3H7,
X = COOCH3 (XI), CN (XXII); R = (CH3)2CHCH2, X =
COOCH3 (XXIII), CN (XXIV).
The reaction yields the corresponding phosphonates.
The products were isolated by vacuum distillation. In
the case of ethyl- and propylfurans, the yields of
phosphonates varied in the range 73 79%, but in the
case of isobutyl derivatives they decreased to 59%.
The decreased yield of phosphonates XXIII XXIV
may be due to mechanical losses associated with the
high viscosity of these products.
Bromo phosphonates XXV XXX were brought
into the reaction with secondary amines (diethylamine,
piperidine, morpholine). The reactions were carried
out in benzene or toluene at 80 90 C for 5 6 h, and
the amination products were extracted with dilute HCl.
The aqueous extracts were alkalized, and amino phos-
phonates were extracted with ether. The solutions
were dried, and the solvent was removed. The prod-
ucts are oils decomposing when heated in a vacuum
Phosphonates XIX XXIV were brominated with
N-bromosuccinimide (NBS) in carbon tetrachloride below their boiling points. Unfortunately, we failed
at the equimolar reactant ratio in the presence of azo- to obtain their crystalline salts, and therefore the
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 5 2005

776
PEVZNER
amino phosphonates were characterized only spec-
troscopically.
Bromide XXV was brought into the reactions with
piperidine and morpholine.
XXV
O
NH
NH
(C2H5O)2OPCH2
(C2H5O)2OPCH2
CH3 CH
N
CH3 CH
N
COOC2H5
COOC2H5
O
O
O
XXXI
XXXII
Amino phosphonates XXXI and XXXII are yellow- XXXI) and at 6.96 and 7.16 ppm (phosphonate
brown oils. Their 1H NMR spectra contained the
XXXII). These data show that the compounds exist
as mixtures of conformers.
signals of the CH N fragment at the furan ring at
3.84 and 3.75 ppm, respectively. The methylene group
at phosphorus in both cases gave two doublets with
the constant JHP 20 Hz (3.02 and 3.08 ppm for XXXI,
and 2.88 and 2.91 ppm for XXXII).
In the solution remaining after the extraction of
amines, we detected no dehydrobromination products.
Elimination of hydrogen bromide from the bromo
phosphonates was not observed even upon refluxing
with triethylamine in toluene. Bromide XXVII reacts
with piperidine and morpholine to form the corre-
sponding phosphonates XXXIII and XXXIV.
The furan ring proton in both compounds also gave
two signals at 7.01 and 7.16 ppm (phosphonate
XXVII
O
NH
NH
(C2H5O)2OPCH2
(C2H5O)2OPCH2
CH3CH2CH
N
COOCH3
CH3CH2CH
N
COOCH3
O
O
O
XXXIII
XXXIV
In these compounds, the methylene groups at
phosphorus give signals at 2.89 and 2.93 ppm, and
the signals of the CH N fragment at the furan ring
are located at 3.40 and 3.39 ppm, respectively. No
spectroscopically distinguishable conformers of these
compounds were revealed. The product of dehydro-
bromination of the side chain was not detected either.
Isobutyl derivative XXIX was brought into the
reactions with piperidine and triethylamine. In the first
case, amino phosphonate XXXV was obtained. The
1
signal of the CH2P fragment in the H NMR spectrum
of this product is observed at 2.85 ppm, and that of
the CH N fragment, at 3.05 ppm. The proton of the
furan ring gives two signals with chemical shifts of
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 5 2005

SYNTHESIS OF 2-FUNCTIONALIZED 4-(DIETHOXYPHOSPHORYLMETHYL)-...
777
7.17 and 7.24 ppm, which suggests the presence of
two conformers.
diethylamine were carried out similarly to those in-
volving the above-mentioned esters.
Phosphorylated amino nitriles XXXVIII XLI are
viscous oils with the color varying from dark yellow
to light brown. They cannot be distilled in a vacuum
and do not form well crystallizing hydrochlorides.
In the 1H NMR spectrum of phosphonate
XXXVIII, the signal of the CH2P group is observed
at 2.96 ppm (d, JHP 20 Hz), and the signal of the
CH N proton, at 3.60 ppm. Phosphonate XXXIX
gives two signals of the CH2P group at 2.98 and
(C2H5O)2OPCH2
H3C
H3C
NH
XXIX
CH CH
COOCH3
O
N
XXXV
Dehydrobromination of phosphonate XXIX was
carried out by refluxing with an excess of triethyl-
amine in toluene. As our goal was to detect the alkene, 3.14 ppm, and the signal of the CH N fragment
only the toluene solution remaining after the extrac-
tion of amines with hydrochloric acid was analyzed.
Evaporation of this solution under reduced pressure
and distillation of the residue in a vacuum gave a
fraction with bp 178 C (2 mm Hg), identified as al-
kene XXXVI with a small impurity of unchanged
phosphonate XXIII from the bromination step. The
yield of alkene XXXVI was low. The signals of sub-
evidently overlaps with the multiplet of the CH2OP
group. Therefore, we failed to identify it.
Phosphonate XL is characterized by the signal of
the CH2P group at 2.94 ppm and the signal of the
CH N fragment at 3.44 ppm.
Phosphonate XLI exists as a mixture of two con-
formers. The isobutyl group in this compound gives
two doublets with chemical shifts of 0.59 and 0.95
ppm, and the signals of the CH2P group are observed
at 2.87 and 2.89 ppm. The CH N fragment gives a
signal at 3.09 ppm.
1
stituents at the double bond in the H NMR spectrum
well agree with the data for previously obtained al-
kene XXXVII {chemical shifts ( , ppm) for XXXVI:
1.94 s, 2.04 s (CH3 at the double bond); 5.91 s
(H C=); for XXXVII [3]: 1.92 s, 1.95 s, 2.02 s,
2.07 s (CH3 at the double bond, two conformers);
5.85 s, 5.94 s (HC=, two conformers)}.
Comparison of the spectral data for esters XXXI
XXXV and nitriles XXXVIII XLI shows that the
signal of the PCH2 group in these compounds is
located approximately in the same place irrespective
of the structure of the alkyl substituent, whereas the
signal of the CH N fragment is regularly shifted up-
field with an increase in the size of the alkyl substit-
uent in the furan ring.
(C2H5O)2OPCH2
N(C2H5)3
H3C
XXIX
C=C
COOCH3
H3C
O
H
XXXVI
(C2H5O)2OPCH2
H3C
COOC2H5
CH3
No products of dehydrobromination of nitriles
XXVI, XXVIII, and XXX were detected.
N(C2H5)3
XXIX
C=C
H3C
O
Thus, introduction of an additional weakly elec-
tron-withdrawing substituent such as dialkoxyphos-
phorylmethyl group in the furan ring significantly
complicates dehydrobromination under the action of
bases. The alkene was detected only in trace amounts
and only in the case of the compound with the most
favorable structure. In all the other cases, alkylation of
the amines took place exclusively.
H
XXXVII
The reaction of bromo phosphonate XXIX with
lithium carbonate leads to decomposition of the
molecule.
The reactions of brominated nitriles XXVI,
XXVIII, and XXX with morpholine, piperidine, and
Our results confirm the previously made assump-
tion that elimination of hydrogen bromide in (1-bro-
moalkyl)furans proceeds through the intermediate
carbenium ion XLII.
(C2H5O)2OPCH2
HNR2
XXVI, XXVIII, XXX
R CH
NR2
CN
O
+
X
XXXVIII XLI
CH R
O
R = CH3, R2 = (CH2)2O(CH2)2 (XXXVIII); R = CH3, R =
C2H5 (XXXIX); R = C2H5, R2 = (CH2)5 (XL); R =
(CH3)2CH, R2 = (CH2)5 (XLI).
XLII
An increase in the electron density in the furan ring
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778
PEVZNER
and the accumulation of methyl groups with branch-
ing of the side-chain radical favor its stabilization [1].
Methyl 4-acetoxymethyl-5-ethylfuran-2-car-
boxylate X. Yield 82%, bp 125 C (1 mm Hg). H
NMR spectrum, , ppm: 1.20 t (CH3-ethyl, JHH 7 Hz),
1.90 s (CH3COO), 2.67 q (CH2-ethyl, JHH 7 Hz),
3.72 s (CH3O), 4.75 s (CH2O-furan), 6.95 s (H3-furan).
1
EXPERIMENTAL
1
The H NMR spectra were measured on a Tesla
Methyl 4-acetoxymethyl-5-propylfuran-2-car-
BS-497C spectrometer (100 MHz) in CDCl3 against
internal HMDS. The chemical shifts of phosphorus
were calculated from the INDOR spectra.
1
boxylate XI. Yield 84%, bp 136 C (1 mm Hg). H
NMR spectrum, , ppm: 0.85 t (CH3-propyl, JHH
7
Hz), 1.65 m (CH2-propyl, JHH 7 Hz), 1.95 s
(CH3COO), 2.60 t (CH2-furan, JHH 7 Hz), 3.69 s
(CH3OOC), 4.75 s (CH2O-furan), 6.98 s (H3-furan).
Chloromethylation of 5-alkylfuran-2-carboxy-
lates (general procedure). To a solution of 0.1 mol of
ester I III in 100 ml of dichloroethane, 0.15 mol of
paraform and 0.025 mol of freshly ground zinc chlo-
ride were added. After that, a vigorous flow of hydro-
gen chloride was passed through the reaction mixture
until the heat evolution ceased. The reaction tempera-
ture was maintained within the range 30 33 C. After
the completion of heat evolution and homogenization
of the mixture, it was kept for 30 min and then treated
with water. The aqueous layer was extracted with
20 ml of dichloroethane, and the combined organic
phases were washed with water and dried over CaCl2.
Methyl 4-acetoxymethyl-5-isobutylfuran-2-
carboxylate XII. Yield 83%, bp 135 C (0.7 mm Hg).
1H NMR spectrum, , ppm: 0.86 d (CH3-isobutyl, JHH
7 Hz), 1.91 m (CH3-acetoxy + CH-isobutyl, over-
lapped), 2.46 d (CH2-isobutyl, JHH 7 Hz), 3.73 s
(CH3OOC), 4.76 s (CH2O-furan), 6.93 s (H3-furan).
4-Chloromethyl-5-ethyl-2-cyanofuran VII.
a. To a solution of 12.5 g of sodium hydroxide in
60 ml of water, 17.6 g of acetate X was added, and
the mixture was refluxed for 6 h. The resulting
The solvent was removed at reduced pressure, and the homogeneous mixture was cooled to 10 C and acidi-
residue was distilled in a vacuum.
fied with HCl to pH 1. The emulsion thus formed was
extracted with ether, and the ether extract was dried
over calcium chloride. After removing the solvent and
keeping the residue for 1 h in a vacuum (1 mm) at
room temperature, 16.3 g of crude 4-hydroxymethyl-
5-ethylfuran-2-carboxylic acid was obtained as a
brown syrup.
Methyl 4-chloromethyl-5-ethylfuran-2-carboxy-
late IV. Yield 74%, bp 103 C (1 mm Hg). H NMR
spectrum, , ppm: 1.20 t (CH3-ethyl, JHH 7 Hz),
2.65 q (CH2-ethyl, JHH 7 Hz), 3.72 s (CH3O), 4.32 s
(CH2Cl), 6.95 s (H3-furan).
1
Methyl 4-chloromethyl-5-propylfuran-2-car-
boxylate V. Yield 67%, bp 114 C (1 mm Hg). H
NMR spectrum, , ppm: 0.92 t (CH3-propyl, JHH
7 Hz), 1.69 m (CH2-propyl, JHH 7 Hz), 2.62 s (CH2-
furan, JHH 7 Hz), 3.73 s (CH3O), 4.29 s (CH2Cl),
6.94 s (H3-furan).
b. The product from the previous step was emulsi-
fied under stirring at elevated temperature in 150 ml
of benzene, and 22 ml of thionyl chloride was added
dropwise. The mixture was refluxed with stirring for
4 h, the solvent was distilled off at reduced pressure,
and the residue was distilled in a vacuum to give
10.5 g of acid chloride XIII, bp 100 101 C (1 mm
Hg).
1
Methyl 4-chloromethyl-5-isobutylfuran-2-car-
boxylate VI. Yield 78%, bp 127 128 C (1 mm Hg).
1H NMR spectrum, , ppm: 0.88 d (CH3-isobutyl, JHH
7 Hz), 2.02 m (CH-isobutyl, JHH 7 Hz); 2.48 d
(CH2-isobutyl, JHH 7 Hz), 3.73 s (CH3O), 4.25 s
(CH2Cl), 7.00 s (H3-furan).
c. Acid chloride XIII, 10.5 g, was added with
vigorous stirring to 40 ml of 25% ammonia cooled to
0 C. The mixture was stirred for 1 h, and the precipi-
tate of chloromethyl carboxamide XVI was filtered
off. Yield 8.4 g, mp 132 133 C.
Reaction of chloromethylfurans IV VI with so-
dium acetate (general procedure). The chloromethyl
d. Amide XVI, 7.2 g, was suspended in 50 ml of
derivative, 0.1 mol, was dissolved in a mixture of toluene, and 4.2 ml of thionyl chloride was added in
acetic acid and acetic anhydride boiling in the range one portion. The mixture was refluxed with stirring
125 132 C, and 0.2 mol of finely pulverized anhy-
drous sodium acetate was added. The mixture was
refluxed with stirring for 15 h and then poured into
water and extracted with methylene chloride. The
extract was washed with water and dried over CaCl2,
the solvent was removed at reduced pressure, and the
residue was distilled in a vacuum.
for 8 h and cooled to room temperature, and a solution
of 5 g of sodium carbonate in 50 ml of water was
added dropwise. The resulting mixture was stirred for
90 min, washed with water, and dried over CaCl2.
The solvent was removed at reduced pressure, and the
residue was distilled in a vacuum to give 2.9 g of
1
nitrile VII, bp 92 C (1 mm Hg). H NMR spectrum,
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SYNTHESIS OF 2-FUNCTIONALIZED 4-(DIETHOXYPHOSPHORYLMETHYL)-...
779
, ppm: 1.22 t (CH3-ethyl, JHH 7 Hz), 2.70 q (CH2-
ethyl, JHH 7 Hz), 4.35 s (ClCH2), 7.10 s (H3-furan).
extract was dried over CaCl2, the solvent was distilled
off, and the residue was dried in a vacuum (1 mm)
for 1 h at 20 25 C. The crude hydroxy acid, 3.7 g,
was obtained as a syrup.
4-Chloromethyl-5-propyl-2-cyanofuran VIII.
a. To a solution of 7 g of NaOH in 50 ml of water,
17.9 g of acetate XI was added in one portion, and
the mixture was refluxed with stirring for 6 h. After
that, the reaction mixture was cooled to room tem-
perature and acidified with HCl to pH 1. The oil that
separated out was extracted with ether; the extract was
dried over CaCl2, and the solvent was removed. The
residue was kept in a vacuum (1 mm) for 1 h at 20
25 C to give 14.5 g of crude hydroxy acid as a syrup.
b. The hydroxy acid from the previous step was
suspended at elevated temperature in 50 ml of ben-
zene, and 7 ml of thionyl chloride was added drop-
wise. The resulting mixture was refluxed for 4 h, the
solvent was distilled off, and the residue was distilled
in a vacuum to give 3.4 g of acid chloride XV, bp
119 C (1 mm Hg).
c. Ammonia, 25 ml of 25% solution, was cooled to
0 C, and 3.4 g of acid chloride XV was added drop-
wise with vigorous stirring. A colorless precipitate
started to form within several minutes. The mixture
was stirred for 2 h and diluted with water; the precip-
itate thus formed was filtered off and dried. Amide
XVIII, 2.9 g, was obtained; mp 143 144 C.
b. The syrup from the previous step was emulsified
by stirring at elevated temperature in 150 ml of
benzene, and 17 ml of thionyl chloride was added
dropwise. The mixture was refluxed with stirring for
4 h, the solvent was removed at reduced pressure, and
the residue was distilled in a vacuum to give 12.5 g
1
of acid chloride XIV, bp 103 105 C (1 mm Hg). H
d. A mixture of 2.9 g of amide XVIII, 2 ml of
thionyl chloride, and 20 ml of toluene was refluxed
with stirring for 5 h. The resulting solution was
cooled to room temperature, and a solution of 5 g of
sodium carbonate in 25 ml of water was added. The
mixture was stirred for 1 h at 50 C, the aqueous layer
was removed, and the toluene layer was washed with
water, dried over CaCl2, and distilled to give 0.6 g of
NMR spectrum, , ppm: 0.94 t (CH3-propyl, JHH
7 Hz), 1.73 m (CH2-propyl, JHH 7 Hz), 2.68 t (CH2-
furan, JHH 7 Hz), 4.36 s (ClCH2), 7.36 s (H3-furan).
c. Ammonia, 50 ml of 25% solution, was cooled to
0 C, and 12.5 g of acid chloride XIV was added
dropwise with vigorous stirring and cooling. A white
precipitate formed almost immediately. The mixture
was stirred for 15 min, and the crystals of amide XVI
were filtered off, washed with a small amount of
1
nitrile IX, bp 109 C (1 mm Hg). H NMR spectrum,
, ppm: 0.89 d (CH3-isobutyl, JHH 7 Hz), 1.97 m
(CH-isobutyl), 2.52 d (CH2-isobutyl, JHH 7 Hz),
4.32 s (ClCH2), 6.94 s (H3-furan).
1
water, and dried. Yield 10.8 g, mp 123 124 C. H
NMR spectrum (DMSO-d6), , ppm: 0.88 t (CH3-
propyl, JHH 7 Hz), 1.64 m (CH2-propyl, JHH 7 Hz),
2.66 t (CH2-furan, JHH 7 Hz), 4.64 s (CH2Cl), 7.08 s
(H3-furan), 7.30 br.s and 7.67 br.s (NH2).
Phosphorylation of halomethylfurans IV IX
with triethyl phosphite (general procedure). A mix-
ture of 0.05 mol of halomethylfuran IV IX and
0.075 mol of triethyl phosphite was heated with stir-
ring. At 150 155 C, it came to boil, and in the course
of 2 2.5 h its boiling point gradually rose to 185
190 C. After the release of volatiles was complete, the
mixture was cooled and distilled in a vacuum.
d. Amide XVII, 3.5 g, was suspended in 15 ml of
benzene, 2.5 ml of thionyl chloride were added in one
portion, and the mixture was refluxed with stirring
for 6 h. The resulting solution was distilled in a
vacuum, and 2.6 g of the fraction with bp 110 140 C
(1 mm Hg) was collected. This product was dissolved
in benzene, and 4 ml of triethylamine was added. The
mixture was stirred for 30 min, washed with two por-
tions of water, dried over CaCl2, and distilled to give
Methyl 4-(diethoxyphosphorylmethyl)-5-ethyl-
furan-2-carboxylate XIX. Yield 73%, bp 154 155 C
1
(1 mm Hg). H NMR spectrum, , ppm: 1.17 t (CH3-
ethyl, JHH 7 Hz), 2.60 q (CH2-furan from ethyl, JHH
7
1
Hz), 2.71 d (CH2P, JHP 21 Hz), 3.70 s (CH3COO),
3.92 s (CH2OP, JHH 7, JHP 11 Hz), 6.95 s (H3-furan).
1.9 g of nitrile VIII, bp 96 C (1 mm Hg). H NMR
spectrum, , ppm: 0.92 t (CH3-propyl, JHH 7 Hz),
1.67 m (CH2-propyl, JHH 7 Hz), 2.65 t (CH2-furan,
JHH 7 Hz), 4.35 s (ClCH2), 7.00 s (H3-furan).
22.7 ppm.
P
4-(Diethoxyphosphorylmethyl)-5-ethyl-2-cyano-
1
furan XX. Yield 79%, bp 152 C (1 mm Hg). H
4-Chloromethyl-5-isobutyl-2-cyanofuran IX.
a. To a solution of 3 g of NaOH in 30 ml of water,
4.7 g of acetate XII was added, and the mixture was
refluxed for 4 h. After cooling to room temperature,
the mixture was acidified with HCl to pH 1, and the
oil that separated out was extracted with ether. The
NMR spectrum , ppm: 1.22 t (CH3-ethyl, JHH 7 Hz),
2.64 q (CH2-furan, JHH 7 Hz), 2.74 d (CH2P, JHP
21 Hz), 3.95 m (CH2OP, JHH 7, JHP 11 Hz), 7.00 s
(H3-furan).
22.1 ppm.
P
Methyl 4-(diethoxyphosphorylmethyl)-5-pro-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 5 2005

780
PEVZNER
pylfuran-2-carboxylate XXI. Yield 70%, bp 168 C
(1 mm Hg). H NMR spectrum, , ppm: 0.88 t (CH3-
propyl, JHH 7 Hz), 1.18 t (CH3-ethyl, JHH 7 Hz), 1.65
m (CH2-propyl, JHH 7 Hz), 2.53 t (CH2-furan, JHH
7 Hz), 2.67 d (CH2P, JHP 20 Hz), 3.69 s (CH3OOC),
3.91 m (CH2OP, JHH 7, JHP 11 Hz), 6.93 s (H3-furan).
1.95 d (CH3 CHBr, JHH 8 Hz), 2.80 d (CH2P, JHP
1 Hz), 3.94 m (CH2OP, JHH 7, JHP 11 Hz), 5.26 q
1
(CHBr, JHH 8 Hz), 6.95 s (H3-furan). P 21.0 ppm.
Methyl 4-(diethoxyphosphorylmethyl)-5-(1-
bromopropyl)furan-2-carboxylate XXVII. Dark
1
orange oil. H NMR spectrum, , ppm: 0.94 t (CH3-
22.7 ppm.
P
propyl, JHH 7 Hz), 1.17 t (CH3-ethyl, JHH 7 Hz),
2.40 m (CH2-propyl, JHH 7 Hz), 2.77 d (CH2P, JHP
20 Hz), 3.73 s (CH3OOC), 3.80 m (CH2OP, JHH 7,
JHP 11 Hz), 5.00 t (CHBr, JHH 7 Hz), 6.91 d (H3-
4-(Diethoxyphosphorylmethyl)-5-propyl-2-
cyanofuran XXII. Yield 74%, bp 167 168 C (1 mm
1
Hg). H NMR spectrum, , ppm: 0.84 t (CH3-propyl,
JHH 7 Hz), 1.11 t (CH3-ethyl, JHH 7 Hz), 1.56 m
(CH2-propyl, JHH 7 Hz), 2.53 t (CH2-furan, JHH 22
Hz), 3.90 m (CH2OP, JHH 7, JHP 11 Hz), 6.94 s (H3-
furan, JHP 2 Hz).
21.5 ppm.
P
4-(Diethoxyphosphorylmethyl)-5-(1-bromopro-
pyl)-2-cyanofuran XXVIII. Orange oil. 1H NMR
spectrum, , ppm: 0.93 t (CH3-propyl, JHH 7 Hz),
1.16 m (CH3-ethyl, JHH 7 Hz), 2.16 m (CH2-propyl,
JHH 7 Hz), 2.80 d (CH2P, JHP 20 Hz), 3.93 m (CH2OP,
JHH 7, JHP 11 Hz), 4.94 t (CHBr, JHH 7 Hz), 6.93 s
furan).
20.7 ppm.
P
Methyl 4-(diethoxyphosphorylmetyl)-5-isobu-
tylfuran-2-carboxylate XXIII. Yield 59%, bp 166
1
168 C (1 mm Hg). H NMR spectrum, , ppm: 0.87 d
(CH3-isobutyl, JHH 7 Hz), 1.38 t (CH3-ethyl, JHH
7 Hz), 2.03 m (CH-isobutyl, JHH 7 Hz), 2.45 d (CH2-
isobutyl, JHH 7 Hz), 2.70 d (CH2P, JHP 21 Hz), 3.71 s
(CH3OOC), 3.92 m (CH2OP, JHH 7, JHP 11 Hz),
(H3-furan).
20.7 ppm.
P
Methyl 4-(diethoxyphosphorylmethyl)-5-(1-
bromoisobutyl)furan-2-carboxylate XXIX. Yellow
1
oil. H NMR spectrum, , ppm: 0.87 d (CH3-isobutyl,
6.96 s (H3-furan).
22.3 ppm.
P
JHH 7 Hz), 1.40 m (CH3-ethyl), 2.50 m (CH-isobutyl),
2.67 d (CH2P, JHP 21 Hz), 2.79 d (CH2P, JHP 21 Hz),
3.75 s (CH3OOC), 3.94 m (CH2OP, JHH 7, JHP 11 Hz),
4-(Diethoxyphosphorylmethyl)-5-isobutyl-2-
cyanofuran XXIV. Yield 59%, bp 169 C (1 mm Hg).
1H NMR spectrum, , ppm: 0.83 d (CH3-isobutyl, JHH
7 Hz), 1.27 t (CH3-ethyl, JHH 7 Hz), 1.92 m (CH-
isobutyl, JHH 7 Hz), 2.43 d (CH2-isobutyl, JHH 7 Hz),
2.69 d (CH2P, JHP 21 Hz), 3.95 m (CH2OP, JHH 7,
4.84 d (CHBr, JHH 7 Hz), 6.95 s (H3-furan).
P
21.1 ppm.
4-(Diethoxyphosphorylmethyl)-5-(1-bromoiso-
butyl)-2-cyanofuran XXX. Yellow oil. 1H NMR
spectrum, , ppm: 0.88 d (CH3-isobutyl, JHH 7 Hz),
1.20 t (CH3-ethyl, JHH 7 Hz), 2.50 m (CH-isobutyl),
2.78 d (CH2P, JHP 22 Hz), 3.95 m (CH2OP, JHH 7,
JHP 11 Hz), 4.78 d (CHBr, JHH 9 Hz), 6.98 s (H3-
JHP 11 Hz), 6.99 s (H3-furan).
22.0 ppm.
P
Bromination of phosphonates XIX XXIV with
N-bromosuccinimide (general procedure). To a so-
lution of 0.03 mol of appropriate phosphonate in
50 ml of carbon tetrachloride, 0.031 mol of N-bromo-
succinimide and 0.1 g of azodiisobutyronitrile were
added. The mixture was refluxed with stirring until
the precipitate of N-bromosuccinimide disappeared
(1.5 2 h). The resulting mixture was left overnight at
room temperature, succinimide was filtered off, the
solvent was removed at reduced pressure, and the
residue was kept in a vacuum (1 mm) for 1 h in at
room temperature. The products were not subjected
to any additional purification.
furan).
Reaction of bromophosphonates with secondary
amines (general procedure). mixture of
20.7 ppm.
P
A
0.01 mol of bromo phosphonate, 0.25 mol of second-
ary amine, and 30 ml of toluene were heated with
stirring at 80 90 C for 5 6 h and left overnight. On
the next day, the mixture was washed witih three or
four portions of dilute HCl, and the combined
aqueous extracts were alkalized with stirring to pH
9 9.5 and immediately extracted with ether. The ether
extracts were kept until the emulsified aqueous layer
settled and were then carefully decanted. The resulting
solutions were dried over CaCl2, the solvent was re-
moved, and the residue was kept in a vacuum (1 mm)
at room temperature for 1 h. The product yields can
be estimated at 60 80%. More accurate estimation is
not convincing because the purity of the starting
bromides is unknown.
Ethyl 4-(diethoxyphosphorylmethyl)-5-(1-bro-
1
moethyl)furan-2-carboxylate XXV. Orange oil. H
NMR spectrum, , ppm: 1.14 m (CH3-ethyl), 1.80 d
(CH3 CHBr, JHH 7 Hz), 2.71 d (CH2P, JHP 21 Hz),
3.84 m (CH2OP, JHH 7, JHP 13 Hz), 4.12 q (CH2OOC,
JHH 7 Hz), 5.22 q (CHBr, JHH 7 Hz), 6.81 s (H3-
furan).
21.4 ppm.
P
4-(Diethoxyphosphorylmethyl)-5-(1-bromo-
ethyl)-2-cyanofuran XXVI. Orange oil. 1H NMR
spectrum, , ppm: 1.20 q (CH3-ethyl, JHH 7 Hz),
Ethyl 4-(diethoxyphosphorylmethyl)-5-[1-(N-
piperidyl)ethyl]furan-2-carboxylate XXXI. Yellow-
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SYNTHESIS OF 2-FUNCTIONALIZED 4-(DIETHOXYPHOSPHORYLMETHYL)-...
781
1
brown oil. H NMR spectrum, , ppm: 1.10 1.35 m
4-(Diethoxyphosphorylmethyl)-5-[1-(N-diethyl-
amino)ethyl]-2-cyanofuran XXXIX. Brown oil. H
1
(CH3 + CH2 of the ring), 2.37 m (CH2N-piperidyl),
3.02 d + 3.08 d (CH2P, JHP 20 Hz), 3.84 q (CH2N,
JHH 7 Hz), 4.00 m (CH2OP, JHH 7, JHP 11 Hz), 4.17 q
NMR spectrum, , ppm: 0.75 m (CH3-ethyl, JHH
7
Hz), 1.24 m (CH2-ethyl, JHH 7 Hz), 2.43 m (CH2N,
JHH 7 Hz), 2.98 d (CH2P, JHP 20 Hz), 3.14 d (CH2P,
JHP 20 Hz), 4.00 m (CH N, CH2OP, JHH 7, JHP
(CH2OOC, JHH 7 Hz), 7.01 s + 7.16 s (H3-furan).
P
23.0 ppm.
11 Hz); 7.05 s (H3-furan).
22.9 ppm.
P
Ethyl 4-(diethoxyphosphorylmethyl)-5-[1-(N-
morpholyl)ethyl]furan-2-carboxylate XXXII.
Yellow-brown oil. H NMR spectrum, , ppm: 1.10
4-(Diethoxyphosphorylmethyl)-5-[1-(N-piperi-
dyl)propyl]-2-cyanofuran XL. Light brown oil. H
1
1
1.38 m (CH3), 2.35 m (CH2-morpholine), 2.88 d +
2.91 d (CH2P, JHP 20 Hz), 3.50 m (CH2O-morpho-
line), 3.75 q (CHN, JHH 7 Hz), 3.93 m + 3.96 m
(CH2OP, JHH 7, JHP 11 Hz), 4.16 q (CH2OOC, JHH
NMR spectrum, , ppm: 0.72 t (CH3-propyl, JHH
7
Hz), 1.19 t (CH3-ethyl, JHH 7 Hz), 1.42 m (CH2-pi-
peridyl), 1.77 m (CH2-propyl, JHH 7 Hz), 2.30 m
(N CH2-piperidyl), 2.94 d (CH2P, JHP 20 Hz), 3.44 t
(CHN, JHH 7 Hz), 4.02 m (CH2OP, JHH 7, JHP 11 Hz),
7 Hz), 6.96 s + 7.17 s (H3-furan).
22.7 ppm.
P
7.15 s (H3-furan).
22.4 ppm.
Methyl 4-(diethoxyphosphorylmethyl)-5-(1-N-
piperidyl)propyl]furan-2-carboxylate XXXIII.
Brown syrup. 1H NMR spectrum, , ppm: 0.75 t
P
4-(Diethoxyphosphorylmethyl)-5-[1-(N-pipe-
ridyl)isobutyl]-2-cyanofuran XLI. Light brown oil.
1H NMR spectrum, , ppm: 0.59 d (CH3-isobutyl, JHH
7 Hz), 0.95 d (CH3-isobutyl, JHH 7 Hz), 1.23 t (CH3-
ethyl, JHH 7 Hz), 1.49 m (CH2-piperidyl), 2.31 m
(CH2N-piperidyl + CH-isobutyl), 2.87 d + 2.89 d
(CH2P, JHP 22 Hz), 3.09 d (CHN, JHH 7 Hz), 4.02 m
(CH3-propyl, JHH 7 Hz), 1.18 t (CH3-ethyl, JHH 7 Hz),
1.21 m (CH2 of the ring), 1.84 m (CH2-propyl, JHH
7
Hz), 2.33 m (CH2N-piperidyl), 2.89 d (CH2P, JHP 21
Hz), 3.40 t (NCH-furan, JHH 7 Hz), 3.73 s (CH3OOC),
4.02 m (CH2OP, JHH 7, JHP 11 Hz), 7.17 s (H3-furan).
23.2 ppm.
P
(CH2OP, JHH 7, JHP 11 Hz), 7.14 s (H-furan).
21.0 ppm.
P
Methyl 4-(diethoxyphosphorylmethyl)-5-[1-(N-
morpholyl)propyl]furan-2-carboxylate XXXIV.
Brown syrup. 1H NMR spectrum, , ppm: 0.86 t
(CH3-propyl, JHH 7 Hz), 1.20 t (CH3-ethyl, JHH 7 Hz),
1.86 m (CH2-propyl, JHH 7 Hz), 2.35 m (CH2N-
morpholyl), 2.93 d (CH2P, JHP 20 Hz), 3.39 t (NCH-
furan, JHH 7 Hz), 3.50 m (CH2O-morpholine), 3.75 s
(CH2OOC), 4.02 m (CH2OP, JHH 7, JHP 11 Hz),
Dehydrobromination of phosphonate XXIX
with triethylamine. A solution of 2.6 g of phospho-
nate XXIX and 3 ml of triethylamine in 25 ml of
toluene was refluxed for 8 h. The resulting mixture
was washed with dilute HCl and water, dried over
calcium chloride, and distilled in a vacuum to give the
product with bp 178 C (2 mm Hg) as a very viscous
7.16 s (H3-furan).
1
Methyl 4-(diethoxyphosphorylmethyl)-5-[1-(N-
dark yellow oil. Yield 0.5 g. H NMR spectrum, ,
piperidyl)isobutyl]furan-2-carboxylate XXXV.
ppm: 1.16 t (CH3-ethyl, JHH 7 Hz), 1.94 s (CH3-trans),
2.04 (CH3-cis), 2.65 d (CH2P, JHP 21 Hz), 3.70 s
(CH3OOC), 3.90 m (CH2OP, JHH 7, JHP 11 Hz), 5.91
br.s (CH=), 6.94 s (H3-furan).
1
Light brown oil. H NMR spectrum, , ppm: 0.95 d
(CH3-isobutyl, JHH 7 Hz), 1.19 t (CH3-ethyl, JHH
7 Hz), 1.46 m (CH2-piperidyl), 2.30 m (CH2N + CH-
isobutyl), 2.85 d (CH2P, JHP 20 Hz), 3.05 d (CHN,
JHH 8 Hz), 3.76 s (CH3OOC), 4.00 m (CH2OP, JHH 7,
REFERENCES
JHP 11 Hz), 7.17 s + 7.24 s (H3-furan).
22.6 ppm.
P
4-(Diethoxyphosphorylmethyl)-5-[1-(N-mor-
pholyl)ethyl]-2-cyanofuran XXXVIII. Yellow oil.
1. Pevzner, L.M., Zh. Obshch. Khim., 2005, vol. 75, no. 2,
p. 258.
1H NMR spectrum, , ppm: 1.25 m (CH3-ethyl, JHH
7 Hz), 2.39 m (CH2N-morpholyl), 2.96 d (CH2P, JHH
21 Hz), 3.60 m (CH2O-morpholine + N CH), 4.00 m
2. Pevzner, L.M., Zh. Obshch. Khim., 2003, vol. 73,
no. 11, p. 1812.
(CH2OP, JHH 7, JHP 11 Hz), 7.04 s (H3-furan).
3. Pevzner, L.M., Zh. Obshch. Khim., 2003, vol. 73, no. 2,
P
22.1 ppm.
p. 281.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 5 2005