Synthesis and selected reactions of ethyl 5-(1-chloroethyl)-2-methylfuran- 3-carboxylate

Article abstract of DOI:10.1134/S107036320701015X

Ethyl 2-methylfuran-3-carboxylate is smoothly chloroethylated at 0°C in the 5 position of the ring. The resulting halide alkylates secondary amines but eliminates HCl with sodium diethyl phosphite under the Michaelis-Becker reaction conditions and with trimethyl phosphite under the Arbuzov reaction conditions. In the reaction with sodium diethyl phosphite, small amounts of 5-[1-(diethoxyphosphoryl)ethyl]furan-3-carboxylate and 5-ethylfuran-3- carboxylate are formed. In the Arbuzov reaction at a 1: 1.22 furan: trimethyl phosphite molar ratio, methyl 2,4-dimethyl-1-methoxy-1-oxo- 1λ⁵-1,2-dihydrophospheto[3,2-b]furan-5-carboxylate was isolated.

Full text of DOI:10.1134/S107036320701015X

ISSN 1070-3632, Russian Journal of General Chemistry, 2007, Vol. 77, No. 1, pp. 111 115.
Pleiades Publishing, Ltd., 2007.
Original Russian Text
L.M. Pevzner, 2007, published in Zhurnal Obshchei Khimii, 2007, Vol. 77, No. 1, pp. 120 124.
Synthesis and Selected Reactions
of Ethyl 5-(1-Chloroethyl)-2-methylfuran-3-carboxylate
L. M. Pevzner
Russian Research Institute of Hydrolysis of Plant Materials,
ul. Kalinina 13, St. Petersburg, 198099 Russia
Received October 25, 2006
Abstract Ethyl 2-methylfuran-3-carboxylate is smoothly chloroethylated at 0 C in the 5 position of the
ring. The resulting halide alkylates secondary amines but eliminates HCl with sodium diethyl phosphite under
the Michaelis Becker reaction conditions and with trimethyl phosphite under the Arbuzov reaction conditions.
In the reaction with sodium diethyl phosphite, small amounts of 5-[1-(diethoxyphosphoryl)ethyl]furan-3-
carboxylate and 5-ethylfuran-3-carboxylate are formed. In the Arbuzov reaction at a 1: 1.22 furan: trimethyl
phosphite molar ratio, methyl 2,4-dimethyl-1-methoxy-1-oxo-1 5-1,2-dihydrophospheto[3,2-b]furan-5-car-
boxylate was isolated.
DOI: 10.1134/S107036320701015X
Chloroethylation of furan derivatives with the
acetaldehyde hydrogen chloride zinc chloride system
was studied formerly by Midzhoyan and co-workers
[1, 2] on an example of alkyl furan-2-carboxylates.
This research was not continued, probably, because
of the limited choice of furan derivatives available at
that time. At the same time, this is one of the simple,
convenient, and cheap methods for forming an asym-
Since the chemical properties of -(1-chloroethyl)-
furan with the stabilizing -alkoxycarbonyl group are
fairly well studied [1, 3], we turned to the case when
the electronacceptor substituent occupies the posi-
tion of the ring. Ethyl 2-methylfuran-3-carboxylate
(I) was chosen as substrate. The furan I:acetalde-
hyde:zinc chloride molar ratio, like in [1], was
1:2:0.1.
The reaction was carried out in chloroform, and
saturation of the system with hydrogen chloride was
maintained by its bubbling through the reaction
mixture.
metric center in the
position of the side chain of
furan derivatives. Therefore, chemical properties of
the 1-chloroethyl fragment seem actual to study.
COOC2H5
COOC2H5
HCl
+ CH3CHO + ZnCl2
CH3
CH3CHCl
CH3
O
O
I
II
COOC2H5
CH3
CH2=CH
O
III
It was found that controlled chloroethylation pro-
ceeds at 2 to 2 C, and at 15 20 C the amount of
polymeric products sharply increases. The yield of
chloroethyl derivative II was 66%, when the reaction
was carried out in the optimal temperature range. The
product contained a small admixture of compound III.
Chloride II alkylates morpholine (80 C, 5 h,
benzene), and subsequent hydrolysis of crude amino
ester leads to amino acid IV identified as hydro-
chloride.
Attempted dehydrochlorination under the action of
111

112
PEVZNER
COOC2H5
COOC2H5
CH3
HCl
(1) NaOH
(2) HCl
CH3CH
N
CH3
CH3CH
N
O
O
HN
II +
O
O
O
IV
diazabicyclooctane in pyridine [4] and lithium carbo-
nate in DMF [5] led to decomposition of chloride II.
III
Further we turned to reactions of compound II with
phosphorus nucleophiles, such as sodium diethyl
phosphite and trimethyl phosphite.
COOC2H5
CH3
NaPO(OC2H5)2
CH3CH
II
O
(C2H5O)2P=O
The reaction with sodium diethyl phosphite was
carried out in benzene at 80 C for 12 h at a 1:1 molar
ratio and a small excess of diethyl hydrogen phosphite.
Distillation of the reaction mixture in a vacuum
(1 mm Hg) gave two fractions boiling at 85 88 and
156 C. The first fraction comprised alkene III and a
small admixture of diethyl hydrogen phosphate. The
1H NMR spectrum of the second fraction contained
two sets of signals. The first included the following
V
COOC2H5
CH3
CH3CH2
O
VI
tion was considered complete, when a constant boiling
point of the reaction mixture was achieved. Alkene
III and dimethyl hydrogen phosphite were isolated
and identified as reaction products. The yield of al-
kene III increased from 31 to 40% as the phosphite:
chloride II molar ratio was decreased from 5.09 to
3.39 and sharply decreased (to 18%) at a 1.15 reactant
molar ratio. The final boiling point of the reaction
mixture increased from 132 135 to 160 C. In all the
cases, vigorous polymer formation was observed.
signals (here and hereinafter, , P, and
are in ppm
C
and J are in Hz): a singlet at 2.454 (CH3 furan), a
doublet of doublets at 1.454 ppm (JHH 7.4, JHP 17.6),
a doublet of quartets at 3.187 (JHH 7.4, JHP 22.8),
and a singlet at 6.425. The phosphorus signal of this
compound is at
The second set of signals included a singlet at
2.498 (CH3 furan), a quartet at 2.941 (JHH 7.2),
and a singlet at 6.388 (furan H).
26.5.
P
The resulting data are listed in the table.
Hence, chloride II reacts with sodium diethyl
phosphite to give three products, alkene III, phos-
phonate V, and ethylfuran VI. The yields of these
products were evaluated as 53, 8, and 6 %, respec-
tively, and their molar ratio was 9.2:1.4:1.
When the reaction of chloride II with trimethyl
phosphite was carried out at a 1:1.22 molar ratio
under milder conditions (1.5 h, final temperature
135 C), one more product was isolated by vacuum
distillation of the reaction mixture [bp 125 128 C
1
The reaction of chloride II with trimethyl phos-
phite was carried out under reflux at a 5.09 1.15
phosphite:furan molar ratio for 1.5 4 h, depending
on the temperature of the reaction mixture. The reac-
(1 mm Hg)]. Its H NMR spectrum contained two
doublets of doublets at 1.169 (JHH 6.8, JHP 18.4)
and 1.214 (JHH 7.4, JHO 19.4), a singlet at 2.111
(CH3 furan), a singlet at
3.590 (CH3OOC), two
Yields of alkene III in the reaction of chloride II with trimethyl phosphite in at varied reactant molar ratio and temperature
Exp.
no.
Phosphite: chloride
molar ratio
Final boiling point
of the reaction mixture
Yield of alkene III,
Reaction time
%
1
2
3
4
5.05
4.77
3.39
1.15
3 h 45 min
3 h 45 min
1 h 25 min
3 h
132
132
135
160
31
37
40
18
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SYNTHESIS AND SELECTED REACTIONS
113
1
doublets at 3.685 (JHP 10.4) and 3.759 (JHP 10.8)
with the intensity ratio 2.6:1, two multiplets at
2.740 and 4.090, and a multiplet of low intensity at
2.885, evidently belonging to the minor product.
Under conditions of phosphorus decoupling, these
multiplets transformed to strongly distorted quartets
with broadened lines. The 31P NMR spectrum of the
isolated substance displayed two strong signals at
In the H NMR spectrum of the reaction mixture, the
signal of the methyl group in the furan ring ( 2.557)
does not alter, and the signal of the furan ring proton
shifts downfield [ 6.457 in starting alkene III and
6.679 in the bromination product]. The signal of the
Htrans proton ( 5.618, JHH 17.6) disappears, and the
signal at
6.384 (=CH furan) shifts downfield
(
6.416, d.d). Vacuum distillation of the reaction
49.14 and 46.64 and two signals of low intensity
mixture after removal of N-bromosuccinimide leads to
decomposition of the products.
P
at
48.09 and 45.50. The spectral data suggest that
P
the major product contains a methoxycarbonyl group
and a phosphinate phosphorus atom bound to aliphatic
and aromatic carbon atoms. The product was assigned
structure VII.
Thus, even though we failed to isolate individual
products, it is safe to state that the radical reaction
with N-bromosuccinimide involves, instead of allylic
bromination, the double bond of alkene III.
O
Alkene III was also reduced with lithium alumo-
hydride in ether. The reaction mixture was decom-
posed with saturated ammonium chloride and dried
over sodium sulfate. The product obtained is relatively
stable in solution but readily polymerizes in the
course of vacuum distillation. Nevertheless, we
managed to isolate alcohol VIII in 31% yield and to
C13H3O P
H3C6 C5H
C11
C7
C8 C10
C12O O C14H3
C15H3
O
VII
This substance should be a mixture of cis and trans
isomers differing in mutual location of the methyl and
methoxy groups in the four-membered ring. It was
confirmed by means of 13C NMR spectroscopy. The
13C NMR spectrum of compound VII contained by
1
take its H NMR spectrum before it had polymerized
completely.
CH2OH
LiAlH4
two signals of C5 ( 28.086, JPC 120.9;
29.071,
III
C
C
JPC 19.1), C13
(
P 52.124, JPC 8.5; C 53.219, JPC 5.9),
119.239, JPC 9.6; C 110.342, JPC 9.3), and C8
CH3
CH2=CH
O
C11
(
(
C
VIII
162.266, JPC 7.4;
162.986, JPC 9.2), which
prCovides evidence for theCexistence of two compounds
having the four-membered phosphorus-containing
heterocycle.
The spectral data showed that the reaction involves
exclusively the reduction of the carboxy group, lead-
ing to compound VIII, but the resulting unsaturated
alcohol, being highly labile, could not be brought in
further transformations.
Product VII contained some amount of admixtures,
and, therefore, its yield was estimated approximately
(20%). Such an unusual cyclization was not pre-
viously observed in the furan series. Most surprising
is the formation of a stable four-membered heteroring,
because even a five-membered fused carbocycle
cannot be formed in the furan series [6].
Hence, 2-(1-chloroethyl)furan II alkylates secon-
dary amines, but with phosphorus nucleophiles it
gives mainly dehydrochlorination product III. The
reaction of compound II with a slight excess of tri-
methyl phosphite also involves an unusual cyclization
to form a four-membered phosphorus-containing
heteroring fused with the furan ring.
Hence, it was shown that alkene III is a fairly
available product. Therefore, we tried to involve it in
reactions leading to substrates suitable for phos-
phorylation.
EXPERIMENTAL
1
The H NMR spectra were taken on a Bruker DPX-
The presence of the methyl group in the furan ring
of alkene III induced us to brominate it with
N-bromosuccinimide. The reaction was carried out in
carbon tetrachloride at 80 C and initiated with azobis-
(isobutyronitrile).
400 (400.13 MHz) spectrometer. The 13C and 31P
NMR spectra were measured on a Bruker AC-200
spectrometer (50.328 MHz for 13C; 81.014 MHz for
31P) in CDCl3. The INDOR spectrum was obtained
on a Tesla BS-497C (100 MHz) spectrometer.
It occurred that in the course of the reaction
N-bromosuccinimide is consumed very slowly. Its
complete convertion was achieved only in 10 h, pro-
vided the initiator was continuously added every 2 h.
Ethyl 5-(1-chloroethyl)-2-methylfuran-3-car-
boxylate (II). Acetaldehyde, 13 ml, was added drop-
wise at 0 C to a vigorously stirred mixture of 16.6 g
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 1 2007

114
PEVZNER
of ethyl 2-methylfuran-3-carboxylate, 1.5 g of a finely reduced pressure, and the residue was distilled in a
pulverized zinc chloride, and 150 ml of chloroform, vacuum to give 1.5 g of alkene III, bp 85 88 C
after which a strong stream of hydrogen chloride was (1 mm Hg) and 0.6 g of a fraction, bp 156 C (1 mm
passed through the reaction mixture until saturation. Hg), consisting of phosphonate V and ethylfuran VI.
The resulting mixture was kept for 2 h at 0 2 C, the According to the 1H NMR spectrum, the phosphonate:
conditions of saturation with hydrogen chloride being ethylfuran ratio was 1.4:1.
maintained. After that it was decomposed with water,
the organic layer was separated, and the aqueous layer
was extracted with chloroform. The combined solu-
tions were washed with water, dried over CaCl2, the
Ethyl 2-methyl-5-vinylfuran-3-carboxylate (III).
1
Yield 53%, bp 80 C (1 mm Hg). H NMR spectrum,
, ppm: 1.314 t (ethyl CH3, JHH 6.8 Hz), 2.561 s
(furan H3), 4.245 q (CH2OOC, JHH 6.8 Hz), 5.140 d
solvent was removed at reduced pressure, and the
(Hcis, JHH 11.2 Hz), 5.618 d (Htrans, JHH 17.6 Hz),
6.384 d.d (=CH furan, Jcis 11.2 Hz, Jtrans 17.6 Hz),
residue was distilled in a vacuum to give 15.5 g
1
(66%) of chloride II, bp 99 102 C (1 mm Hg). H
6.457 s (furan H4). Furan III slowly polymerizes on
NMR spectrum, , ppm: 1.255 t (ethyl CH3, JHH
handling.
7 Hz), 1.766 d (chloroethyl CH3, JHH 7 Hz), 2.514 s
(CH3 furan), 4.219 q (CH2OOC, JHH 7 Hz), 5.002 q
(chloroethyl CH, JHH 7 Hz), 6.504 s (furan H).
Ethyl 5-[1-(diethoxyphosphoryl)ethyl]-2-me-
thylfuran-3-carboxylate (V). Yield 8%. 1H NMR
spectrum, , ppm: 1.259 m (ethyl CH3), 1.454 d.d
(ethoxyphosphoryl CH3, JHH 7.4 Hz, JHP 17.6 Hz),
3.187 d.q (CHP, JHH 7.4 Hz, JHP 22.8 Hz), 4.040 m
(CH2OP), 4.204 m (CH2OOC), 6.425 s (furan H4).
2-Methylfuran-5-[1-(N-morpholyl)ethyl]-3-car-
boxylate hydrochloride (IV). Morpholine, 3 ml, was
added in one portion to a vigorously stirred solution
of 3 g of chloride II in 40 ml of benzene, and the
resulting mixture was refluxed for 5 h. After that the
reaction mixture was washed with two 20-ml portions
of of 10% HCl. The combined extracts were cooled to
0 C, saturated with sodium chloride, and treated with
40% aqueous NaOH to pH 9. The mixture was im-
mediately extracted with ether, the ethereal extracts
were dried over sodium sulfate, and the solvent was
distilled off. The residue was dissolved in 3 ml of
ethanol, and a solution of 1.7 g of sodium hydroxide
in 17 ml of water was added. The solution was boiled
with stirring and distillation of a water ethanol mix-
ture until the distillate temperature of 100 C was
achieved. The hydrolyzate was cooled, acidified with
36% HCl to pH 2, saturated with sodium chloride,
and extracted with several portions of butanol. The
combined extracts were evaporated at reduced pres-
sure until a tarry residue formed. It was triturated with
ethyl acetate, the crystals obtained were filtered off,
washed with acetone, and dried. Amino acid hydro-
chloride IV, 1.5 g, was obtained, decomp. point
195 C. 1H NMR spectrum (DMSO-d6), , ppm:
1.662 d (aminoethyl CH3, JHH 7 Hz), 2.500 s (CH3
furan), 2.758 2.914 br.s (CH2N), 3.884 m (CH2O),
4.628 br.s (N CH furan), 6.899 s (furan H4),
12.103 br.s (HOOC + HCl).
26.5 ppm.
P
Ethyl 5-ethyl-2-methylfuran-3-carboxylate (VI).
1
Yield 6%. H NMR spectrum, , ppm: 1.259 m (ethyl
CH3), 2.498 s (CH3 furan), 2.941 q (CH2 furan, JHH
7.2 Hz), 6.388 s (furan H4).
Reaction of chloride II with trimethyl phos-
phite. A mixture of chloride II and trimethyl phos-
phite was refluxed with stirring until a constant boil-
ing point was achieved. After that the reaction mixture
was distilled in a vacuum. The fraction boiling in the
range 78 90 C (1 mm Hg) was collected and distilled
in a vacuum once more to give product III, bp 80 C
(1 mm Hg). The conditions and results of exp. nos. 1
4 are listed in the table.
Experiment no. 5. A mixture of 12.0 g of chloride
II and 8 ml of trimethyl phosphite was heated for
1.5 h to 135 C and then distilled in a vacuum to give
1 g (10%) of alkene III and 2.7 of a fraction, bp 125
128 C (1 mm Hg), consisting mainly of product VII,
yield 20%, n2D0 1.4700.
5
Methyl 2,4-dimethyl-1-methoxy-1-oxo-1 -1,2-
dihydrophospheto[3,2-b]furan-5-carboxylate (VII).
1
bp 121 122 C (1 mm Hg). H NMR spectrum,
,
ppm: 1.169 d.d (CH3 phosphetane, JHH 6.8 Hz, JHP
18.4 Hz), 1.214 d.d (CH3 phosphete, JHH 7.4 Hz, JHP
19.4 Hz), 2.111 s (CH3 furan), 3.590 s (CH3OOC),
3.685 d (CH3OP, JHP 10.4 Hz), 3.759 d (CH3OP, JHP
Reaction of chloride II with sodium diethyl
phosphite. A solution of 3.4 g of chloride II in 4 ml
of benzene was added in one portion at 80 C to a
solution of sodium diethyl phosphite, prepared from
0.4 g of sodium and 3 ml of diethyl hydrogen phos- 10.8 Hz), 2.740 br.m, 4.090 br.m (phosphate CH). 13
C
phite in 40 ml of benzene. The resulting mixture was NMR spectrum, C, ppm: 12.726 s, 13.488 s (C15),
refluxed with stirring for 12 h, sodium chloride was 15.402 d (C6, JCP 7.7 Hz), 28.086 d (C5, JCP
removed on a centrifuge, the solvent was removed at 120.9 Hz), 29.971 d (C5, JCP 119.1 Hz), 58.530 s
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 1 2007

SYNTHESIS AND SELECTED REACTIONS
115
1
(C14), 52.124 d (C13, JCP 8.5 Hz), 53.219 d (C13, JCP
(31%), was obtained, bp 91 93 C (1 mm Hg). H
NMR spectrum, , ppm: 2.260 s (CH3 furan), 4.377 s
5.9 Hz), 109.853 d (C7, JCP 198.5 Hz), 110.342 d (C11,
JCP 9.3 Hz), 111.239 d (C11, JCP 9.6 Hz), 162.266 d
(CH2OH), 5.055 d (Hcis, JHH 12 Hz), 5.555 d (Htrans
,
(C8, JCP 7.4 Hz), 162.986 d (C8, JCP 9.2 Hz),
163.572 s (C10), 163.950 s (C12). 31P NMR spectrum,
P, ppm: 49.140 s, 46.642 s.
JHH 16.8 Hz), 6.387 d.d (=CH furan, Jcis 12 Hz, Jtrans
16.8 Hz), 6.192 s (furan H4). In a refrigerator (ca.
4 C), the product polymerizes within several hours.
3-(Hydroxymethyl)-2-methyl-5-vinylfuran
(VIII). To a suspension of 0.9 g of lithium aluminum
hydride in 40 ml of ether, a solution of 4.2 g of ester
III in 5 ml of ether was added dropwise with stirring
at a rate providing slight boiling of the reaction mix-
ture. After the addition was complete, the mixture was
stirred for 1 h and left overnight. On the next day it
was treated with stirring with 10 ml of ethyl acetate
and decomposed with saturated ammonium chloride
until phase separation. The organic phase was de-
canted, and the water salt gel was stirred with 30 ml
of ether. The combined organic layers were dried for
1 h over sodium sulfate, the solvent was evaporated
in a waterjet-pump vacuum, and the residue was distil-
led in a vacuum. The solution darkened just during
its concentration, and vacuum distillation is accom-
panied by polymerization. Compound VIII, 1.0 g
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