Reaction of 2,4-Difunctional Esters of 5-tert-Butylfuran-3-carboxylic Acid with Nucleophilic Reagents

Article abstract of DOI:10.1023/A:1024962020862

Ethyl 5-tert-butyl-4-(chloromethyl)-2-methylfuran-3-carboxylate was brominated with N-bromosuccinimide to obtain the corresponding 2-bromomethyl derivative. The latter is selectively phosphorylated with trimethyl and triethyl phosphites by the bromomethyl group. The resulting [4-(chloromethyl) furyl]methylphosphonates in the presence of secondary amines and sodium butanethiolate behave as alkylating agents, while sodium phenolate causes their decomposition. 4-Acetoxymethyl- and 4-phenoxymethyl derivatives of the starting product are also selectively brominated with N-bromosuccinimide by the 2-methyl group. The first of the 2-(bromomethyl)furans formed is smoothly phosphorylated with trimethyl phosphite, while the second one under the action of triethyl phosphite gives a mixture of phosphorylation and debromination products. In all the cases, an additional electron-acceptor group in position 4 of alkyl 2-(bromomethyl)-5-tert-butylfuran-3-carboxylate considerably accelerates the Arbuzov reaction.

Full text of DOI:10.1023/A:1024962020862

Russian Journal of General Chemistry, Vol. 73, No. 3, 2003, pp. 413 417. Translated from Zhurnal Obshchei Khimii, Vol. 73, No. 3, 2003,
pp. 442 446.
Original Russian Text Copyright
2003 by Pevzner.
Reaction of 2,4-Difunctional Esters
of 5-tert-Butylfuran-3-carboxylic Acid with Nucleophilic Reagents
L. M. Pevzner
St. Petersburg State Institute of Technology, St. Petersburg, Russia
Received February 4, 2002
Abstract Ethyl 5-tert-butyl-4-(chloromethyl)-2-methylfuran-3-carboxylate was brominated with N-bromo-
succinimide to obtain the corresponding 2-bromomethyl derivative. The latter is selectively phosphorylated
with trimethyl and triethyl phosphites by the bromomethyl group. The resulting [4-(chloromethyl)furyl]methyl-
phosphonates in the presence of secondary amines and sodium butanethiolate behave as alkylating agents,
while sodium phenolate causes their decomposition. 4-Acetoxymethyl- and 4-phenoxymethyl derivatives of
the starting product are also selectively brominated with N-bromosuccinimide by the 2-methyl group. The first
of the 2-(bromomethyl)furans formed is smoothly phosphorylated with trimethyl phosphite, while the second
one under the action of triethyl phosphite gives a mixture of phosphorylation and debromination products. In
all the cases, an additional electron-acceptor group in position 4 of alkyl 2-(bromomethyl)-5-tert-butylfuran-3-
carboxylate considerably accelerates the Arbuzov reaction.
Recently [1] we established that the 4-chloromethyl
substituent in ethyl 5-tert-butyl-4-(chloromethyl)-2-
methylfuran-3-carboxylate (Ia) is rather inert in phos-
phorylation reactions. Basing on this fact we sug-
gested that by bromination of the 2-methyl group we
could prepare a compound with the halomethyl groups
differing considerably in their activity and thus
capable of selective phosphorylation. Therewith, the
chloromethyl group in the products could be used for
their further functionalization.
conditions. The reaction with trimethyl phosphite was
considered complete when the boiling point of the
reaction mixture achieved 135 140 C. With triethyl
phosphite, after the reaction mixture was heated to
80 C, an exothermic reaction commenced. Therewith,
the temperature of the reaction mixture spontaneously
rose to 125 C. After heat release was complete, the
temperature fell fast to 90 95 C, which was accom-
panied by distillation of ethyl bromide. After that the
reaction mixture was heated to 135 C for 2 3 min. In
both cases, phosphorylation was complete within
15 min. Volatile by-product phosphonates were re-
moved to isolate target products III and IV as viscous
syrups. These compounds are stable at room tem-
perature but decompose in a vacuum (1 mm) below
the boiling point. Hence, the 4-chloromethyl group
fails to enter the Arbuzov reaction under the condi-
tions studied, even though an excess of the phos-
phorylating agent is present.
Ester Ia was brominated with N-bromosuccinimide
(NBS) in CCl4 in the presence of 2,2 -azobisisobutyro-
nitrile (AIBN) for 3 h to obtain dihalide IIa as a
stable crystalline substance melting at 59 60 C. Di-
halide IIb was obtained in a similar way.
COOR
COOR
ClCH2
ClCH2
NBS
(CH3)3C
CH3
(CH3)3C
CH2Br
O
O
I
II
Investigation of reactions of compounds III and IV
with nucleophilic agents we began with the reaction
with secondary amines. Diethylamine and morpholine
were chosen as typical representatives. The alkylation
was carried out in the presence of excess amine in
benzene or toluene at 70 80 C.
COOR
CH2PO(OR )2
ClCH2
P(OR )3
(CH3)3C
O
III
COOCH3
R2NCH2
I, II, R = CH3 (a), C2H5 (b); III, R = CH3, R = C2H5; IV,
III + NR2
R = C2H5, R = CH3.
(CH3)3C
CH2PO(OC2H5)2
O
V, VI
R = C2H5 (V), R2 = CH2CH2OCH2CH2 (VI).
Dihalides IIa, IIb were phosphorylated with excess
trimethyl or triethyl phosphite under Arbuzov reaction
1070-3632/03/7303-0413$25.00 2003 MAIK Nauka/Interperiodica

414
PEVZNER
With compound IV, decomposition of the phos-
phorus-containing fragment is observed, while phos-
phonate III gives tertiary amines V and VI.
COOC2H5
CH2Br
CH3COOCH2
(CH3)3C
NBS
VIII
IX
O
X
Treatment of phosphonate III with equimolar
amount of sodium butanethiolate in a methanol
benzene mixture for 5 h affords sulfide VII.
OCH2
COOC2H5
CH2Br
NBS
C4H9SCH2
(CH3)3C
COOCH3
(CH3)3C
III + C4H9SNa
O
XI
CH2PO(OC2H5)2
O
VII
reach 140 C within 12 min. Volatile products were
removed in a vacuum, and acetate XIII was obtained
as a light brown syrup. The acetyl protection was
removed by treating the product with methanol in the
presence of a catalytic amount of sodium methylate.
Boiling for 6 h gave phosphorus-containing alcohol
XIV.
Treatment of phosphonate IV with sodium pheno-
late in the methanol benzene medium leads to decom-
position of the latter.
Hence, the presence of a phosphorus-containing
fragment in the starting halide allows nucleophilic
substitution reactions with nitrogen- and sulfur-con-
taining nucleophiles only. The same situation we
5-phosphonomethylated
2-bromomethyl derivatives of 3- and 4-furancar-
boxylic acids [2].
COOC2H5
CH3COOCH2
(CH3)3C
P(OCH3)3
X
CH2PO(OCH3)2
earlier
observed with
O
XII
HOCH2
COOC2H5
Having established the scope of application of
halogen substitution in phosphonate IV, we tried to
prepare compounds having an oxygen-containing
fragment in position 4, by altering the order of intro-
duction of substituents.
CH3OH
CH3ONa
(CH3)3C
CH2PO(OCH3)2
O
XIV
One of the unsolved problems of furan chemistry is
preparation of phosphorus-containing aldehydes.
Therefore, an attempt was made to find some suitable
oxidant for alcohol XIV. Active manganese dioxide
prepared according to Attenburrow, and a solution of
chromic acid in pyridine, we successfully used pre-
viously for oxidation of hydroxymethylfurancarboxy-
lates [3, 4], were tested. The first oxidant did not react
with the substrate even on prolonged boiling in
benzene or carbon tetrachloride. Contrary to that, the
second oxidant caused profound destruction of the
starting compound.
COOC2H5
CH3
CH3COOCH2
(CH3)3C
Ib + CH3COONa
O
VIII
OCH2
COOC2H5
CH3
C6H5ONa
Ia
C2H5OH
(CH3)3C
O
IX
Treatment of halide Ib with sodium acetate in
acetic acid at 120 C gives acetate VIII. Phenyl ether
IX was obtained by reaction of compound Ia with
sodium phenolate in ethanol. Both products are re-
adily and selectively brominated with N-bromo-
succinimide in carbon tetrachloride by the 2-methyl
group.
OCH2
(CH3)3C
COOC2H5
CH2PO(OC2H5)2
P(OC2H5)3
+ IX
XI
O
XV
Acetate X was phosphosphorylated with trimethyl
phoshite under Arbuzov reaction conditions. Similarly
to the above-mentioned case, the reaction was con-
sidered complete when the boiling point of the reac-
tion mixture reached 130 140 C. After methyl
bromide began to evolve at 100 C, the temperature of
the reaction mixture virtually continuously rose to
Phenyl ether XI was phosphorylated with triethyl
phosphite under Arbuzov reaction conditions. The
reaction mixture began to change its color at 80 C.
At 100 110 C, ethyl bromide evolution was observed,
and then the temperature of the reaction mixture rose
to 130 C. The total reaction time was 5 7 min. The
reaction mixture was additionally kept at 130 140 C
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REACTION OF 2,4-DIFUNCTIONAL ESTERS
415
for 10 min, and volatile products were removed in a
vacuum. Triethyl phosphite and diethyl ethylphospho-
nate were found among them. The residue was a dark
(CH2OP, JHH 7 Hz, JHP 11 Hz), 4.81 s (CH2Cl); major
conformer: 3.51 d (CH2P, JHP 21 Hz), 18.1 ppm;
P
minor conformer: 3.39 d (CH2P, JHP 20 Hz).
P
1
yellow syrup. The H NMR spectrum permitted us to
23.5 ppm. Conformer ratio 10:3.
characterize it as a mixture of phosphonate XV and
phenyl ether IX. Hence, with bromide XI, an addi-
tional reaction pathway appears, beginning with halo-
genophilic attack of the phosphite on the substrate.
Though this pathway is minor (the XV:IX ratio is
6:1), its appearance provides evidence suggesting that
the remote and shielded phenoxymethyl substituent
exerts a significant effect on the reaction center.
Ethyl 5-tert-butyl-4-(chloromethyl)-2-(dimeth-
oxyphosphorylmethyl)furan-3-carboxylate (IV). A
solution of 4.9 g of dihalide IIb in 4 ml of trimethyl
phosphite was heated with stirring. At 40 C the mix-
ture became turbid, at 105 C it boiled up, and methyl
bromide evolution began. The temperature of the re-
action mixture gradually rose to 135 C within 15 min.
Then gas evolution ceased, and the mixture became
clear. The product was kept in a vacuum at 1 mm.
Therewith, the by-product dimethyl methylphos-
phonate distilled (bp 30 C, 1 mm). The target phos-
phonate IV was obtained as a yellow viscous syrup.
EXPERIMENTAL
1
The H NMR spectra were obtained on Tesla BS-
1
487C and Tesla BS-497C (100 MHz) spectrometers
in CCl4 against internal HMDS. The phosphorus
chemical shifts were calculated from INDOR spectra.
The yield of the target product was quantitative. H
NMR spectrum, , ppm: 1.36 m [(CH3)3C + ethyl
CH3], 4.21 q (CH2OOC, JHH 7 Hz), 4.74 s (CH2Cl);
major conformer: 3.52 d (CH2P, JHP 20 Hz), 3.67 d
Methyl 2-(bromomethyl)-5-tert-butyl-4-(chloro-
methyl)furan-3-carboxylate (IIa). To a solution of
15.7 g of chloromethyl derivative Ia in 100 ml of
CCl4, 12.5 g of N-bromosuccinimide and 0.5 g of
AIBN were added in one portion with stirring. The
resulting suspension was heated to 80 C and, after the
exothermic reaction was complete, stirred under refux
for 3 h. After cooling to room temperature, the suc-
cinimide precipitate was filtered off, the solvent was
removed at reduced pressure, and the residue was kept
(CH2OP, JHP 10 Hz),
21.0 ppm; minor conformer:
P
3.34 d (CH2P, JHP 20 Hz), 3.58 d (CH2OP, JHP
10 Hz). 25.4 ppm. Conformer ratio 11:5.
P
Methyl 5-tert-butyl-2-(diethoxyphosphoryl-
methyl)-4-(diethylaminomethyl)furan-3-carboxy-
late (V). A mixture of 2.1 g of phosphonate IV, 3 ml
of diethylamine, and 10 ml of benzene was heated
with stirring at 70 80 C for 10 h. An abundant pre-
cipitate formed. The reaction mixture was washed
with dilute hydrochloric acid (1:1, 2 15 ml). The
aqueous extract was treated with sodium carbonate to
pH 10, saturated with sodium chloride, and extracted
with ether (3 30 ml). The ethereal extract was dried
over calcium chloride, filtered, and the ether was
distilled off. The residue was kept in a vacuum for 2 h
to give 1.1 g (48%) of aminophosphonate V as a
in a vacuum (1 mm) for 1 h to obtain 20.1 g (97%) of
1
compound II, mp 59 60 C. H NMR spectrum,
,
ppm: 1.37 s [(CH3)3C], 3.79 s (CH3OOC), 4.59 s
(CH2Br), 4.71 s (CH2Cl). Ethyl ester IIb was ob-
1
tained analogously, mp 45 46 C. H NMR spectrum,
, ppm: 1.35 m [(CH3)3C + ethyl CH3], 4.22 q
(CH2OOC, JHH 7 Hz), 4.60 s (CH2Br), 4.68 s (CH2Cl).
brown oil. 1H NMR spectrum, , ppm: 0.94 t
(N ethyl CH3, JHH 7 Hz), 1.26 t (O ethyl CH3, JHH
7 Hz), 1.40 s [(CH3)3C], 2.45 q (N ethyl CH2, JHH
7 Hz), 3.59 d (furan CH2P, JHP 20 Hz), 3.68 s (furan
CH2N), 3.82 s (CH3OOC), 4.06 m (CH2OP, JHP
Methyl 5-tert-butyl-4-(chloromethyl)-2-(di-
ethoxyphosphorylmethyl)-furan-3-carboxylate
(III). A mixture of 10 g of dihalide IIa and 7 ml of
triethyl phosphite was heated at vigorous stirring. At
80 C, the reaction mixture changed color, boiled up
vigorously, and the temperature rose to 125 C. Ethyl
bromide began to evolve, and the temperature of the
reaction mixture quickly came down to 95 90 C. The
mixture was heated to 135 C for 2 3 min to remove
residual ethyl bromide. The total reaction time was
15 16 min. The reaction mixture was kept in a
vacuum (1 mm). Therewith, diethyl ethylphosphonate
distilled bp 49 C (1 mm). Phosphonate III was ob-
tained as a a light brown very viscous syrup. The
yield of the crude product was quantitative. The
product was identified as a mixture of two conformers.
1H NMR spectrum, , ppm: 1.24 t (ethyl CH3, JHH
7 Hz), 1.37 s [(CH3)3C], 3.76 s (CH3OOC), 3.91 m
11 Hz, JHH 7 Hz).
19.7 ppm.
P
Methyl 5-tert-butyl-2-(diethoxyphosphoryl-
methyl)-4-(morpholinomethyl)furan-3-carboxylate
(VI). A mixture of 2.0 g of phosphonate IV, 3 ml of
morpholine, and 15 ml of benzene was heated at 70
80 C for 12 h. An abundant precipitate formed. The
mixture was washed with dilute hydrochloric acid
(1:1, 2 15 ml), the aqueous extract was treated with
sodium carbonate to pH 9, saturated with sodium
chloride, and extracted with ether (3 30 ml). The
ethereal extract was dried over calcium chloride, fil-
tered, the ether was distilled off, and the residue was
kept in a vacuum for 1 h to obtain 1.1 g (49%) of
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416
PEVZNER
1
aminophosphonate VI as a light yellow oil. H NMR
spectrum, , ppm: 1.28 t (ethyl CH3, JHH 7 Hz),
1.40 br.s [(CH3)3C], 2.40 m (morpholine CH2N),
3.55 d (CH2P, JHP 20 Hz), 3.62 br.s (morpholine
CH2O + furan CH2N), 3.84 s (CH3OOC), 4.06 m
N-bromosuccinimide and 0.1 g of AIBN were added
in one portion. The resulting mixture was refluxed
with stirring for 1 h, cooled to room temperature, the
succinimide precipitate was filtered off, the solvent
was removed at reduced pressure, and the residue was
kept for 2 h in a vacuum (1 mm) at room temperature
to obtain 1.7 g (84%) of bromide XI as a yellow
syrup. 1H NMR spectrum, , ppm: 1.25 1.40 m
[(CH2)3C + ethyl CH3], 3.72 q (ethyl CH2, JHH 7 Hz),
4.75 s (CH2Br), 5.05 (CH2O phenyl), 6.55 7.25 m
(phenyl).
(CH2OP, JHH 7 Hz, JHP 11 Hz).
19.7 ppm.
P
Methyl 5-tert-butyl-4-(butylthiomethyl)-2-(di-
ethoxyphosphoryl)furan-3-carboxylate (VII). To a
solution of sodium methylate prepared from 0.17 g of
sodium and a mixture of 4 ml of methanol and 6 ml
of benzene, 0.8 ml of butylmercaptan was added. The
reaction mixture was stirred for 5 min, and then a
solution of 2.8 g of phosphonate IV in 5 ml of
benzene was added. The resulting solution was re-
fluxed for 5 h, poured into 25 ml of water, the
benzene layer was removed, and the aqueous layer
was extracted with benzene (2 10 ml). The combined
extracts were dried over calcium chloride. The solvent
was removed at reduced pressure, and the residue was
kept for 1 h in a vacuum (1 mm) to obtain 2.3 g
Ethyl 4-(acetoxymethyl)-5-tert-butyl-2-(di-
methoxyphosphorylmethyl)furan-3-carboxylate
(XIII). A mixture of 3.3 g of bromide X and 5.5 ml
of trimethyl phosphite was heated with stirring. At
100 C, the mixture boiled up, and its temperature
began to increase, reaching 140 C within 12 min. The
mixture was cooled to room temperature, and di-
methyl methylphosphonate was distilled off at 1 mm.
The residue was kept in a vacuum at 40 C for 2 h to
obtain 3.2 g (90%) of phosphonate XIII as a brown
1
(72%) of phosphonate VII as a light yellow oil. H
1
NMR spectrum, , ppm: 0.86 t (butyl CH3, JHH 7 Hz),
1.14 1.40 m [(CH3)3C + ethyl CH3 + butyl CH2],
2.44 (butyl CH2 S, JHH 7 Hz), 3.60 d (CH2P, JHP
20 Hz), 3.77 s (CH3OOC), 3.84 s (furan CH2S),
4.02 m (CH2OP, JHH 7 Hz, JHP 11 Hz).
syrup. H NMR spectrum, , ppm: 1.36 m [(CH3)3C +
ethyl CH3], 2.00 s (CH3COO), 3.58 d (CH2P, JHP
20 Hz), 3.66 d (CH3OP, JHP 11 Hz), 4.25 q (CH2OOC,
JHH 7 Hz), 5.16 s (furan CH2O).
21.0 ppm.
P
Methyl 5-tert-butyl-2-(dimethoxyphosphoryl-
methyl)-4-(hydroxymethyl)furan-3-carboxylate
(XIV). To a solution of sodium methylate prepared
from 0.2 g of sodium and 15 ml of methanol, 3.2 g of
phosphonate XIII was added with stirring. The result-
ing mixture was refluxed for 6 h with stirring, 1 ml
of acetic acid was added, the methanol was distilled
off at reduced pressure, and the residue was dissolved
in 80 ml of chloroform and washed with 10 ml of
water. The chloroform layer was dried over calcium
chloride and then stirred for 3 h with 1 g of charcoal.
The clarified solution was filtered, the solvent was
distilled off at reduced pressure, and the residue was
kept in a vacuum (1 mm) for 2 h to give 2.1 g (77%)
Ethyl 4-(acetoxymethyl)-2-(bromomethyl)-5-tert-
butylfuran-3-carboxylate (X). To a solution of 3.1 g
of acetate VIII in 30 ml of CCl4, 2.1 g of N-bromo-
succinimide and 0.2 g of AIBN were added in one
portion. The resulting mixture was refluxed for 3 h
with stirring, cooled to room temperature, the suc-
cinimide precipitate was filtered off, the solvent was
removed at reduced pressure, and the residue was kept
in a vacuum (1 mm) for 2 h to obtain 3.1 g of bro-
1
mide X as a yellow viscous oil. H NMR spectrum, ,
ppm: 1.36 m [(CH3)3C + ethyl CH3], 1.92 s
(CH3COO), 4.20 q (ethyl CH2, JHH 7 Hz), 4.62 s
(CH2Br), 5.07 s (furan CH2O).
1
of hydroxymethyl derivative XIV. H NMR spectrum,
Ethyl 5-tert-butyl-2-methyl-4-(phenoxymethyl)-
furan-3-carboxylate (IX). To a solution of sodium
ethylate obtained by dissolution of 0.3 g of sodium in
15 ml of ethanol, 1.2 g of phenol was added. The re-
action mixture was stirred for 5 min, and, after addi-
tion of 3.1 g of chloride Ia, refluxed for 13 h. The
sodium chloride precipitate was filtered off, the
ethanol was removed at reduced pressure, and the re-
sidue was distilled in a vacuum to obtain 2.6 g (68%)
of phenyl ether IX, bp 168 170 C (1 mm), mp 56
58 C.
, ppm: 1.40 s [(CH3)3C], 3.63 d (CH2P, JHP 22 Hz),
3.72 d (CH3OP, JHP 11 Hz), 3.88 s (CH3OOC), 4.65 s
(furan CH2O).
Reaction of bromomethylfuran XI with triethyl
phosphite. A mixture of 1.7 g of bromomethylfuran
XI and 4.5 ml of triethyl phosphite was heated with
stirring. At 80 C the mixture began to darken, at 100
110 C ethyl bromide began to evolve, and then the
temperature spontaneously rose to 130 C and main-
tained for 5 min. After that the reaction mixture was
kept at 130 140 C for 10 min, volatile products (tri-
ethyl phosphite and diethyl ethylphosphonate) were
removed in a vacuum. The residue was kept in a
Ethyl 2-(bromomethyl)-5-tert-butyl-4-(phenoxy-
methyl)furan-3-carboxylate (XI). To a solution of
1.6 g of phenyl ether IX in 15 ml of CCl4, 1 g of
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REACTION OF 2,4-DIFUNCTIONAL ESTERS
417
vacuum (1 mm) at 50 C for 2 h to give 1.3 g of a
REFERENCES
brown syrup. 1H NMR spectrum, , ppm: 1.00
1.50 m [(CH3)3C + ethyl CH3], 2.41 s (CH3 furan),
3.53 d (CH2P, JHP 22 Hz), 4.00 m (CH2OP +
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CH2OOC), 5.07 (CH2O phenyl), 6.70 7.27
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2. Pevzner, L.M., Ignat’ev, V.M., and Ionin, B.I., Zh.
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(phenyl), 18.1 ppm. From the spectral data it
P
follows that we deal with a mixture of phosphonate
XV and phenyl ether IX. From the intensity ratio of
the signals at 2.41 and 3.53 ppm their ratio was
estimated at 6:1.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 73 No. 3 2003