REACTION OF ETHYL 5-SUBSTITUTED-2-FUROYLMALONATES WITH SECONDARY AMINES

Article abstract of DOI:10.1135/cccc19941400

In situ prepared magnesium salts of ethyl malonate react with 5-X-2-furoyl chlorides (X=Br.NO2.C6H5S and C6H5SO2) to give the corresponding ethyl 5-X-2-furoylmalonates.On treatment of these compounds with secondary amines no nucleophilic substitution of the group X in position 5 of the furan nucleus took place but, instead, amides of 5-X-2-furancarboxylic acids were isolated.

Full text of DOI:10.1135/cccc19941400

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Kada, Brunckova, Bobal:
REACTION OF ETHYL 5-SUBSTITUTED-2-FUROYLMALONATES
WITH SECONDARY AMINES
Rudolf KADA, Jarmila BRUNCKOVA and Pavol BOBAL
Department of Organic Chemistry,
Slovak Technical University, 812 37 Bratislava, The Slovak Republic
Received May 12, 1993
Accepted November 7, 1993
In situ prepared magnesium salts of ethyl malonate react with 5-X-2-furoyl chlorides (X = Br, NO2,
C6H5S and C6H5SO2) to give the corresponding ethyl 5-X-2-furoylmalonates. On treatment of these
compounds with secondary amines no nucleophilic substitution of the group X in position 5 of the
furan nucleus took place but, instead, amides of 5-X-2-furancarboxylic acids were isolated.
In our previous studies on reactions of furan derivatives with nucleophilic reagents we
described nucleophilic substitution of the arylthio, heteroarylthio, arylsulfonyl and aryl-
oxy groups with nitrogen nucleophilic reagents in 2-cyano-3-(5-arylthio-2-furyl)-,
2-cyano-3-(5-heteroarylthio-2-furyl)-, 2-cyano-3-(5-arylsulfonyl-2-furyl)- and 2-cyano-
3-(5-aryloxy-2-furyl)acrylonitrile or -metacrylate1 – 5. At the same time we have shown
that the SN reaction in position 5 of the furan nucleus takes place thanks to the presence
of a strong electron-accepting substituent in position 2. This finding is confirmed also
by studies of condensations of 5-X-furaldehydes with ethyl malonate, ethyl acetoace-
tate and acetylacetone with secondary amines which afforded products of SN and AdN
reactions6.
The present study concerns the preparation of ethyl 5-X-2-furoylmalonates (X = Br,
NO2, C6H5S, C6H5SO2) and their reactions with secondary amines. The ethyl 5-X-2-
furoylmalonates were prepared using a method described by Bowman7, which is based
on reaction of ethoxymagnesium salt of ethyl malonate (prepared in situ) with 5-X-2-
furoyl chloride in an inert solvent and which leads unequivocally to C-acylated prod-
ucts (Scheme 1). The reaction time was 2 h in the case of compounds IIa, IIc, IId but
only 1 h for derivative IIb. In the latter case, prolongation of the reaction time resulted
in darkening of the reaction mixture, formation of tars and drop in the yield. The start-
ing 5-X-2-furoyl chlorides Ia – Id were prepared by reaction of the corresponding 5-X-
2-furancarboxylic acids with thionyl chloride. When the thionyl chloride was added to
the carboxylic acid in one portion and the reaction mixture was refluxed, the reaction
was accompanied by formation of black tar and the yield decreased to 70%. On the
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

5-Substituted-2-furoylmalonates
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SCHEME 1
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Kada, Brunckova, Bobal:
other hand, when the reaction was carried out in anhydrous benzene and thionyl
chloride was added during the reflux, the yield increased to 81 – 89%.
Ethyl 5-X-2-furoylmalonates have five potential sites suitable for a nucleophilic at-
tack: the two ester groups, the carbonyl in position 2 of the furan ring, the position 5 of
the furan ring and the strongly acidic hydrogen atom on the sp3-hybridized carbon
atom. The more interesting is the fact that reactions with secondary amines afford
solely amides of 5-X-2-furancarboxylic acids under simultaneous expulsion of ethyl
malonate which was detected by thin-layer chromatography. The reaction probably
starts by nucleophilic addition to the keto group, followed by elimination of ethyl ma-
lonate molecule. Of 5-bromo- and 5-nitro-2-furancarboxylic acid amides, compounds
IIIe (ref.9), IIIj (ref.8,9), IIIf (ref.8,10,11), IIIg (ref.8) and IIIh (ref.11) are already described:
they were prepared from the corresponding acid chlorides and secondary amines.
EXPERIMENTAL
Infrared absorption spectra (ν, cm−1) were measured on a Specord M 80 (Zeiss, Jena) instrument in
KBr pellets (unless stated otherwise), UV spectra (in methanol) were obtained with a Specord M 40,
(Zeiss, Jena) spectrometer. 1H NMR spectra (δ, ppm; J, Hz) were measured on a BS 487 C Tesla
instrument (80 MHz) in deuteriochloroform (compounds I and II) and hexadeuterioacetone (com-
pounds III) with tetramethylsilane as internal standard.
The 5-bromo-, 5-phenylthio- and 5-phenylsulfonyl-2-furancarboxylic acids were prepared by oxi-
dation of the corresponding aldehydes with silver oxide12. 5-Nitro-2-furancarboxylic acid was ob-
tained starting from 2-furancarboxylic acid: its esterification and subsequent nitration afforded ethyl
5-nitro-2-furancarboxylate which upon acid hydrolysis gave 5-nitro-2-furancarboxylic acid in 94%
yield13.
5-X-2-Furoyl Chlorides I (General Procedure)
Thionyl chloride (6.53 g, 0.055 mol) in anhydrous benzene (5 ml) was added in the course of 9 – 12 h
to a refluxing solution of the appropriate 5-X-2-furancarboxylic acid (0.05 mol) and several drops of
distilled dimethylformamide in anhydrous benzene (15 ml). After removal of the benzene and excess
thionyl chloride, the product was isolated by distillation under diminished pressure (compounds Ia –
Ic). 5-Phenylsulfonyl-2-furoyl chloride (Id) separated from the reaction mixture as a white crys-
talline compound which was collected, washed with anhydrous benzene (2 – 3 times 10 ml) and
dried.
5-Bromo-2-furoyl chloride (Ia). Yield 87%, b.p. 78 – 80 °C/2.39 kPa (reported14 b.p. 89 °C/107 kPa).
IR spectrum (chloroform): 1 735 (CO). UV spectrum (λmax, nm (log ε)): 215 (2.53), 268 (3.00), 284 sh
1
(2.98). H NMR spectrum: 7.63 d, 1 H, J(3,4) = 3.75 (H-3); 6.86 d, 1 H (H-4).
5-Nitro-2-furoyl chloride (Ib). Yield 82%, b.p. 129 – 131 °C/1.59 kPa (reported15 b.p. 110 – 123 °C
/0.53 kPa). IR spectrum (chloroform): 1 760 (CO). UV spectrum (λmax, nm (log ε)): 212 (3.22), 285
1
(3.33). H NMR spectrum: 7.73 d, 1 H, J(3,4) = 4.00 (H-3); 7.92 d, 1 H (H-4).
5-Phenylthio-2-furoyl chloride (Ic). Yield 89%, b.p. 140 – 142 °C/0.16 kPa. For C12H7ClO2S
(238.7) calculated: 55.35% C, 2.96% H, 13.43% S; found: 55.23% C, 2.95% H, 13.52% S. IR spec-
trum (chloroform): 1 754 (CO). UV spectrum (λmax, nm (log ε)): 242 i (3.15), 252 (3.19), 292 (2.68).
1H NMR spectrum: 7.67 d, 1 H, J(3,4) = 3.80 (H-3); 6.79 d, 1 H (H-4); 7.33 – 7.45 m, 5 H (H-aryl).
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5-Phenylsulfonyl-2-furoyl chloride (Id). Yield 83%, m.p. 112 – 113 °C. For C11H7ClO4S (270.7)
calculated: 48.78% C, 2.60% H, 11.84% S; found: 48.69% C, 2.78% H, 11.76% S. IR spectrum
1
(chloroform): 1 760 (CO). UV spectrum (λmax, nm (log ε)): 222 (3.04), 261 (3.31), 269 i (3.19). H
NMR spectrum: 7.59 d, 1 H, J(3,4) = 3.80 (H-3); 7.43 d, 1 H (H-4); 7.70 – 7.78 m, 3 H (H-3′,
H-5′); 8.00 – 8.33 m, 2 H (H-2′, H-6′).
Ethyl 5-X-2-Furoylmalonates II (General Procedure)
Approximately 2 ml of a solution of ethyl malonate (16 g, 0.1 mol) in anhydrous ethanol (4.6 ml)
and anhydrous benzene (20 ml) was added dropwise to a stirred mixture of magnesium (2.4 g, 0.1 mol),
anhydrous benzene (7.33 ml), anhydrous ethanol (0.6 ml) and carbon tetrachloride (0.5 ml). The mix-
ture was warmed until a vigorous reaction spontaneously commenced. The remaining solution of the
malonate was gradually added so as to keep the mixture boiling (about 2 – 3 h). The mixture was
then heated until all the magnesium reacted and the alcohol and benzene were removed by distilla-
tion. A solution of the corresponding furoyl chloride I (0.05 mol) in benzene was added dropwise to
the residue under cooling and the mixture was refluxed for 1 – 2 h. After cooling, the mixture was
decomposed with ice and dilute sulfuric acid, the organic layer was separated, washed with dilute
sulfuric acid, several times with water, and dried over sodium sulfate. The benzene and excess ethyl
malonate were distilled off and the crude product was purified by distillation in vacuo.
Ethyl 5-bromo-2-furoylmalonate (IIa). Yield 83%, b.p. 138 – 140 °C/2 kPa. For C12H13BrO6
(333.1) calculated: 43.26% C, 3.93% H; found 43.21% C, 3.91% H. IR spectrum (chloroform): 1 750
(CO ester), 1 690 (CO ketone). UV spectrum (λmax, nm (log ε)): 202 (2.78), 217 (2.56), 290 (3.26).
1H NMR spectrum: 1.20 t, 6 H, J = 7.0 (CH3); 4.20 q, 4 H, J = 7.0 (CH2); 5.25 s, 1 H (CH); 7.42 d,
1 H, J(3,4) = 3.50 (H-3); 6.75 d, 1 H (H-4).
Ethyl 5-nitro-2-furoylmalonate (IIb). Yield 77%, b.p. 155 – 159 °C/0.12 kPa. For C12H13NO8
(299.2) calculated: 48.17% C, 4.38% H, 4.67% N; found: 48.09% C, 4.41% H, 4.52% N. IR spec-
trum: 1 740 (CO ester), 1 650 (CO ketone). UV spectrum (λmax, nm (log ε)): 225 (2.93), 285 sh
1
(2.98), 309 (3.06). H NMR spectrum: 1.23 t, 6 H, J = 7.0 (CH3); 4.25 q, 4 H, J = 7.0 (CH2); 5.43 s,
1 H (CH); 7.65 s, 1 H (H-3); 7.65 s, 1 H (H-4).
Ethyl 5-phenylthio-2-furoylmalonate (IIc). Yield 66%, m.p. 59 – 60 °C. For C18H18O6S (362.4)
calculated: 59.66% C, 5.01% H, 8.84% S; found: 59.42% C, 4.92% H, 8.68% S. IR spectrum (chlo-
roform): 1 750 (CO ester), 1 690 (CO ketone). UV spectrum (λmax, nm (log ε)): 240 (2.98), 278
1
(2.93), 322 (3.04). H NMR spectrum: 1.13 t, 6 H, J = 7.0 (CH3); 4.13 q, 4 H, J = 7.0 (CH2); 5.20 s,
1 H (CH); 7.45 d, 1 H, J(3,4) = 3.5 (H-3); 6.80 d, 1 H (H-4); 7.30 s, 5 H (H-aryl).
Ethyl 5-phenylsulfonyl-2-furoylmalonate (IId). Yield 75%, m.p. 25 – 27 °C. For C18H18O8S
(394.4) calculated: 54.82% C, 4.60% H, 8.13% S; found: 54.51% C, 4.72% H, 8.02% S. IR spectrum
(chloroform): 1 735 (CO ester), 1 700 (CO ketone). UV spectrum (λmax, nm (log ε)): 221 (3.29), 261
1
(3.47), 266 i (3.40). H NMR spectrum: 1.15 t, 6 H, J = 7.0 (CH3); 4.15 q, 4 H, J = 7.0 (CH2); 5.33 s,
1 H (CH); 7.49 s, 1 H (H-3); 7.49 s, 1 H (H-4); 7.65 – 7.75 m, 3 H (H-3′, H-4′, H-5′); 7.95 – 8.13 m,
2 H (H-2′, H-6′).
5-X-2-Furancarboxylic Acid Amides III (General Procedure)
The appropriate secondary amine (0.05 mol) was added to a stirred solution of the ethyl 5-X-2-fu-
roylmalonate (0.05 mol) in acetonitrile (10 ml) and the reaction mixture was stirred for 8 h. The
reaction course was monitored by thin-layer chromatography. After the reaction had ended, the reac-
tion mixture was cooled, the crude product collected on filter and crystallized from ethanol. The ob-
1
tained compounds and their physicochemical properties are listed in Table I, their H NMR spectral
data are given in Table II.
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Kada, Brunckova, Bobal:
TABLE II
1H NMR chemical shiftsa (δ, ppm) for 5-X-2-furancarboxylic acid amides III
Compound
H-3
H-4
X, Y
IIIa
IIIb
6.98 d
6.87 d
6.63 d 3.68 s, 8 H (H-2, H-3)
6.56 d 1.58 – 1.65 m, 6 H (H-3, H-4, H-5); 3.58 – 3.68 m,
4 H (H-2, H-6)
IIIc
IIId
7.00 d
7.04 d
6.60 d 3.50 t, 4 H (H-3, H-4); 3.77 t, 4 H (H-2, H-5)
6.67 d 3.27 t, 4 H (H-3, H-5); 3.92 t, 4 H (H-4, H-6); 6.78 – 7.35 m,
5 H (H-aryl)
IIIe
IIIf
IIIg
6.85 d
7.18 d
7.10 d
6.52 d 1.12 t, 6 H (2 × CH3); 2.85 q, 4 H (2 × NCH2)
7.54 d 3.70 s, 8 H (H-2, H-3)
7.53 d 1.64 – 1.69 m, 6 H (H-3, H-4, H-5); 3.61 – 3.72 m,
4 H (H-2, H-6)
IIIh
IIIi
7.25 d
7.26 d
7.56 d 3.56 t, 4 H (H-3, H-4); 3.89 t, 4 H (H-2, H-5)
7.62 d 3.31 t, 4 H (H-3, H-5); 3.87 t, 4 H (H-2, H-6);
6.78 – 7.21 m, 5 H (H-aryl)
IIIj
IIIk
IIIl
7.05 d
7.00 d
7.10 d
7.50 d 1.16 t, 6 H (2 × CH3); 3.06 q, 4 H (2 × NCH2)
6.85 d 7.26 s, 5 H (H-aryl); 3.61 s, 8 H (H-2, H-3)
6.90 d 7.29 s, 5 H (H-aryl); 1.58 – 1.65 m, 6 H (H-3, H-4, H-5);
3.42 – 3.65 m, 4 H (H-2, H-6)
IIIm
IIIn
IIIo
IIIp
IIIr
IIIs
IIIt
7.11 d
7.09 d
6.92 d
7.38 d
7.39 d
7.39 d
7.42 d
7.30 d
6.91 d 7.31 s, 5 H (H-aryl); 3.53 t, 4 H (H-3, H-4); 3.75 t,
4 H (H-2, H-6)
6.94 d 7.36 s, 5 H (H-aryl); 3.21 t, 4 H (H-3, H-5); 3.86 t,
4 H (H-2, H-6); 7.00 – 7.28 m, 5 H (H-aryl)
6.86 d 7.27 s, 5 H (H-aryl); 1.11 t, 6 H (2 × CH3); 2.80 q,
4 H (2 × NCH2)
7.06 d 7.66 – 7.80 m, 3 H (m, p); 7.98 – 8.12 m, 2 H (o); 3.64 s,
8 H (H-2, H-3)
7.00 d 7.65 – 7.80 m, 3 H (m, p); 7.99 – 8.13 m, 2 H (o); 1.55 – 1.68
m, 6 H (H-3, H-4, H-5); 3.49 – 3.59 m, 4 H (H-2, H-6)
7.14 d 7.66 – 7.82 m, 3 H (m, p); 8.00 – 8.15 m, 2 H (o);
3.51 t, 4 H (H-3, H-4); 3.75 t, 4 H (H-2, H-5)
7.12 d 7.78 – 7.80 m, 3 H (m, p); 8.03 – 8.14 m, 2 H (o); 3.28 t, 4 H
(H-3); 3.84 t, 4 H (H-2); 6.85 – 7.36 m, 5 H (H-aryl)
IIIv
6.96 d 7.57 – 7.72 m, 3 H (m, p); 7.00 – 8.05 m, 2 H (o); 1.15 t,
6 H (2 × CH3); 3.00 q, 4 H (2 × NCH2)
a J(3,4) = 3.5 – 3.8 Hz.
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