ONE-STEP SYNTHESIS OF 2-AMINO-3-FURANCARBOXYLIC ACID DERIVATIVES FROM 2-FURANCARBALDEHYDE

Article abstract of DOI:10.1135/cccc19942481

Reaction of derivatives of 2-furancarbaldehyde or 2-acetylfuran with malononitrile, methyl cyanoacetate or cyanoacetamide in the presence of secondary amines afforded derivatives of 2-amino-3-furancarboxylic acid in 45 - 88percent yields.

Full text of DOI:10.1135/cccc19942481

2-Amino-3-furancarboxylic Acid Derivatives
2481
ONE-STEP SYNTHESIS OF 2-AMINO-3-FURANCARBOXYLIC ACID
DERIVATIVES FROM 2-FURANCARBALDEHYDE
a
b
a
a
Peter SAFAR , Pavel CEPEC , Frantisek POVAZANEC , Anna KORENOVA
c
and Nada PRONAYOVA
a Department of Organic Chemistry,
Slovak Technical University, 812 37 Bratislava, The Slovak Republic
b Wood Research Institute,
841 05 Bratislava, The Slovak Republic
c Central Laboratory,
Slovak Technical University, 812 37 Bratislava, The Slovak Republic
Received September 14, 1993
Accepted June 22, 1994
Reaction of derivatives of 2-furancarbaldehyde or 2-acetylfuran with malononitrile, methyl
cyanoacetate or cyanoacetamide in the presence of secondary amines afforded derivatives of
2-amino-3-furancarboxylic acid in 45 – 88% yields.
Iminium salts of 1,5-diarylamino-2-hydroxy-2,4-pentadienal1 (I) are important inter-
mediates in the synthesis of N-arylpyrrol-2-carbaldehydes2,3, N-aryl-3-hydroxy-
pyridinium salts4,5 or 2,4-diarylamino-2-cyclopentenones6–8 . The present study
concerns the synthetic utilization of reactive intermediates arising in the base-induced
opening of 2-substituted furan derivatives for the preparation of polysubstituted amino-
furan compounds.
Reaction of iminium salt of 1,5-dianilino-2-hydroxy-2,4-pentadienal (I) with
malononitrile in pyridine afforded 2-amino-5-(E)-(4,4-dicyano-1,3-butadienyl)-3-furan-
carbonitrile (VIIa) in 62% yield. In an attempt to increase the yield of compound VIIa,
we performed the reaction of compound I with malononitrile in a mixture of pyridine
and acetic anhydride (1 : 6). However, subsequent reaction of the obtained 5-(N-
phenylacetamido)-2-acetoxy-2,4-pentadienylidenemalononitrile (IIa) with malono-
nitrile and morpholine did not give the compound VIIa but, instead, a nucleophilic
substitution product, 5-morpholin-1-yl-2-acetoxy-2,4-pentadienylidenemalononitrile
(IIb). Similarly unsuccessful were also the reactions of compound I with methyl
cyanoacetate or cyanoacetamide: instead of the expected aminofuran derivatives VIIb
and VIIc we obtained only cyclopentenones IIIa and IIIb.
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

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Safar, Cepec, Povazanec, Korenova, Pronayova:
The aminofuran derivative VIIa was obtained by reaction of 2-furancarbaldehyde
(IVa) with malononitrile in the presence of amine in molar ratio 1 : 2 : 1 (with aniline
the yield was 11%, with morpholine 88%).
Under the same conditions, aldehyde IVa reacted with methyl cyanoacetate or
cyanoacetamide to give methyl 2-amino-5-[(1E,3E)-4-cyano-4-methoxycarbonyl-1,3-
butadienyl]-3-furancarboxylate (VIIb) or 2-amino-5-[(1E,3E)-4-aminocarbonyl-4-
cyano-1,3-butadienyl]-3-furancarboxamide (VIIc). The aminofurans VIIa – VIIc were
prepared also from the condensation products Va – Vc.
Similarly reacted the 3-bromo- and 3-methyl-substituted 2-furancarbaldehydes IVb
and IVc or their condensation products Vd – Vi with malonic acid derivatives under
formation of aminofurans VIId – VIIi. Reaction of compound Vd with malononitrile
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2-Amino-3-furancarboxylic Acid Derivatives
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gave compound VIId and 2-imino-5-(1-bromo-3-morpholin-1-yl-2-propenylidene)-2,5-
dihydrofuran-3-carbonitrile (VIII) which is probably an intermediate in the conversion
of compound Vd into compound VIId. On reaction with malononitrile in methanol the
compound VIII was converted almost quantitatively into compound VIId (as evidenced
1
by H NMR spectrum and TLC).
Under the described reaction conditions, 4-bromo-2-furancarbaldehyde gave only
condensation products IXa – IXc and 5-bromo-2-furancarbaldehyde was converted into
a secondary amine by nucleophilic substitution of the bromine atom9.
Using the method of opening and recyclization of the furan ring, we prepared poly-
substituted 2-aminofuran derivatives XIa and XIb by reaction of 2-acetylfuran (X) with
malononitrile or cyanoacetamide in the presence of pyrrolidine.
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Safar, Cepec, Povazanec, Korenova, Pronayova:
1
The structure of the synthesized compounds was determined on the basis of H and
13C NMR spectra, IR spectra and elemental analysis; compound VIIa was also prepared
by an independent synthesis16. Vicinal coupling constants in the spectrum of compound
VIIa (3J(C-3,H-6) = 0 Hz; 3J(C-10,H-8) = 12.4 Hz; 3J(R2,H-8) = 7.0 Hz and 3J(C-6,H-8) =
3
3
4.4 Hz) and compound IIb (3J(C-3,H-6) = 0 Hz, J(C-10,H-8) = 12.4 Hz; J(R2,H-8) =
3
7.6 Hz and J(C-6, H-8) = 4.4 Hz) have shown that the configuration of the multiple
bonds is 1E,3E (refs10,11).
The described synthetic method makes possible the synthesis of derivatives of
2-amino-3-furancarboxylic acid from 2-furancarbaldehyde or 2-acetylfuran by opening
and recyclization of the furan ring.
EXPERIMENTAL
The melting points were determined on a Kofler block Boetius and are uncorrected. UV spectra were
measured in methanol on an M-40 (Zeiss, Jena) spectrophotometer; concentration 1 . 10−4 mol dm3,
ε values are given in m2 mol−1. IR spectra were recorded on a PU 9800 FTIR Philips analytical spec-
trometer in KBr pellets (wavenumbers in cm−1). Proton (300 MHz) and 13C NMR (75.05 MHz) spectra
were obtained with a Varian VXR-300 instrument at 25 °C in hexadeuteriodimethyl sulfoxide with
tetramethylsilane as internal standard. Chemical shifts are given in ppm (δ-scale), coupling constants
(J) in Hz. 3-Bromofuran was prepared according to ref.12, 3-methyl-2-furancarbaldehyde
(IVc) according to ref.13, 2-cyano-3-(2-furyl)propenenitrile (Va), methyl (E)-2-cyano-3-(2-
furyl)propenoate (Vb) and (E)-2-cyano-3-(2-furyl)propenamide (Vc) according to ref.10.
2-Amino-5-[(E)-4,4-dicyano-1,3-butadienyl]-3-furancarbonitrile (VIIa)
1,5-Bis(phenylamino)-2-hydroxypentamethinium chloride (I; 3 g, 0.01 mol) was added in one portion
to a solution of malononitrile (2.0 g, 0.03 mol) in pyridine (10 ml). After stirring and heating at
70 – 80 °C for 10 min, the mixture was allowed to cool slowly to ambient temperature. The de-
posited precipitate was filtered, washed with ice-cold methanol and crystallized from methanol; yield
1.3 g (62%) of compound VIIa. For the physicochemical characteristics see Tables I, II and V.
2,4-Bis(phenylamino)-2-cyclopentenone (IIIa)
A. Salt I (3.0 g, 0.01 mol) was added in one portion to a solution of methyl cyanoacetate (3.0 g,
0.03 mol) in pyridine (10 ml). After stirring and heating at 70 °C for 30 min, the mixture was cooled
to room temperature and poured into water (200 ml). The solid was collected on filter and purified
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2-Amino-3-furancarboxylic Acid Derivatives
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TABLE I
Yields, melting points and elemental analyses of compounds Vd – Vi, VIIa – VIIi and IXa – IXc
Calculated/Found
IR spectrum, cm−1
M.p., °C
Yield, %
Formula
(M.w.)
Compound
%
C
%
H
%
Brν%(C≡N) Nν(C=O)
Vd
167 – 168 C8H3BrN2O
89 (223.0)
132 – 134 C9H6BrNO3
81 (256.1)
189 –192 C8H5BrN2O2
86 (241.0)
123 – 124 C9H6N2O
91 (158.2)
90 – 93 C10H9NO3
79 (191.2)
160 – 161 C9H8N2O2
83 (176.2)
222 – 224 C11H6N4O
88 (210.2)
228 – 228 C13H12N2O5
65 (276.3)
240 – 244 C11H10N4O3
47 (246.2)
217 – 219 C11H5BrN4O
79 (289.1)
43.08
42.92
1.36
1.21
35.83
35.78
12.56
12.42
2 222
2 228
2 226
2 230
2 236
2 233
2 220
2 203
2 205
2 200
2 230
2 210
2 220
2 221
2 219
–
Ve
42.22
42.09
2.36
2.21
31.21
31.16
5.47
5.35
1 657
1 660
–
Vf
39.86
39.74
2.09
1.93
33.15
33.08
11.62
11.52
Vg
68.35
68.21
3.82
3.74
–
–
–
–
–
–
17.71
17.66
Vh
62.82
62.75
4.74
4.64
7.33
7.24
1 652
1 649
1 606
1 686
1 655
1 600
1 663
1 649
–
Vi
61.36
61.29
4.58
4.50
15.90
15.84
VIIa
VIIb
VIIc
VIId
VIIe
VIIf
VIIg
VIIh
VIIi
62.86
62.79
2.88
2.69
26.65
26.58
56.52
56.46
4.38
4.28
10.14
10.04
53.66
53.57
4.09
4.01
22.75
22.69
45.70
45.61
1.74
1.66
27.64
27.58
19.38
19.25
179 – 181 C13H11BrN2O5 43.97
3.12
3.06
22.50
22.44
7.89
7.82
62
243 – 246 C11H9BrN4O
45 (293.1)
199 – 201 C12H8N4O
76 (224.2)
177 – 179 C11H14N2O5
55 (290.3)
244 – 246 C12H12N4O3
45 (260.3)
(355.2)
43.88
45.07
44.97
3.09
2.98
27.26
27.20
19.11
19.07
64.28
64.21
3.60
3.53
–
–
–
24.99
24.90
57.93
57.88
4.86
4.79
9.65
9.58
1 651
1 653
55.38
55.31
4.65
4.59
21.53
21.48
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Safar, Cepec, Povazanec, Korenova, Pronayova:
TABLE I
(Continued)
Calculated/Found
IR spectrum, cm−1
M.p., °C
Yield, %
Formula
(M.w.)
Compound
% C
% H
% Br
% N
ν(C≡N) ν(C=O)
IXa
IXb
IXc
142 – 144 C8H3BrN2O
89 (223.0)
139 – 140.5 C9H6BrNO3
82 (256.1)
186 – 187.5 C8H5BrN2O2
78 (241.0)
43.08
43.02
1.36
1.28
35.83
35.77
12.56
12.51
2 221
2 226
2 225
–
42.22
42.17
2.36
2.31
31.21
31.16
5.47
5.43
1 653
1 662
39.86
39.81
2.09
2.04
33.15
33.08
11.62
11.57
TABLE II
1H NMR spectral parameters for compounds Vd – Vi and IXa – IXc. Chemical shifts in ppm
(δ-scale), coupling constants (J) in Hz
H-4, d
J(4,5)
H-5, d
J(5,4)
Compound
H-3, s
H-6, s
Other signal
Vd
Ve
Vf
–
–
–
7.19
2.1
8.35
2.1
8.09
7.80
7.77
8.27
7.93
7.85
7.16
1.8
8.32
1.8
3.82 s, 3 H (OCH3)
7.92 bs, 2 H (NH2)
7.07
1.7
8.21
1.7
Vg
Vh
Vi
6.76
1.5
8.16
1.5
–
–
6.75
1.8
8.12
1.8
2.26 s, 3 H (CH3)
3.82 s, 3 H (OCH3)
–
6.69
1.5
8.03
1.5
2.23 s, 3 H (CH3)
IXa
IXb
IXc
7.57
7.58
7.46
–
–
–
8.28a
8.20a
8.12a
8.08
8.07
7.99
3.91 s, 3 H (OCH3)
7.08 bs, 2 H (NH2)
a
Singlets.
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2-Amino-3-furancarboxylic Acid Derivatives
2487
by crystallization from benzene; yield 0.85 g (33%) of IIIa, m.p. 141 – 142 °C (decomp.); reported7
m.p. 140 – 143 °C and m.p. 144 °C (ref.6).
B. Cyanoacetamide (2.5 g, 0.03 mol) reacted with the salt I (3.0 g, 0.01 mol) as described in proce-
dure A; yield of compound IIIa was 1.0 g (39%), m.p. 141 – 142 °C.
2-Phenylamino-4-(piperidin-1-yl)-2-cyclopentenone (IIIb)
A. Salt I (3.0 g, 0.01 mol) was added in one portion to a solution of methyl cyanoacetate (3.0 g,
0.03 mol) and piperidine (2.6 g, 0.03 mol) in pyridine (10 ml) and the reaction mixture was treated
as described for the preparation of compound IIIa. Yield 1.8 g (68%) of IIIb, m.p. 121 – 123 °C
(reported14 m.p. 123 – 124 °C).
B. Reaction of cyanoacetamide (2.5 g, 0.03 mol) with the salt I (3.0 g, 0.01 mol) according to
procedure A afforded 1.5 g (57%) of the product, m.p. 121 – 123 °C.
2-Acetoxy-5-(N-phenylacetamido)-2,4-pentadienylidenemalononitrile (IIa)
A. Malononitrile (0.8 g, 0.012 mol) was dissolved in a mixture of acetic acid (20 ml), pyridine
(1.5 ml) and acetic anhydride (10 ml). The salt I (3.0 g, 0.01 mol) was rapidly added portionwise to
the vigorously stirred mixture. After stirring at room temperature for 24 h, the mixture was poured
into ice-cold water (100 ml), the solid material was filtered, washed with water, dilute methanol and
crystallized from methanol. Yield 2.88 g (90%) of compound IIa, m.p. 188 – 190 °C. For
C18H15N3O3 (321.3) calculated: 67.28% C, 4.71% H, 13.08% N; found: 67.06% C, 4.65% H, 13.19% N.
1H NMR spectrum: 1.85 s, 3 H (NCOCH3); 1.94 s, 3 H (OCOCH3); 4.78 dd, 1 H (H-6, J(5,6) = 12.0,
J(6,7) = 14.0); 7.23 d, 1 H (H-5, J(5,6) = 12); 7.86 s, 1 H (H-3); 7.31 – 7.62 m, 5 H (arom. H); 8.23 d,
1 H (H-7, J(7,6) = 14.0). 13C NMR spectrum: 19.4 q (CH3); 23.1 q (CH3); 72.9 s (C-2); 114.8 s
(2 × CN); 104.7 d (C-6); 128 d (C-2′ and C-6′); 129.4 d (C-4′); 130.2 d (C-3′ and C-5′); 139.5 s
(C-1′); 137.8 s (C-4); 140.5 d (C-5); 143.7 d (C-3); 153.3 d (C-7); 167.5 s (N−C=O); 169.0 s (O−C=O).
B. Malononitrile (0.8 g, 0.012 mol) was dissolved in a suspension of sodium acetate (1.7 g,
0.02 mol) and acetic anhydride (30 ml). Salt I (3.0 g, 0.01 mol) was added in portions to the vigor-
ously stirred mixture. After 24 h, the mixture was processed as described in the procedure A. Yield
1.93 g (60%) of IIa.
2-Acetoxy-5-(morpholin-1-yl)-2,4-pentadienylidenemalononitrile (IIb)
A solution of morpholine (0.87 g, 0.01 mol) in methanol (5 ml) was added to a vigorously stirred
suspension of compound IIa (3.21 g, 0.01 mol) in dry methanol (100 ml). After several minutes the
mixture became homogeneous and a solid deposited. After stirring for 2 h the solid was collected,
washed with ice-cold methanol and purified by crystallization from methanol. Yield 2.1 g (77%) of
compound IIb, m.p. 165 – 167 °C. For C14H15N3O3 (273.3) calculated: 61.53% C, 5.53% H, 15.38% N;
1
found: 61.49% C, 5.48% H, 15.35% N. H NMR spectrum: 2.1 s, 3 H (OCOCH3); 3.38 – 3.75 m, 8 H
(4 × CH2 of morpholine); 5.44 m, 1 H (H-6); 6.98 d, 1 H (H-5, J(5,6) = 12.0); 7.26 s, 1 H (H-3);
7.52 d, 1 H (H-7, J(7,6) = 12.0). 13C NMR spectrum: 20.2 q (CH3); 46.0 t (2 × NCH2); 53.5 t
(2 × OCH2); 55.3 s (C-2); 116.9 s (CN); 118.5 s (C-1); 96.0 d (C-6); 133.2 s (C-4); 147.5 d (C-5);
147.7 d (C-3); 158.2 d (C-7); 168.4 s (C=O).
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

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Safar, Cepec, Povazanec, Korenova, Pronayova:
General Procedure for Preparation of Nitriles VIIa, VIId, VIIg, Methyl Esters VIIb, VIIe, VIIh, and
Amides VIIc, VIIf and VIIi
A. The corresponding aldehyde (0.01 mol), and the methylene component (0.02 mol) were dis-
solved in methanol (15 ml) and a solution of the secondary amine (0.01 mol, morpholine, piperidine
or pyrrolidine) in methanol (3 ml) was added under vigorous stirring. After a short exothermic reac-
tion, the solution was stirred at room temperature for 3 h and then allowed to stand at 0 °C for 12 h.
After acidification with dilute acetic acid, the deposited solid was collected and purified by crystal-
lization from methanol.
B. The corresponding compound Va – Vi (0.01 mol) was dissolved in methanol (10 ml) and the
methylene component (0.01 mol) was added. The mixture was vigorously stirred and a solution of
the secondary amine (0.01 mol; morpholine, piperidine or pyrrolidine) in methanol (3 ml) was added.
The reaction mixture was worked up as described for procedure A. For physicochemical and spectral
characteristics of compounds VIIa – VIIi see Tables I, III and V.
5-[(2E)-1-Bromo-(3-morpholin-1-yl)-2-propenylidene]-2-imino-2,5-dihydrofuran-3-carbonitrile (VIII)
The title compound was obtained by reaction of compound IVb (1.75 g, 0.01 mol) with malononitrile
(1.32 g, 0.02 mol) and morpholine (0.87 g, 0.01 mol) as described in procedure A of the preceding
experiment. The reaction mixture was subjected to chromatography on silica gel L100/250 in
benzene–ethyl acetate (5 : 1) and then in ethyl acetate; yield 0.38 g (12.3%) of compound VIII, m.p.
167 – 169 °C. For C12H12BrN3O2 (310.2) calculated: 46.47% C, 3.90% H, 25.76% Br, 13.55% N;
found: 46.21% C, 3.79% H, 25.58% Br, 13.50% N. 1 H NMR spectrum: 3.35 m, 4 H (NCH2); 3.69 m,
4 H (OCH2); 5.65 d, 1 H (H-7, J(7,8) = 12.6); 7.26 s, 1 H (H-4); 7.57 d, 1 H (H-8, J(8,7) = 12.6);
8.20 s, 1 H (NH). 13C NMR spectrum: 49.77 t (NCH2); 65.57 t (OCH2); 69.22 s (C-3); 99.48 d (C-7);
114.93 s (CN); 117.96 s (C-6); 124.19 d (C-4); 132.15 s (C-5); 157.71 d (C-8); 165.73 s (C-2).
Reaction of Compound VIII with Malononitrile
A solution of compound VIII (320 mg, 1 mmol) in methanol (5 ml) was warmed to 45 °C. Malono-
nitrile (100 mg, 1.5 mmol) in methanol (2 ml) was added in one portion and the mixture was re-
fluxed for 30 min. After cooling and standing at 0 °C for 12 h, the solid was filtered, washed with a
small amount of methanol and purified by crystallization from methanol to give 185 mg (65%) of
compound VIId.
2-Amino-4-methyl-[(E)-4,4-dicyano-1,3-butadienyl]-3-furancarbonitrile (XIa)
A. A solution of pyrrolidine (0.71 g, 0.01 mol) in methanol (3 ml) was added at once to a vigorously
stirred solution of (Z)-2-cyano-3-methyl-3-(2-furyl)propenenitrile10 (1.5 g, 0.01 mol) in methanol (10
ml). After stirring for 2 min, a solution of malononitrile (0.7 g, 0.01 mol) in methanol (5 ml) was
added and stirring was continued for 10 min. The mixture was acidified with dilute acetic acid, the
precipitate was collected and crystallized from methanol. Yield 1.45 g (65%) of compound XIa. For
physicochemical characteristics and NMR spectra see Tables I, II and IV.
B. 2-Acetylfuran (1.1 g, 0.01 mol), malononitrile (1.33 g, 0.02 mol) and pyrrolidine (0.7 g, 0.01 mol)
in methanol (10 ml) reacted as described under A; yield 1.05 g (47%) of compound XIa.
C. The same procedure as described under A, applied to 2-acetylfuran (1.1 g, 0.01 mol), malono-
nitrile (1.33 g, 0.02 mol) and sodium ethoxide (0.68 g, 0.01 mol) in ethanol (10 ml), afforded 0.92 g
(41%) of compound XIa, m.p. 266 – 270 °C (decomp.). For C12H8N4O (224.2) calculated: 64.28% C,
1
3.60% H, 24.99% N; found: 64.15% C, 3.51% H, 25.10% N. H NMR spectrum: 6.38 dd, 1 H (H-7,
J(8,7) = 12.0, J(7,6) = 14.0); 7.33 d, 1 H (H-6, J(7,6) = 14.0); 7.89 d, 1 H (H-8, J(8,7) = 12.0); 8.91 m,
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

2-Amino-3-furancarboxylic Acid Derivatives
2489
2 H (NH2); 2.14 s, 3 H (CH3). 13C NMR spectrum: 9.8 q (CH3); 70.8 s (C-9); 75.4 s (C-4); 112.8 d
(C-7); 114.1 s (CN); 115.8 s (C-10); 132.2 d (C-6); 137.9 s (C-2); 139.3 s (C-3); 160.1 d (C-8);
165.8 s (C-5).
2-Amino-4-methyl-5-[(1E,3E)-4-cyano-4-aminocarbonyl-1,3-butadienyl]-3-furancarboxamide (XIb)
A solution of 2-acetylfuran (1.1 g, 0.01 mol), cyanoacetamide (1.9 g, 0.02 mol) and pyrrolidine (0.71 g,
0.01 mol) in ethanol (10 ml) was refluxed for 3 h. After standing at room temperature for 12 h and
at 0 °C for 5 h, the deposited precipitate was collected, washed with anhydrous methanol and dried;
yield 0.47 g (18%) of compound XIb, m.p. 278 – 280 °C (decomp.). For C12H12N4O3 (260.3) calcu-
1
lated: 55.38% C, 4.65% H, 21.53% N; found: 55.16% C, 4.70% H, 21.62% N. H NMR spectrum:
2.20 s, 3 H (CH3); 6.41 dd, 1 H (H-7, J(8,7) = 12.0, J(7,6) = 14.0); 6.69 bs, 2 H (CONH2); 7.21 d,
1 H (H-6, J(6,7) = 14.0); 7.25 bs, 2 H (CONH2); 7.80 d, 1 H (H-8, J(8,7) = 12.0). 13C NMR spec-
trum: 9.8 q, (CH3); 95.2 s (C-9); 100.9 s (C-4); 114.4 d (C-7); 115.4 s (C-10); 116.8 s (CONH2);
129.1 s (C-3); 132.2 d (C-6); 139.6 s (C-2); 151.8 d (C-8); 165.3 s (C-5).
TABLE III
1H NMR spectral parameters for compounds VIIa – VIIi. Chemical shifts in ppm (δ-scale), coupling
constants (J) in Hz
H-6, d
J(6,7)
H-7, dd
J(7,6), J(7,8)
H-8, d
J(8,7)
Compound H-3, s
Other signals
VIIa
VIIb
7.47
7.18
7.14
14.1
6.50
12.3; 14.1
8.06
12.3
8.84 bs, 2 H (NH2)
7.27
14.1
6.54
12.1; 14.1
8.03
12.1
3.71 s, 3 H (OCH3)
3.75 s, 3 H (OCH3)
8.22 bs, 2 H (NH2)
VIIc
VIId
VIIe
7.27
7.89
7.31
7.07
14.7
6.50
12.3; 14.7
7.88
12.6
7.81 bs, 2 H (NH2)
7.42 m, 4 H (2 × NH2)
–
7.39
12.0
8.52
12.0
9.56 s, 2 H (NH2)
–
6.90
12.0
8.03
12.0
3.72 s, 3 H (OCH3)
3.79 s, 3 H (OCH3)
8.42 bs, 2 H (NH2)
VIIf
VIIg
VIIh
7.66
7.61
7.42
–
–
–
6.87
11.7
7.98
11.7
7.99 bs, 2 H (NH2)
7.99 bs, 2 H (NH2)
6.59
12.6
8.24
12.6
2.20 s, 3 H (CH3)
8.70 bs, 2 H (NH2)
6.65
12.9
8.12
12.9
2.21 s, 3 H (CH3)
3.72 and 3.77 s, 2 × 3 H (2 × OCH3)
8.12 s, 2 H (NH2)
VIIi
7.45
–
6.62
12.3
8.03
12.3
2.16 s, 3 H (CH3)
6.92 bs, 2 H (NH2)
7.35 – 7.72 b, 4 H (2 × NH2)
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

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Safar, Cepec, Povazanec, Korenova, Pronayova:
3-Bromo-2-furancarbaldehyde (IVb)
Phosphorus oxychloride (16.1 g, 0.105 mol) was added dropwise at 0 °C to a stirred solution of
3-bromofuran (14.7 g, 0.1 mol) and N,N-dimethylformamide (8.0 g, 0.11 mol). The mixture was
allowed to stand at room temperature for 1 h, heated at 80 °C for 2 h, cooled, poured on ice (1 kg)
and neutralized with solid potassium carbonate. After standing for 2 h, the deposited oil was separ-
ated, the aqueous layer extracted with ether (2 × 100 ml), and the combined organic layers were
dried. The solvent was evaporated and the product was distilled in vacuo. Fraction b.p. 89 – 90 °C/1.6
kPa was collected, yield 15.1 g (86%) of compound IVb (reported15 b.p. 97 – 98 °C/1.8 kPa.
General Procedure for Preparation of 2-Cyano-(3-bromo-2-furyl)propenenitrile (Vd), Methyl (E)-2-
Cyano-(3-bromo-2-furyl)propenoate (Ve) and (E)-2-Cyano-(3-bromo-2-furyl)propenamide (Vf)
Malononitrile, methyl cyanoacetate or cyanoacetamide (25 mmol) was dissolved in methanol (5 ml)
and sodium methoxide (27 mg, 0.5 mmol) was added. 3-Bromo-2-furancarbaldehyde (4.4 g,
25 mmol) in methanol (3 ml) was added in one portion to the vigorously stirred mixture. After stir-
ring at room temperature for 2 h, the mixture was decomposed with water (0.2 ml) and allowed to
stand at 0 °C for 12 h. The solid was collected, washed with water and purified by crystallization
from aqueous ethanol. For physicochemical and spectral characteristics of the obtained compounds
Vd – Vf see Tables I, II and IV.
General Procedure for Preparation of 2-Cyano-(3-methyl-2-furyl)propenenitrile (Vg),
Methyl (E)-2-Cyano-(3-methyl-2-furyl)propenoate (Vg) and
(E)-2-Cyano-(3-methyl-2-furyl)propenamide (Vi)
Malononitrile, methyl cyanoacetate or cyanoacetamide (25 mmol) was dissolved in methanol (10 ml)
and triethylamine (several drops) was added. The mixture was heated at 50 °C and 3-methyl-2-furan-
carbaldehyde (2.75 g, 25 mmol) in methanol (3 ml) was added. After heating at reflux for 15 min,
TABLE IV
13C NMR chemical shifts (ppm, δ-scale) of compounds Vd – Vi and IXa – IXc
Compound
C-2
C-3
C-4
C-5
C-6
C-7
C-8
R2
Vd
Vea
145.6
145.2
145.4
145.2
144.7
144.6
149.9
150.3
150.7
116.6
115.4
115.8
138.8
137.1
133.9
126.0
124.4
122.6
118.1
117.4
116.9
116.7
116.5
115.9
104.1
101.0
104.0
151.6
150.8
149.3
150.8
149.7
148.1
148.9
147.8
146.7
140.4
131.2
131.4
141.6
135.9
132.5
143.9
139.0
136.5
76.8
98.4
114.4 113.5 (CN)
114.8 162.8 (COO)
112.5 162.2 (CON)
115.1 113.8 (CN)
115.6 163.2 (COO)
116.6 163.2 (CON)
113.3 114.5 (CN)
115.3 163.1 (COO)
116.5 162.1 (CON)
Vf
102.8
72.4
Vgb
Vhc
Vid
IXa
IXbe
IXc
94.6
99.4
79.6
103.7
103.3
a
b
c
Other signal: 53.1 (OCH3). Other signal: 10.4 (CH3). Other signals: 53.0 (OCH3); 10.4
d
e
(CH3). Other signal: 10.3 (CH3). Other signal: 53.6 (OCH3).
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

2-Amino-3-furancarboxylic Acid Derivatives
2491
water (0.5 ml) was added and the mixture was set aside at 0 °C for 12 h. The solid was collected and
crystallized from aqueous ethanol. For physicochemical and spectral characteristics of the products
Vg – Vi see Tables I, II and IV.
General Procedure for Preparation of 2-Cyano-(4-bromo-2-furyl)propenenitrile (IXa), Methyl (E)-2-
Cyano-(4-bromo-2-furyl)propenoate (IXb) and (E)-2-Cyano-(4-bromo-2-furyl)propenamide (IXc)
The title compounds were prepared from 4-bromo-2-furancarbaldehyde17 in the same manner as de-
scribed for the preparation of compounds Vg – Vi in the preceding experiment. For physicochemical
and spectral characteristics of the products IXa – IXc see Tables I, II and IV.
Methyl (E)-2-Amino-5-(3-oxopropenyl)furan-3-carboxylate16 (VI)
Methyl 2-cyano-3-(2-furyl)propenoate (5.3 g, 0.02 mol) was added in one portion under stirring into
piperidine (20 ml). After the exothermic reaction had subsided, the deep-red mixture was stirred at
room temperature for 30 min. After standing for 12 h, the viscous solution was poured under vi-
gorous stirring into water (500 ml). The separated solid was collected, washed with dilute methanol
and crystallized from methanol. Yield 2.4 g (41%) of compound VI; m.p. 173 – 174 °C. For
C9H9NO4 (195.2) calculated: 55.39% C, 4.65% H, 7.18% N; found: 55.11% C, 4.47% H, 7.82% N.
1H NMR spectrum: 9.48 d, 1 H (CH=O, J = 8.0); 7.91 bs, 1 H (NH2); 7.31 d, 1 H (H-6, J(6,7) =
15.1); 7.19 s, 1 H (H of furan); 6.10 dd, 1 H (H-7, J(7,8) = 8.0, J(6,7) = 15.1; 3.75 s, 3 H (OCH3).
Independent Synthesis of Compound VIIb from VI
Compound VI (1.95 g, 0.01 mol) and methyl cyanoacetate (1.1 g, 0.011 mol) were dissolved in N,N-
dimethylformamide (20 ml) at 35 °C and piperidine (3 drops) was added with stirring. The mixture
was stirred for 5 h, poured into water (100 ml), the solid was collected, washed with dilute methanol
and crystallized from methanol. Yield 2.15 g (78%) of compound VIIb.
TABLE V
13C NMR chemical shifts (ppm, δ-scale) of compounds VIIa – VIIi
Compound C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10
R2
VIIa
VIIba
VIIc
140.4 126.6 73.5 166.5 134.1 114.8 160.4 72.3 113.6 114.2; 115.3 (2 × CN)
140.6 122.9 96.3 164.7 134.5 114.6 155.5 93.0 115.8 162.9; 163.2 (2 × COO)
139.6 120.0 100.9 165.3 132.3 114.4 151.7 95.2 116.8 163.3; 164.0 (2 × CON)
138.8 127.2 76.3 166.2 126.3 113.4 156.0 73.3 113.2 113.5; 114.6 (2 × CN)
139.0 123.8 99.6 165.0 126.7 113.2 150.9 93.9 115.6 162.6; 162.7 (2 × COO)
138.2 121.8 104.1 162.1 124.2 112.8 147.7 96.0 116.6 164.6; 165.0 (2 × CON)
142.2 123.4 73.7 166.1 142.7 113.3 156.1 71.6 115.8 113.6; 114.2 (2 × CN)
142.3 120.5 96.0 164.5 142.4 112.6 150.5 92.7 116.1 163.1; 164.5 (2 × COO)
141.5 117.2 101.5 165.4 139.2 112.5 146.4 94.7 117.0 163.7; 163.8 (2 × CON)
VIId
VIIeb
VIIf
VIIgc
VIIhd
VIIie
a
b
c
Other signals: 50.9; 52.5 (2 × OCH3). Other signals: 51.0; 52.9 (2 × OCH3). Other signal: 13.5
d
e
(CH3). Other signals: 13.5 (CH3); 50.8; 52.5 (2 × OCH3). Other signal: 13.5 (CH3).
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

2492
Safar, Cepec, Povazanec, Korenova, Pronayova:
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Translated by M. Tichy.
Collect. Czech. Chem. Commun. (Vol. 59) (1994)