Gould-Jacobs reaction of 5- and 6-amino-2-substituted benzoxazoles. I. Reaction with diethyl ethoxymethylenemalonate

Article abstract of DOI:10.1135/cccc19960268

Reaction of 2-substituted 5- and 6-aminobenzoxazoles 1 and 2 with diethyl ethoxymethylenemalonate afforded the corresponding diethyl 3-N-(5- and 6-benzoxazolyl)aminomethylenemalonates 3 and 4. Under conditions of the Gould-Jacobs reaction, the compounds 3

Full text of DOI:10.1135/cccc19960268

2
68
Ilavsky, Heleyova, Nadaska, Bobosik:
GOULD–JACOBS REACTION OF 5- AND 6-AMINO-2-SUBSTITUTED
BENZOXAZOLES. I. REACTION WITH DIETHYL
ETHOXYMETHYLENEMALONATE
†
Dusan ILAVSKY, Katarina HELEYOVA, Jana NADASKA and Vladimir BOBOSIK
Department of Organic Chemistry,
Slovak Technical University, 812 37 Bratislava, Slovak Republic
Received June 7, 1995
Accepted September 24, 1995
Reaction of 2-substituted 5- and 6-aminobenzoxazoles 1 and 2 with diethyl ethoxymethylenemalonate
afforded the corresponding diethyl 3-N-(5- and 6-benzoxazolyl)aminomethylenemalonates 3 and 4.
Under conditions of the Gould–Jacobs reaction, the compounds 3 gave a mixture of angularly and
linearly annelated oxazolo[4,5-f]quinolones 5 and oxazolo[5,4-g]quinolones 6, and compounds 4 af-
forded a mixture of oxazolo[5,4-f]quinolones 7 and oxazolo[4,5-g]quinolones 8.
Key words: Gould–Jacobs reaction; Oxazoloquinolones.
The Gould–Jacobs reaction, consisting in addition of a fused 4-pyridone ring to an
aromatic structure, has received an increased attention since the discovery of antimicro-
1
bial properties of nalidixic acid in 1962. In the aminobenzimidazole, aminobenzotriazole
and aminobenzothiazole series, the cyclocondensation with derivatives of alkoxy-
methylenemalonic acid was studied in detail from the viewpoint of the structure of the
2
–5
resulting azoloquinolone and of the interesting stereochemistry and spectral proper-
6
ties of the substitution products . A similar reaction with aminobenzoxazole is men-
7
tioned in an only one Japanese patent . All these papers report the exclusive formation
of the angularly annelated azoloquinolone derivative.
In this study we describe the condensation of 2-substituted 5- and 6-aminobenzoxa-
zoles 1a–1c and 2a–2c with diethyl ethoxymethylenemalonate (EMME) which leads to
the respective substitution products 3a–3c and 4a–4c. Further we describe their thermal
cyclization to oxazoloquinolone derivatives 5–8 and structural proof of the products
(
Scheme 1).
So far, no formation of linearly annelated heterocyclic derivative has been reported
in the benzazole series (benzothiazoles, benzotriazoles). This communication describes
for the first time the formation of mixtures of linearly and angularly annelated oxazolo-
quinolones. However, their structural similarity did not allow the isolation of the indi-
vidual isomers and therefore we describe spectral characteristics and physicochemical
data only for mixtures of both the isomers.
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

Gould–Jacobs Reaction
269
The substitution products 3 and 4 were obtained by refluxing a mixture of compound
or 2 with EMME in boiling toluene. The amino derivatives were prepared immediately
1
before the reaction by catalytic reduction of the corresponding nitro derivative over 5%
palladium on charcoal. The yields of the products are related to the starting nitrobenzo-
O
N
CH CH O
COOCH CH
2
3
3
3
2
H N
R
+
2
H
COOCH CH
2
1
, 5-NH2
, 6-NH2
2
15
14
13
CH CH OOC
3
2
7
9
8
7
a
6
5
O
CH CH OOC
NH
R
2
3
2
12
11
10
N
a
3
4
3, 5-NH-
4
, 6-NH-
O
N
COOCH CH
2
3
R
O
H
N
N
O
H
O
R
COOCH CH3
N
2
5
+
7
+
O
H
N
CH CH OOC
3
2
O
O
R
R
N
N
N
H
CH CH OOC
3
2
O
6
8b, 8c
1-8
R
a
b
c
H
CH3
C6H5
SCHEME 1
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

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70
Ilavsky, Heleyova, Nadaska, Bobosik:
TABLE I
Physicochemical properties of compounds 3–8
Calculated/Found
Compound
or mixture
M.p., °C
Yield, %
Formula
M.w.
%
C
% H
% N
3
3
3
4
4
4
a
b
c
116–117
C15H16N2O5
59.20
59.13
5.30
5.27
9.21
9.16
5
8
304.3
106–107
C16H18N2O5
60.37
60.28
5.70
5.63
8.80
8.75
5
6
318.3
112–113
C21H20N2O5
66.30
66.04
5.30
5.21
7.37
7.23
6
6
380.4
a
b
c
116–117
C15H16N2O5
59.20
59.03
5.30
5.21
9.21
9.15
3
5
304.3
63–65
C16H18N2O5
60.37
60.29
5.70
5.63
8.80
8.71
3
4
318.3
84–85
C21H20N2O5
66.30
66.22
5.30
5.23
7.27
7.41
7
3
380.4
a
5
6
a
a
–
C13H10N2O4
60.46
60.39
3.90
3.65
10.85
10.48
79
258.2
b
5
6
b
b
–
C14H12N2O4
61.76
61.29
4.44
4.12
10.29
9.97
76
272.3
c
5
6
c
c
–
C19H14N2O4
68.25
68.01
4.22
4.08
8.38
8.11
93
334.3
7
a
258–263
C13H10N2O4
60.46
60.17
3.90
3.57
10.85
10.53
9
4
258.2
d
7
8
b
b
–
C14H12N2O4
61.76
61.34
4.44
4.28
10.29
10.07
65
272.3
e
7
8
c
c
–
C19H14N2O4
68.29
68.19
4.22
4.03
8.38
8.21
68
334.3
a
b
c
d
e
Ratio of isomers in mixture: 4 : 1; 4 : 3; 2 : 1; 2 : 1; 2 : 1.
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

Gould–Jacobs Reaction
271
xazoles and are given in Table I. The proton NMR spectra of the products (Table II)
show magnetic nonequivalency of the two ester groups (duplication of triplets and
quadruplets of the ethoxy groups). The magnitude of interaction between the NH and
the olefinic protons (J = 14 Hz) confirms their anti-arrangement in the –NH–CH= group-
3
ing. The spectrum also shows vicinal interaction of the ortho-protons, J(6,7) = 9 Hz
3
4
4
and J(4,5) = 9 Hz, and long-range interactions of the meta-protons, J(4,6) = J(5,7) = 2 Hz.
1
3
The C NMR spectral data of the products are summarized in Table III. The infrared
spectra of compounds 3 and 4 (Table IV) contain two absorption bands of non-equivalent
–
1
ester groups in the region 1 650–1 700 cm , the lower-wavenumber band belonging to
the group that forms a hydrogen bond with the NH group. The ultraviolet spectra
(
Table IV) show that introduction of the strongly polarized propene moiety into the
molecule results in a bathochromic shift (18–50 nm) of the longest-wavelength band
8
relative to that of the corresponding 2-substituted benzoxazole .
Compounds 3a–3c and 4a–4c were cyclized in the inert medium of Dowtherm (di-
phenyl ether–biphenyl mixture) at 250 °C. The isolation and purity of the products
depended on the mutual ratio of the compound to Dowtherm and also on the reaction
time. As optimal we found the ratio 40 ml of Dowtherm to 1 g of the compound; the
optimum time was 15 min. Greater amounts of Dowtherm hindered its deposition from
the solution whereas smaller amounts led to partial carbonization.
As seen from the proton NMR spectra of the cyclization products (Table V), the
cyclization leads to a mixture of angularly and linearly annelated oxazoloquinolone
derivatives 5–8 (Scheme 1). Because of their low solubility in the common solvents,
their spectra were taken in CF COOD. Comparison of proton spectra of the cyclization
3
4
products with those of structurally related angularly annelated azoloquinolones allowed
TABLE II
1
a
H NMR data (δ, ppm; J, Hz ) for compounds 3 and 4
Compound
H-4
H-5
H-6
H-7
H-8
NH
CH2
CH3
R
3
3
a
7.81
7.62
7.66
7.75
7.84
7.80
–
–
7.46
7.28
7.37
–
7.76
7.31
7.40
7.52
6.94
7.74
8.61
8.37
8.41
8.52
8.25
8.44
11.04
10.68
10.76
10.97
10.65
10.84
4.24, 4.21
4.15, 4.05
4.22, 4.14
4.19, 4.12
4.18, 4.10
4.21, 4.12
1.31, 1.24
1.27, 1.19
1.27, 1.23
1.25, 1.23
1.26, 1.21
1.26, 1.19
8.33
2.60
b
b
3
4
c
–
–
a
7.14
6.86
7.39
8.08
4
b
–
2.11
c
4
c
–
–
a
b
J(4,5) = 9, J(4,6) = 2, J(6,7) = 9, J(NH,8) = 14. 8.06–8.21, 2 H (o-position); 7.37–7.53, 3 H (m-
c
and p-positions). 8.14–8.26, 2 H (o-position); 7.04–7.77, 3 H (m- and p-positions).
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

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Ilavsky, Heleyova, Nadaska, Bobosik:
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

Gould–Jacobs Reaction
273
us to assign the signals of individual protons of both the isomers in the mixture. Com-
pounds 3a–3c afforded mixtures of oxazolo[4,5-f]quinolones 5a–5c with characteristic
doublet of benzene protons, J = 9 Hz and oxazolo[5,4-g]quinolones 6a–6c with two
singlets of benzene protons, corresponding to linear annelation. Compound 4a cyclized
to give solely the angularly annelated oxazolo[5,4-f]quinolone derivative 7a whereas
compounds 4b and 4c afforded again mixtures of angularly annelated oxazolo[5,4-f]-
quinolones 7b and 7c and linearly annelated oxazolo[4,5-g]quinolones 8b and 8c. The
ratios of the arising isomers were determined from the integrated intensities and are
given in Table I. In the case of compounds 5b, 6b and 7b, 8b the presence of two
isomers was confirmed by two methyl signals, in the case of derivatives 5a and 6a by
two proton signals.
The low solubility and structural similarity of the compounds made them inseparable
by fractional crystallization or by chromatography. The compounds 5–8 are thermally
very stable: there was no opening of the oxazole ring during the cyclization as con-
firmed by two hours’ heating of the benzoxazole derivative 7a under the conditions of
cyclization. Yields of the compounds 5–8 are given in Table I; the data relate to mix-
tures of both the structural isomers. Therefore, the IR and UV spectral data of these
mixtures (Table IV) are given without detailed assignment of the bands to the indivi-
dual isomers.
EXPERIMENTAL
The melting points were determined on a Kofler block and are uncorrected. Proton and 13C NMR
1
13
spectra were measured on a Varian VXR-300 instrument (300 MHz for H, 75 MHz for C) with
tetramethylsilane as internal standard. IR spectra were taken on an M-80 (Zeiss, Jena) spectrometer
(
1 mg in 300 mg KBr). Electronic absorption spectra were measured on a UV-VIS M-40 spectro-
–
4
–3
photometer (Zeiss, Jena) in methanol, concentration 10 mol dm or saturated solution for sparingly
soluble compounds. The starting nitrobenzoxazoles were prepared by modified published proce-
dures
8
–11
.
Preparation of 5- and 6-Aminobenzoxazoles 1 and 2
A magnetically stirred suspension of the corresponding 2-substituted 5- or 6-nitrobenzoxazole (0.01
mol) and 5% Pd/C (0.5 g) in toluene (100 ml) was hydrogenated at 10 kPa of hydrogen until the
consumption ceased (about 0.66 l, 0.03 mol H ). After filtration, the toluene solution of the amine
2
was immediately used in the next reaction.
Preparation of Diethyl 3-N-[5- or 6-(2-Substituted benzoxazolyl)]aminomethylenemalonates 3 and 4
Diethyl ethoxymethylenepropanedioate (EMME; 3.5 g, 0.016 mol) was added to a stirred solution of
the corresponding aminobenzoxazole 1 or 2 (0.01 mol) in toluene, the mixture was refluxed and the
reaction was monitored by TLC. After cooling, the product was isolated by filtration or by concentration
1
under diminished pressure. For physicochemical data of the products see Table I, for their H NMR
1
3
spectra Table II, for C NMR spectra Table III and for UV and IR spectra Table IV.
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

2
74
Ilavsky, Heleyova, Nadaska, Bobosik:
TABLE IV
–
1
Characteristic IR bands (cm ) and UV maxima (λmax, nm (log ε)) for compounds 3–8
IR spectra
Compound
UV spectra
or mixture
~
~
~
ν(C=O)
ν(C=C), ν(C=N)
a
3
3
3
4
4
4
5
5
5
7
7
7
a
1 650, 1 690
1 650, 1 690
1 650, 1 690
1 645, 1 690
1 650, 1 690
1 690, 1 725
1 720
1 610, 1 640
207 (3.26), 227 (3.28), 298 (3.31), 318 (3.40)
a
b
1 595, 1 630
206 (3.38), 229 (3.41), 297 (3.39), 318 (3.51)
a
a
c
1 530, 1 560
202 (3.48), 223 (3.29), 260 (3.33), 328 (3.54)
a
a
1 595, 1 620
224 (3.26), 290 (3.06), 325 (3.54)
a
b
1 605, 1 625
225 (3.21), 291 (3.00), 326 (3.45)
c
1 590, 1 625
224 (3.34), 342 (3.65)
b
a, 6a
b, 6b
c, 6c
a
1 542, 1 590, 1 630
1 540, 1 590, 1 630
1 555, 1 590, 1 620
1 530, 1 590, 1 620
1 530, 1 590, 1 630
1 535, 1 585, 1 630
221, 256, 337
b
1 715
227, 259, 349
b
1 715
233, 287, 356
a
b
b
b
1 710
227, 261 , 333
a
b, 8b
c, 8c
1 710
227, 262 , 335
a
1 710
208 , 263, 348
a
b
Shoulder. Saturated solutions.
TABLE V
1
a
H NMR data (δ, ppm ) for compounds 5–8
Compound
H-4
H-5
H-6
H-7
H-8
H-9
NH
CH2
CH3
R
5
6
5
6
5
6
7
7
8
7
8
a
a
b
b
c
–
–
–
9.53
9.53
9.55
9.46
9.55
9.48
–
–
–
8.43
–
8.63
9.08
8.60
8.95
8.69
9.13
–
11.87
11.87
12.20
12.20
11.81
11.81
11.82
11.95
11.95
11.95
11.95
4.97
4.97
4.75
4.75
4.76
4.76
4.87
4.72
4.72
4.80
4.80
3.62
3.62
1.58
1.58
1.60
1.60
1.62
1.57
1.57
1.63
1.63
9.18
9.18
3.22
3.04
9.08
–
–
–
8.50
–
8.91
–
–
–
b
b
–
–
–
–
b
b
c
9.01
8.82
8.65
9.09
8.82
9.27
–
–
–
–
a
b
b
c
8.38
8.35
–
9.53
9.47
9.44
9.57
9.53
–
–
–
–
–
9.11
3.12
3.01
–
–
–
8.49
–
c
c
–
–
–
c
c
c
–
–
8.67
–
a
b
c
J(8,9) = J(4,5) = 9 Hz. 7.75–8.53 m, 6 H (H-8, arom.). 7.77–8.53 m, 6 H (H-5, arom.).
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

Gould–Jacobs Reaction
275
Preparation of Mixtures of Oxazolo[4,5-f]quinolones 5a–5c and Oxazolo[5,4-g]quinolones 6a–6c,
and Mixtures of Oxazolo[5,4-f]quinolones 7a–7c and Oxazolo[4,5-g]quinolones 8b and 8c
Compound 3 or 4 (1.0 g) was added to hot Dowtherm (40 ml) and the solution was heated at reflux
(
250 °C) for 15 min. After cooling, the deposited compound was collected and washed with toluene
and ether. The obtained product was dried at 120 °C in vacuo. The physicochemical data of the pro-
1
ducts are given in Table I, their H NMR spectra in Table V, the IR and UV spectra in Table IV.
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