Synthesis and spectral properties of 1-(6-methoxy-2-benzothiazolyl)-2-pyridones

Article abstract of DOI:10.1135/cccc19960921

Substituted 1-(6-methoxy-2-benzothiazolyl)-2-pyridones 5a-5f have been prepared from N-(6-methoxy-2-benzothiazolyl)cyanoacetamide (2) which on reactions with 4-substituted benzaldehydes gives 3-aryl-2-cyano-N-(6-methoxy-2-benzothiazolyl)-2-propenamides 4a

Full text of DOI:10.1135/cccc19960921

1-(6-Methoxy-2-benzothiazolyl)-2-pyridones
921
SYNTHESIS AND SPECTRAL PROPERTIES OF 1-(6-METHOXY-2-BENZO-
THIAZOLYL)-2-PYRIDONES
a1
a2
b
a3
Jarmila STETINOVA , Rudolf KADA , Jan LESKO , Miloslava DANDAROVA
a
and Marcela KRUBLOVA
a Department of Organic Chemistry, Slovak Technical University, 812 37 Bratislava,
Slovak Republic; e-mail: 1 jstetin@chelin.chtf.stuba.sk, 2 rkada@chelin.chtf.stuba.sk,
3 nemcova@chelin.chtf.stuba.sk
b Mass Spectrometry Laboratory, Slovak Technical University, 812 37 Bratislava, Slovak Republic;
e-mail: lesko@cvtstu.cvt.stuba.sk
Received January 19, 1996
Accepted February 24, 1996
Dedicated to the authors’ colleague Dr Dusan Ilavsky who died unexpectedly on July 18, 1995.
Substituted 1-(6-methoxy-2-benzothiazolyl)-2-pyridones 5a–5f have been prepared from N-(6-methoxy-
2-benzothiazolyl)cyanoacetamide (2) which on reactions with 4-substituted benzaldehydes gives
3-aryl-2-cyano-N-(6-methoxy-2-benzothiazolyl)-2-propenamides 4a–4g. Derivatives 4a–4f were cy-
clized with malonodinitrile in the presence of piperidine to give the corresponding 2-pyridones 5a–5f.
1
The IR, UV, H NMR and mass spectra of the substances synthesized are discussed.
Key word: 1-(6-Methoxy-2-benzothiazolyl)-2-pyridones.
Interesting biological properties as well as accessibility of precursors initiated our inte-
rest in the chemistry of both benzothiazoles1–3 and 2-pyridones4.
In continuation of ref.5, the present paper deals with synthesis and study of properties
of some substituted 1-(6-methoxy-2-benzothiazolyl)-2-pyridones prepared from
2-amino-6-methoxybenzothiazole6 (1).
1-Cyanoacetyl-3,5-dimethylpyrazole7 (3) is an efficient reagent for cyanoacetylation
of various amino derivatives5,8, giving the respective cyanoacetamide 2 in the yield of
88% by boiling with arylamine 1 in toluene.
3-Aryl-2-cyano-N-(6-methoxy-2-benzothiazolyl)-2-propenamides 4a–4g were ob-
tained in yields of 79–92% (Table I) by the Knoevenagel reaction of C–H acid 2 with
4-substituted benzaldehydes. The condensation was carried out in boiling solution of
potassium acetate in acetic acid (4a–4d, 4f–4g) or 15% aqueous sodium hydroxide in
ethanol (4e). 2-Cyano-2-propenamides 4 actually are activated nitriles which generally
are suitable precursors for syntheses of other derivatives, e.g., 2-pyridones9,10, 1,4-di-
hydropyridines11, 4H-pyranes12 etc.
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

922
Stetinova, Kada, Lesko, Dandarova, Krublova:
6-Amino-4-aryl-3,5-dicyano-1-(6-methoxy-2-benzothiazolyl)-2-pyridones 5a–5f
were prepared by reactions of malonodinitrile with N-(6-methoxy-2-benzothiazolyl)-2-
propenamides 4a–4f in boiling ethanol with piperidine as a catalyst (yields 29–34%;
Table I). Also in this case5 the reaction most probably goes as a Michael addition of the
H3CO
H3C
S
N
NH R
N
CH3
N
COCH2CN
R
H
1
2
3
COCH2CN
b
H
7’
H3CO
H
1
S
O
2
3
N C
5’
C CH
R
N
4’
a
NC
c
4
R
R
a
b
c
d
e
f
H
NO2
CN
CH3
OCH3
Cl
g
N(CH3)2
O
CN
3
7’
2
H3CO
S
N
N
6
R
4
5’
5
4’
H2N
CN
5
R
R
a
b
c
d
e
f
H
Cl
CH3
NO2
CN
OCH3
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

1-(6-Methoxy-2-benzothiazolyl)-2-pyridones
923
dinitrile to α,β-unsaturated system with subsequent cyclization and splitting off of hy-
drogen.
Both the spectral data and elemental analyses (Tables I–V) confirm the structure of
N-(6-methoxy-2-benzothiazolyl)cyanoacetamide (2), substituted 2-cyano-2-propen-
amides 4 and 1-(6-methoxy-2-benzothiazolyl)-2-pyridones 5. The IR spectra of deriva-
tives 4 show beside the characteristic bands (Table II) also a weak band of the newly
formed multiple bond at 1 595–1 611 cm–1. All the derivatives 4 and 5 exhibit ν(CH3)as
and ν(CH3)s of the 6-methoxy group in benzothiazole in the regions from 2 936 to 2
996 and from 2 831 to 2 845 cm–1, respectively. The corresponding δ(CH3)as and
δ(CH3)s are found at 1 428–1 439 and 1 329–1 395 cm–1, respectively.
The UV spectra of N-(6-methoxy-2-benzothiazolyl)-2-propenamides 4 (Table II) re-
flect the lengthening of conjugated system as compared with cyanoacetamide 2 by a
bathochromic shift of λmax corresponding the electron distribution in the whole molecule,
the substituent having a distinct effect on this maximum. The pyridone grouping in
derivatives 5 is characterized by the absorption maximum in the region of 367–385 nm.
1
The H NMR data unambiguously confirm the structure of compounds 4 and 5. In
the spectra of substituted 2-propenamides 4 (Table III) the olefinic proton H-3 makes
1
itself felt as a singlet at δ 8.49–8.23. The H NMR spectra of 1-(6-methoxy-2-benzo-
thiazolyl)-2-pyridones 5 (Table IV) show a signal of the amino group formed by the
cyclization at δ 8.96–8.65. In both the series studied, as it was expected, the effect of
substituent R was most distinct on the chemical shifts of protons of the benzene ring at
4-position of pyridone. The proton signals H-4′, H-5′, and H-7′ of benzothiazole ring as
well as those of the respective methoxy group in substituted 2-pyridones 5a–5f were
shifted downfield as compared with the corresponding amides 4a–4f, to the regions δ
7.94–7.93 (H-4′), δ 7.76–7.75 (H-7′), δ 7.15 (H-5′), and δ 3.82 (OCH3).
The EI mass spectra of the compounds 4a–4g studied contain relatively intense peaks
of molecular ions (Table V). The main direction of their fragmentation is splitting of
N–C bond at β-position with respect to the benzothiazole ring. Splitting of this bond
with retention of charge at the fragment containing the benzothiazole nucleus produces
fragment ions type a (without hydrogen rearrangement, m/z 179) or b (with hydrogen
rearrangement, m/z 180). If the charge becomes localized at the opposite (other) side of
the molecule, the fragment ions type c are formed.
Also the EI mass spectra of the investigated substituted 2-pyridones 5 contain relatively
intense peaks of molecular ions (Table V). In all the cases, except for 5e (R = NO2), the
basic peak in spectra is that of the (M – H)•+ ion. Decomposition of C–N bond between
benzothiazole and pyridone nuclei in the molecular ion with rearrangement of hydrogen
produces the fragment ion with m/z 165.
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

924
Stetinova, Kada, Lesko, Dandarova, Krublova:
TABLE I
Characteristic data of compounds 4a–4g and 5a–5f
Calculated/Found
M.p., °C
Yield, %
Formula
(M.w.)
Compound
%C
%H
%N
4a
4b
4c
4d
4e
4f
220–222a
90
C18H13N3O2S
(335.4)
64.46
64.26
3.91
4.01
12.53
12.50
219–221a
86
C19H15N3O2S
(349.4)
65.31
64.40
4.33
4.54
12.03
12.12
218–220a
82
C19H15N3O3S
(365.4)
62.45
62.29
4.14
4.21
11.50
11.62
236–239a
81
C18H12ClN3O2S
(369.8)
58.46
57.75
3.27
3.11
11.36
11.36
265–267a
92
C18H12N4O4S
(380.4)
56.83
56.06
3.18
3.42
14.73
14.29
279–281a
90
C19H12N4O2S
(360.4)
63.32
63.99
3.36
3.99
15.55
15.61
4g
5a
5b
5c
5d
5e
5f
284–286a
79
C20H18N4O2S
(378.4)
63.47
63.86
4.79
5.45
14.81
14.88
284–287a
30
C21H13N5O2S
(399.4)
63.15
62.95
3.28
3.15
17.54
17.52
286–290a
30
C22H15N5O2S
(413.4)
63.91
63.27
3.66
3.84
16.94
17.02
300–305a
34
C22H15N5O3S
(429.4)
61.53
61.40
3.52
3.66
16.31
16.42
310–312b
29
C21H12ClN5O2S
(433.9)
58.13
58.36
2.79
2.97
16.14
15.42
313–317a
30
C21H12N6O4S
(444.4)
56.75
57.16
2.72
2.84
18.91
19.08
336–338c
34
C22H12N6O2S
(424.4)
62.25
62.52
2.85
3.30
19.80
19.85
c
Recrystallized from: a acetic acid, b dioxane, acetic acid–dimethylformamide (10 : 1).
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

1-(6-Methoxy-2-benzothiazolyl)-2-pyridones
TABLE II
925
IR spectra (KBr) and UV spectra (dioxane, c 1 . 10–4 mol l–1) of compounds 2, 4a–4g, and 5a–5f
IR spectrum
ν(C≡N)
UV spectrum
Compound
ν(NH)a
ν(C=O)
λmax
log ε
2
3 216
2 263
1 705
252
290
308
2.81
3.12
3.08
4a
4b
4c
4d
4e
4f
3 198
3 177
3 196
3 206
3 198
3 206
3 179
3 426
2 228
2 224
2 222
2 224
2 226
2 224
2 216
2 211
1 673
1 624
1 671
1 674
1 682
1 674
1 663
1 673
313
363
3.34
3.22
328
3.35
3.27
360b
269
360
2.93
3.54
320
365
3.31
3.19
310
383
3.34
3.14
306
380
3.40
3.18
4g
5a
266
429
3.12
3.69
272
336
370
3.52
3.18
3.14
5b
5c
3 289
3 430
2 222
2 206
1 671
1 671
276
332
372
3.52
3.22
3.13
2 226
2 218
277
341
385b
3.49
3.44
3.20
5d
3 438
2 227
2 211
1 680
276
342
367b
3.53
3.22
3.13
5e
5f
3 441
3 438
2 226
2 216
1 686
1 680
273
345
383b
3.62
3.18
3.15
c
2 228
2 211
268
385
–
c
–
b
a ν(NH2) for compounds 5a–5f; shoulder; c measured in saturated solution.
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

926
Stetinova, Kada, Lesko, Dandarova, Krublova:
TABLE III
1H NMR spectra of compounds 4a–4g
H-7′ (d) H-4′ (d) H-5′
OCH3
(s)
Compound NH (s) H-3 (s)
4-Substituted phenyl
J(7′,5′) J(4′,5′)
(dd)
4a
4b
4c
4d
4e
4f
12.71
13.22
12.73
12.52
12.84
13.17
12.33
8.42
8.38
8.35
8.39
8.49
8.45
8.23
7.54
2.8
7.50
8.8
7.03
7.02
7.01
7.02
7.03
7.04
6.99
3.76 8.15–7.80 m and 7.70–7.39 m,
2 H and 3 H
7.54
2.4
7.50
8.8
3.76 7.89 d and 7.36 d, 2 H and
2 H, J = 8.2; 2.35 s, 3 H
7.52
2.6
7.50
8.9
3.76 8.00 d and 7.11 d, 2 H and
2 H, J = 8.9; 3.82 s, 3 H
7.52
2.6
7.60
8.8
3.76 7.98 d and 7.48 d, 2 H and
2 H, J = 8.8
7.52
2.6
7.49
8.1
3.77 8.35 d and 8.14 d, 2 H and
2 H, J = 8.7
7.54
2.4
7.48
8.7
3.76 8.08–8.01 m, 4 H
4g
7.50
2.6
7.51
8.8
3.76 7.88 d and 8.00 d, 2 H and
2 H, J = 9.0; 3.21 s, 6 H
TABLE IV
1H NMR spectra of compounds 5a–5f
H-4′ (d) H-7′ (d)
Compound NH2 (s)
H-5′ (dd) OCH3 (s)
4-Substituted phenyl
J(4′,5′)
J(7′,5′)
5a
5b
5c
5d
5e
5f
8.65
8.96
8.66
8.72
8.79
8.84
7.94
8.8
7.75
2.4
7.15
7.15
7.15
7.15
7.15
7.15
3.82
3.82
3.80
3.82
3.82
3.82
7.65–7.33 m, 5 H
7.93
9.0
7.75
2.6
7.50–7.29 m, 4 H; 2.36 s, 3 H
7.93
9.1
7.75
2.5
7.49 d and 7.07 d, 2 H and
2 H, J = 8.8; 3.80, 3 H
7.93
9.1
7.75
2.6
7.67–7.54 m, 4 H
7.94
9.0
7.76
2.6
8.40 d and 7.81 d, 2 H and
2 H, J = 8.8
7.94
8.9
7.75
2.5
8.04 d and 7.71 d, 2 H and
2 H, J = 8.3
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

1-(6-Methoxy-2-benzothiazolyl)-2-pyridones
927
EXPERIMENTAL
The melting points were determined with a Kofler apparatus. The IR spectra were measured with a
FTIR PU 9800 (Philips) spectrometer, the UV spectra (λ, nm; log ε) were recorded with a Specord
1
UV-VIS M-40 apparatus. The H NMR spectra (δ, ppm; J, Hz) were measured with a Tesla BS 587
(80 MHz) spectrometer in hexadeuteriodimethyl sulfoxide with hexamethyldisiloxane as the internal
standard. The EI mass spectra were recorded with an MS 902 S (A.E.I. Manchester) spectrometer
with direct inlet system, electron energy 70 eV, trap current 100 µA, ion source temperature 220–240 °C
(for compounds 2, 4a–4g) or 150–200 °C (for compounds 5a–5f).
TABLE V
Mass spectra (EI) of 2, 4a–4g, 5a–5c, and 5e–5f derivatives. For each compound 10 most abundant
peaks are given
Compound
m/z (rel. abundance, %)
2
248 (15), 247 (M+•, 100), 207 (44), 181 (10), 180 (84), 179 (14), 166 (10), 165 (89),
138 (9), 135 (11)
4a
4b
4c
4d
4e
4f
336 (20), 335 (M+•, 99), 334 (20), 180 (37), 179 (37), 156 (100), 128 (83), 101 (30),
77 (53), 51 (23)
350 (21), 349 (M+•, 85), 348 (17), 180 (23), 171 (14), 170 (100), 142 (28), 116 (17),
115 (66), 65 (14)
366 (10), 365 (M+•, 42), 364 (8), 188 (16), 187 (13), 186 (100), 165 (12), 158 (27),
143 (10), 115 (8)
371 (43), 370 (30), 369 (M+•, 100), 192 (29), 190 (77), 180 (37), 179 (46), 162 (37),
127 (38), 126 (30)
380 (M+•, 75), 351 (27), 207 (33), 180 (68), 179 (100), 171 (84), 165 (40), 143 (29),
135 (28), 116 (20)
361 (23), 360 (M+•, 93), 359 (25), 258 (20), 207 (30), 181 (33), 180 (39), 179 (100),
153 (31), 135 (25)
4g
5a
5b
5c
5e
5f
378 (M+•, 16), 200 (15), 199 (100), 185 (16), 180 (7), 171 (40), 159 (9), 156 (9),
155 (7), 128 (8)
400 (22), 399 (M+•, 82), 398 (100), 383 (9), 371 (8), 355 (9), 165 (31), 138 (9), 77 (8),
45 (15)
414 (22), 413 (M+•, 78), 412 (100), 398 (10), 207 (11), 206 (10), 180 (13), 179 (11),
165 (28), 145 (11)
430 (18), 429 (M+•, 55), 428 (100), 223 (13), 206 (18), 191 (24), 183 (16), 180 (18),
165 (32), 149 (18)
445 (27), 444 (M+•, 100), 443 (90), 414 (43), 413 (72), 397 (55), 206 (21), 191 (25),
180 (25), 165 (45)
425 (30), 424 (M+•, 84), 423 (100), 191 (12), 190 (19), 180 (13), 165 (37), 138 (12),
110 (11), 63 (12)
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

928
Stetinova, Kada, Lesko, Dandarova, Krublova:
N-(6-Methoxy-2-benzothiazolyl)cyanoacetamide (2)
A solution of 2-amino-6-methoxybenzothiazole6 (1; 6.1 g, 34 mmol) in anhydrous toluene (150 ml)
was added to a solution of 1-cyanoacetyl-3,5-dimethylpyrazole7 (3; 5.3 g, 34 mmol) in the same sol-
vent (100 ml) and the mixture was refluxed 4 h. After cooling, the solid portion was isolated and
recrystallized from acetic acid; yield 7.4 g (88%), m.p. 224–226 °C. The IR, UV, and mass spectra
1
are given in Tables II and V. H NMR spectrum: 7.66 d, 1 H, J(4,5) = 8.9 (H-4); 7.59 d, 1 H, J(7,5) = 2.5
(H-7); 7.04 dd, 1 H (H-5); 4.08 s, 2 H (CH2); 3.81 s, 3 H (OCH3). For C11H9N3O2S (247.3) calcu-
lated: 53.43% C, 3.67% H, 16.99% N; found: 53.58% C, 3.40% H, 17.21% N.
General Procedure for Preparation of 3-Aryl-2-cyano-N-(6-methoxy-2-benzothiazolyl)-2-propen-
amides 4a–4d and 4f–4g
A mixture of 4-substituted benzaldehyde (6 mmol), N-(6-methoxy-2-benzothiazolyl)cyanoacetamide
(2; 1.48 g, 6 mmol), anhydrous potassium acetate (1.48 g, 15 mmol), and acetic acid (30 ml) was
stirred while refluxing 3 h. After pouring on ice, the raw product was collected by filtration, washed
with water, dried, and recrystallized from a suitable solvent. The yields, melting points, and elemental
analyses are presented in Table I.
2-Cyano-N-(6-methoxy-2-benzothiazolyl)-3-(4-nitrophenyl)-2-propenamide (4e)
A solution of 4-nitrobenzaldehyde (0.6 g, 4 mmol) in ethanol (30 ml) and 15% aqueous sodium
hydroxide (5 drops) were added to a hot solution of N-(6-methoxy-2-benzothiazolyl)cyanoacetamide
(2; 1 g, 4 mmol) in the same solvent (50 ml) with stirring. The reaction mixture was refluxed 1 h,
whereupon it was gradually cooled to room temperature with stirring. The solid portion was filtered
off and recrystallized from acetic acid. The yield, melting point, and elemental analyses are given in
Table I.
General Procedure for Preparation of 6-Amino-4-aryl-3,5-dicyano-1-(6-methoxy-2-benzothiazolyl)-
2-pyridones 5a–5f
A mixture of 3-aryl-2-cyano-N-(6-methoxy-2-benzothiazolyl)-2-propenamide 4a–4f (1.5 mmol),
malonodinitrile (0.13 g, 2 mmol), and piperidine (4 drops) in anhydrous ethanol (30 ml) was stirred
at boiling temperature 3 h, whereupon it was left to cool to room temperature with stirring. The solid
portion was filtered off and recrystallized from a suitable solvent. The yields, melting points, and
elemental analyses are given in Table I.
The authors are indebted to Mrs M. Hrobonova and Mrs S. Markusova for measuring the UV and IR
spectra, respectively. The research was supported by the Grant Agency of Ministry of Education of the
Slovak Republic (Grant No. 1/1415/94).
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1-(6-Methoxy-2-benzothiazolyl)-2-pyridones
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