SYNTHESIS OF 2-SUBSTITUTED BENZOTHIAZOLES CONTAINING AMINO ACID, IMINO OR HETEROARYL MOIETIES WITH ANTICIPATED FUNGICIDAL ACTIVITY

Full text of DOI:10.1135/cccc19952200

2200
Nawwar, Shafik:
SYNTHESIS OF 2-SUBSTITUTED BENZOTHIAZOLES CONTAINING
AMINO ACID, IMINO OR HETEROARYL MOIETIES
WITH ANTICIPATED FUNGICIDAL ACTIVITY
Galal A. M. NAWWAR and Nancy A. SHAFIK
National Research Center, Dokki, Cairo, Egypt
Received January 19, 1995
Accepted July 13, 1995
The chemistry of benzoazoles is of continuous interest for their various biological acti-
vities, the most interesting being the antifungal one1,2. Following our laboratory policy
directed to the searching of new agrochemicals and in continuation to our previous
work3,4, the present paper deals with the synthesis of 2-substituted benzothiazoles with
anticipated biological activity.
Cyanoacetic acid and 2-aminothiophenol (I) in one-pot reaction gave benzothiazol-2-
ylacetic acid (II) in spite of the two step method previously reported5 (Scheme 1).
Coupling of II with methyl glycinate in presence of dicyclohexylcarbodiimide
afforded the compound IIIa, with phenylalanine methyl ester benzothiazolyl phenyl-
alanine6 (IIIb) was obtained. The method7 of benzothiazol-2-ylacetohydrazide (IV)
preparation from 2-aminothiophenol (I) and cyanoacetohydrazide was improved and
methanol–acetic acid was used as the reaction medium. It is worthy to mention that
preparation of the derivative IV in ethanol–piperidine failed and the only product was
3-amino-5-pyrazolone coming from the self-cyclization of cyanoacetohydrazide8. Com-
pound IV was further condensed with acetylacetone to give 2-(1-amino-4,6-dimethyl-2-
oxo-pyridin-3-yl)benzothiazole (V). Its 1H NMR spectrum showed no methylene proton
signals detected in the parent compound IV at 4.1 ppm. 2-Aminothiophenol (I) and
N-acetylcyanoacetohydrazide afforded the corresponding N-acetylbenzothiazol-2-yla-
cetohydrazide (VI).
Compound VI condensed with nitrous acid to form the corresponding oxime deriva-
tive VII. Coupling of VI with aryl diazonium salts gave the corresponding hydrazones
VIIIa, VIIIb. The marked downfield shift of the azo-NH resonance signals in the 1H NMR
spectra indicates the presence of N–H...O=C bridges9 (Scheme 2). The hydrazones VIII
underwent hydrolysis affording their deacetylated derivatives IXa, IXb. The latter could
not be obtained directly by the diazotization reaction of the deacetylated derivative IV.
Condensation of VI with aryl aldehydes afforded the corresponding arylidene deriva-
tives Xa, Xb. When compound Xa was treated with 6 M hydrochloric acid, a product XI
was formed by deacetylation and subsequent self-cyclization and oxidation. When com-
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

New Compounds
2201
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

2202
Nawar, Shafik:
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

New Compounds
2203
pound Xb was treated with 6 M hydrochloric acid, a different product was obtained,
which was identified as 2-hydroxy-3-(benzothiazol-2-yl)quinoline (XII). Similar nu-
cleophilic displacement by the hydrazino nitrogen in acetohydrazide derivatives has
been previously reported10.
Compounds Xa, Xb reacted with malononitrile in dioxane–piperidine in a Michael
type reaction to afford 3-(benzothiazol-2-yl)dihydropyridines XIII. Their IR spectra
showed NH2, NH, OH and CN group absorption at 3 450–3 200 and 2 200 cm–1, respec-
1
tively, their H NMR spectra showed the dihydropyridine H-4 as doublet at 4.6 ppm and
the mass spectrum of XIIIb contained the ion base peak at m/z = 380 corresponding to
the 2-hydroxy-3-(benzothiazol-2-yl)-4-(2-chlorophenyl)-5-cyano-6-amino-1,4-dihydro-
pyridine fragment. Reaction of the compound VI with 2-(benzimidazol-2-yl)cinnamoni-
trile11 under similar reaction conditions afforded a new product lacking the CN
absorption and showing a dihydropyridine H-4 as doublet at 4.0 ppm and dihydropy-
ridine H-5 as doublet at 5.8 ppm. Based on these data and our previous report12, the
3-(benzothiazol-2-yl)-5-(benzimidazol-2-yl)dihydropyridine structure XIV was assigned
to this product.
Preliminary fungicidal tests showed that compounds VI, XIIIb and Xa, as repre-
sentative examples, exhibit remarkable activity against Fusarium manilifarum, Penicil-
lium oxalicum and Aspergillus niger. Further work is in progress and will be published
elsewhere13.
EXPERIMENTAL
Melting points were uncorrected. The IR spectra were recorded in KBr with a Pye–Unicam Sp-1000
spectrometer. The 1H NMR spectra were run on a Jeol GLM. EX (270 MHz) or Gemini-200 (200 MHz)
spectrometer using TMS as an internal standard. The mass spectra were recorded at 70 eV with a
Schimadzu GC/MS QP 1000 EX spectrometer. Elemental analyses were performed by the Central
Service Unit at Cairo University and National Research Center. The characteristic data of the pre-
1
pared compounds are given in Table I, their IR and H NMR spectra in Table II.
2-(Benzothiazol-2-yl)acetic Acid (II) and 2-(Benzothiazol-2-yl)acetohydrazide (IV)
A mixture of 2-aminothiophenol (I, 1.25 g, 0.01 mol) and cyanoacetohydrazide or cyanoacetic acid
(0.01 mol) was heated to 60 °C in a mixture of methanol–glacial acetic acid (10 ml each) for one
hour, then refluxed for 15 min. After cooling, ether was added to the solution, the precipitate formed
was collected by filtration and crystallized.
Methyl 2-[2-(Benzothiazol-2-yl)acetamido]acetate (IIIa) and -3-phenylpropionate (IIIb)
A mixture of the amino acid (glycine or phenylalanine) methyl ester hydrochloride (0.01 mol) and
triethylamine (2.0 g, 0.02 mol) in dry tetrahydrofuran (30 ml) was stirred at room temperature for 15 min.
The solution of the amino acid ester was decanted and an equimolar amount of the acid II (1.93 g)
was added to this reaction mixture, a solution of dicyclohexylcarbodiimide (2.1 g, 0.01 mol in 20 ml
dry tetrahydrofuran) was dropped during a period of 2 h at 0–5 °C and the stirring was maintained
for further 6 h. Working up of the reaction mixture was carried out as previously reported6.
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

2204
Nawwar, Shafik:
2-(1-Amino-4,6-dimethyl-2-oxopyridin-3-yl)benzothiazole (V)
Compound IV (2.07 g, 0.01 mol) was refluxed with acetyl acetone (0.01 mol, 1 ml) in methanolic
potassium hydroxide (30 ml) for 3 h. The reaction mixture was then neutralized with diluted hydro-
chloric acid, the precipitate obtained was filtered off, washed with water and crystallized from proper
solvent (Table I). Mass spectrum (m/z): 271.
2-(Benzothiazol-2-yl)-N-acetylacetohydrazide (VI)
A mixture of 2-aminothiophenol (I, 1.25 g, 0.01 mol) and N-acetylcyanoacetohydrazide (0.01 mol,
2.49 g) was boiled under reflux in methanol (25 ml) for 3 h in the presence of piperidine (3 drops).
The solution was concentrated and left to cool. The solid formed was filtered off and crystallized
from the appropriate solvent (Table I). Mass spectrum (m/z): 249.
2-(Benzothiazole-2-yl)-2-hydroxyimino-N-acetylacetohydrazide (VII)
To a stirred solution of compound VI (2.49 g, 0.01 mol) in acetic acid (20 ml) and methanol (10 ml)
in an ice bath, an equimolecular amount of sodium nitrite was added during a period of 30 min and
stirring was continued for further 9 h. The formed precipitate was filtered off and crystallized. Mass
spectrum (m/z): 278.
2-(Benzothiazol-2-yl)-2-arylhydrazo-N-acetylacetohydrazides VIIIa, VIIIb
The diazonium salts of aniline and 2-hydroxyaniline were prepared according to the literature14. To a
stirred solution of compound VI (2.49 g, 0.01 mol) in methanol (30 ml) in an ice bath, the prepared
diazonium salt was added. After removing the ice bath, the stirring was maintained for 30 min, water
was added to the solution till precipitation occurred. The formed solid product was washed with
water and crystallized (Table I).
2-(Benzothiazol-2-yl)-2-arylhydrazonoacetohydrazides IXa, IXb, 3-Hydroxy-4-(benzothiazol-2-yl)-5-
(4-nitrophenyl)pyrazole (XI) and 2-Hydroxy-3-(benzothiazol-2-yl)quinoline (XII)
A solution of each of compounds VIIIa, VIIIb and Xa, Xb in methanol (30 ml) in presence of 6 M
HCl (10 ml) was refluxed for 3 h. The precipitate formed was filtered off, washed with water and
crystallized (Table I). Mass spectra (m/z): 311 (IXa), 338 (XI), 278 (XII).
N-Acetyl-2-(benzothiazole-2-yl)cinnamohydrazides Xa, Xb
A mixture of compound VI (2.49 g, 0.01 mol) with the corresponding aldehyde (0.01 mol) in methanol
(30 ml) in presence of piperidine (4 drops) was refluxed for 4–5 h. A precipitate was formed imme-
diately, filtered and crystallized (Table I).
1-Acetamido-6-amino-4-aryl-3-(benzothiazol-2-yl)-5-cyano-2-hydroxy-1,4-dihydropyridines XIIIa, XIIIb
A solution of Xa or Xb (0.01 mol) in dioxane (25 ml) was refluxed with malononitrile (0.66 g, 0.01 mol)
in presence of piperidine (4 drops) for 4 h. The reaction mixture was then evaporated to dryness,
leaving an oily residue which was triturated with methanol and the solid obtained was crystallized
from the proper solvent (Table I).
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

New Compounds
2205
TABLE I
Characteristic data of the compounds prepared
Calculated/Found
M.p., °C
Solvent
Formula
M.w.
Compound
Yiekd, %
% C
% H
% N
% S
IIIa
V
65
40
80
80
70
65
60
60
80
80
55
50
65
45
70
176–178
C12H12N2O3S
acetate
54.534.58
10.65 12.13
ethyl
264.354.41
4.50
10.40 11.93
>300
C14H13N3OS
61.97
4.82
15.48 11.81
dioxane
271.3641..6823
C11H11N3O2S
249.352.92
15.14 11.73
VI
170–172
methanol
53.00
4.24
4.45
16.86 12.86
1126..5513
VII
185–186
dioxane
C11H10N4O3S
278.3
47.47
47.23
3.62
3.34
20.13
11.52
20.00 11.23
VIIIa
VIIIb
IXa
IXb
Xa
252–254
dioxane
C17H15N5O2S
353.4
57.77
57.52
4.28
4.04
19.82
19.73
9.07
8.93
256–257
dioxane
C17H15N5O3S
369.4
55.27
55.04
4.09
4.03
18.96
18.72
8.68
8.44
237–239
dioxane
C15H13N5OS
311.4
57.86
57.64
4.20
4.10
22.50 10.30
22.30 10.13
242–243C
dioxane
15H13N5O2S
327.4
55.034.00
55.01
21.40
9.78
3.94
21.32
9.63
228–229
methanol
C18H14N4O4S
382.4
56.54
56.50
3.69
3.52
14.65
14.44
8.38
8.23
Xba
XI
224–226
dioxane
C18H14ClN3O2S
371.8
58.14
58.04
3.80
3.82
11.30
11.14
8.62
8.40
273–274
methanol
C16H10N4O3S
338.3
56.79
56.62
2.98
2.74
16.56
16.33
9.48
9.24
XII
147–149
dioxane
C16H10N2OS
.44278.3638.93
69.04
9.84
3.62
10.07 11.50
11.41
XIIIa
XIIIbb
XIV
225–226
dioxane
C21H16N6O4S
448.5
56.24
3.60
18.74
6.91
7.15
56..81033 18.44
208–210
C21H16ClN5O2S
437.9
57.60
57.52
3.68
3.54
16.00
15.90
7.31
7.14
DMF–water
283–285
dioxane
C27H22N6O2S
494.6
65.57
65.34
4.48
4.42
17.00
16.93
6.48
6.24
% Cl: a Calculated 9.53, found 9.24. b Calculated 8.10, found 7.93.
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

2206
Nawwar, Shafik:
TABLE II
1
IR and H NMR spectra of the compounds prepared
1H NMR (δ, ppm)
Compound
IR (ν, cm–1)
benzothiazole and aryl
other protons
protons
IIIa
V
3 300 (NH), 1 700 (CO
ester), 1 650 (CONH)
7.4 m, 2 H (H-5,H-6);
7.9–8.1 m, 2 H (H-4,H-7)
3.65 s, 3 H (CH3); 3.95 s
(NHCH2); 4.15 s, 2 H
(CH2); 8.8 brs, 1 H (NH)
3 300–2 800 (NH2),
1 650 (CO)
7.4–7.5 m, 2 H (H-5,H-6);
8.0–8.1 m, 2 H (H-4,H-7)
2.6 s, 3 H (CH3); 2.65 s,
3 H (CH3); 4.75 s, 1 H
(H-5); 5.8 s, 2 H (NH2)
VI
3 185 (NH–NH), 1 606
(CONH)
7.4–7.5 m, 2 H (H-5,H-6);
7.9–8.1 m, 2 H (H-4,H-7)
1.9 s, 3 H (CH3); 4.1 s, 2 H
(CH2); 9.95 s, 1 H (NH);
10.3 s, 1 H (NH)
VII
3 200–2 700 (NH–NH and 7.5–7.6 m, 2 H (H-5,H-6);
oximino OH), 1 680, 1 640 8.0–8.2 m, 2 H (H-4,H-7)
(CONH)
1.95 s, 3 H (CH 3); 10.2 s,
1 H (NH); 10.7 s, 1 H (NH)
VIIIa
VIIIb
3 400–3 200 (NH–NH and 7.0–7.5 m, 5 H (C6H5);
NH), 1 680, 1 640 (CONH) 7.8 m, 2 H (H-5,H-6);
8.1–8.3 m, 2 H (H-4,H-7)
1.95 s, 3 H (CH 3); 9.85 s,
1 H (NH); 10.1 s, 1 H
(NH); 14.9 s, 1 H (NH)
3 400 (OH), 3 200–2 850
(NH–NH and NH), 1 670,
1 640 (CONH)
7.0 m, 4 H (C6H4); 7.5 m,
2 H (H-5,H-6); 7.9–8.2 m,
2 H (H-4,H-7)
2.0 s, 3 H (CH3); 9.9–10.2
brs, 1 H (NH); 10.15 s, 1 H
(NH); 10.5 brs, 1 H (OH);
15.0 s, 1 H (NH)
IXa
IXb
Xa
3 400 (NH), 2 900, 2 600
(NH–NH), 1 645 (CO)
7.2–7.6 m, 5 H (C6H5); 7.8 11.0 s, 1 H (NH); 15.0 s,
m, 2 H (H-5,H-6); 8.2–8.4
m, 2 H (H-4,H-7)
1 H (NH)
3 450–3 400 (OH,NH),
2 900–2 600 (NH–NH),
1 650 (CO)
6.95–8.2 m, 8 H
10.3 s, 1 H (NH); 10.5 brs,
1 H (OH); 15.0 s, 1 H (NH)
3 000–3 100 (NH), 1 600
(CONH)
7.4–7.6 m, 2 H (H-5,H-6);
7.9–8.2 m, 6 H
(H-4,H-7,C6H4)
2.0 s, 3 H (CH3); 7.8 s, 1 H
(CH); 10.1 s, 1 H (NH);
10.3 s, 1 H (NH)
Xb
3 200–3 100 (NH),
1 605–1 600 (CONH)
7.3–7.6 m, 4 H (C6H4);
8.0–8.2 m, 4 H
(H-4,H-5,H-6,H-7)
2.1 s, 3 H (CH3); 7.9 s, 1 H
(CH); 10.1 s, 1 H (NH);
10.85 s, 1 H (NH)
XI
3 400–3 200 (OH,NH)
3 400 (OH)
7.5 m, 2 H (H-5,H-6);
7.8–8.4 m, 6 H
(H-4,H-7,C6H4)
8.8 s, 1 H (NH)
XII
7.4–7.6 m, 6 H
9.0 s, 1 H (H-4)
(H-5,H-6,C6H4); 8.1–8.2 m,
2 H (H-4,H-7)
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

New Compounds
2207
TABLE II
(Continued)
1H NMR (δ, ppm)
Compound
IR (ν, cm–1)
benzothiazole and aryl
protons
other protons
XIIIa
XIIIb
XIV
3 400–3 200 (NH2,NH and 7.0–8.1 m, 8 H
OH), 2 200 (CN), 1 650
(CO)
2.0 s, 3 H (CH3); 4.5 d,
1 H (H-4); 6.4 s, 2 H
(NH2); 10.1 s, 1 H (NH);
12.4 s, 1 H (OH)
3 450–3 200 (NH2,NH and 7.0–8.0 m, 8 H
OH), 2 200 (CN), 1 650
(CO)
2.0 s, 3 H (CH3); 4.6 d,
1 H (H-4); 6.4 s, 2 H
(NH2); 10.0 s, 1 H (NH);
12.4 s, 1 H (OH)
3 240–2 923
7.4–7.5 m, 5 H (C6H5);
2.2 s, 3 H (CH3); 4.05 d,
1 H, J = 10 Hz (H-4);
5.8 d, 1 H, J = 10 Hz (H-5);
6.8–7.1 m, 4 H
(OH,NH,NHCO and ring
NH), 1 630 (NHCO)
7.7–8.2 m, 4 H
(H-4,H-5,H-6,H-7)
(benzimidazole protons);
11.2 s, 1 H (NH); 11.8 s,
1 H (NH)
1-(Acetamido-5-(benzimidazol-2-yl)-3-(benzothiazol-2-yl)-2-hydroxy-6-imino-4-phenyl-4,5-dihydro-
pyridine (XIV)
A solution of the compound VI (2.49 g, 0.01 mol) in dioxane (25 ml) was boiled under reflux with
2-(benzimidazol-2-yl)cinnamonitrile (2.45 g, 0.01 mol) in presence of triethylamine (3 drops) for 6 h.
The solution was concentrated and left to cool. The solid formed was filtered off, and crystallized
from the appropriate solvent (Table I). Mass spectrum (m/z): 494.
REFERENCES
1. Green M. B., Hartley G. S., West T. F.: Chemicals for Crop Improvement and Pest Management,
3rd ed., pp. 526 and 538. Pergamon, New York 1987.
2. Allen P. M., Gottlieb D.: Appl. Microbiol. 20, 919 (1970).
3. Nawwar G. A. M., Chabaka L. M., Omar M. T.: Phosphorus, Sulfur Silicon Relat. Elem. 57, 65
(1991).
4. Nawwar G. A. M., Chabaka L. M.: An. Quim., C 1993, 375.
5. Borsche W., Doeller W.: Justus Liebigs Ann. Chem. 537, 53 (1938).
6. Nawwar G. A. M., Shalabi A. M., Ahmed S. A. H.: J. Chem. Res., S 1993, 1533; M 1993, 258.
7. Van Dormael A. E., Nys J.: Chem. Ind. (London) 63, 483 (1950).
8. Hepner B., Fajersztejn S.: Bull. Soc. Chim. Fr. 4, 854 (1937).
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

2208
Nawwar, Shafik:
9. Prasad D., Prasad N., Prasad R. M., Ferrier R. J., Milgate S. M.: J. Chem. Soc., Perkin Trans. 1
1984, 1397.
10. Abdel-Latif F. M.: Asian J. Chem. 5, 184 (1993).
11. Matei S., Russu J., Coltea P.: Rev. Roum. Chim. 26, 985 (1981); Chem. Abstr. 95, 186207
(1981).
12. Nawwar G. A. M., Zohdi H. F., Swellen R. H., Osman S. A.: Heterocycles 34, 457 (1992).
13. Nancy A. S.: M S. Thesis. Cairo University, Cairo 1995.
14. Heinisch G., Holzer W., Nawwar G. A. M.: J. Heterocycl. Chem. 3, 93 (1986).
Collect. Czech. Chem. Commun. (Vol. 60) (1995)