Synthesis of benzamide-benzothiazole conjugates via palladium-catalysed aminocarbonylation (hydrazinocarbonylation)

Article abstract of DOI:10.1016/j.tet.2019.02.026

The palladium-catalysed aminocarbonylation of iodoarenes was investigated using 2-amino- and 2-hydrazinobenzothiazole as N-nucleophile. The reaction proved to be highly chemoselective in all cases: carboxamides and the corresponding carbohydrazides, obtained by the acylation at the nitrogen adjacent to the C-2 of the benzothiazole moiety, were obtained exclusively and isolated in moderate to high yields. Systematic investigation of the reaction conditions revealed that the reaction requires relatively high temperature (higher than 70 °C). The effect of the carbon monoxide pressure is different in the synthesis of the two types of products: while the carboxamide formation is favoured, the carbohydrazide formation is lowered by the increasing CO pressure.

Full text of DOI:10.1016/j.tet.2019.02.026

Accepted Manuscript
Synthesis of benzamide-benzothiazole conjugates via palladium-catalysed
aminocarbonylation (hydrazinocarbonylation)
Máté Gergely, László Kollár
PII:
S0040-4020(19)30176-0
https://doi.org/10.1016/j.tet.2019.02.026
TET 30149
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 8 December 2018
Revised Date: 7 February 2019
Accepted Date: 9 February 2019
Please cite this article as: Gergely Máé, Kollár Láó, Synthesis of benzamide-benzothiazole conjugates
via palladium-catalysed aminocarbonylation (hydrazinocarbonylation), Tetrahedron (2019), doi: https://
doi.org/10.1016/j.tet.2019.02.026.
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ACCEPTED MANUSCRIPT
Synthesis of Benzamide-Benzothiazole Conjugates via Palladium-Catalysed Aminocarbonylation
(Hydrazinocarbonylation).
M. Gergely and L. Kollár*
Graphical abstract
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Synthesis of Benzamide-Benzothiazole Conjugates via Palladium-
Catalysed Aminocarbonylation (Hydrazinocarbonylation).
Máté Gergelyb and László Kollár a,b*
a) MTA-PTE Research Group for Selective Chemical Syntheses, H-7624 Pécs, Ifjúság u. 6., Hungary
b) Department of Inorganic Chemistry, University of Pécs and Szentágothai Research Centre, H-7624
Pécs, P.O. Box 266, Hungary; e-mail: kollar@gamma.ttk.pte.hu
Abstract:
The palladium-catalysed aminocarbonylation of iodoarenes was investigated using 2-
amino- and 2-hydrazinobenzothiazole as N-nucleophile. The reaction proved to be
highly chemoselective in all cases: carboxamides and the corresponding
carbohydrazides, obtained by the acylation at the nitrogen adjacent to the C-2 of the
benzothiazole moiety, were obtained exclusively and isolated in moderate to high
yields. Systematic investigation of the reaction conditions revealed that the reaction
o
requires relatively high temperature (higher than 70 C). The effect of the carbon
monoxide pressure is different in the synthesis of the two types of products: while the
carboxamide formation is favoured, the carbohydrazide formation is lowered by the
increasing CO pressure.
Key-words: aminocarbonylation, acylation, palladium, carbon monoxide, thiazole.
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1. Introduction
There are a number of conventional organic reactions providing carboxamides.1 One of the most
elegant ways of forming carboxamides is the palladium-catalysed aminocarbonylation discovered by Heck.2
The structural variability of both the substrate and the N-nucleophile makes this reaction highly favored in the
synthesis of carboxamides (and 2-ketocarboxamides).3 During the past decade the structure-reactivity and
structure-selectivity relations of palladium-catalysed aminocarbonylation were investigated in our laboratory.4
Among the most relevant examples the introduction of carboxamide functionality into heterocycle frameworks
has to be mentioned.5
Although the palladium-catalysed aminocarbonylation is a suitable reaction for the coupling of
functionalised haloaromatics (or their synthetic surrogates, aryl triflates)/iodoalkenes (or their surrogates, enol
triflates) and N-nucleophiles to form conjugates via carboxamide link, there are relatively few examples for
the synthesis of more complex structures. Due to the functional group tolerance of this reaction rather
complicated substrates and N-nucleophiles can be used.
N-Benzothiazol-2-yl-carboxamides proved to be of practical importance. For instance, the synthesis of
amides possessing antimicrobial activity6, adenosine A2B receptor antagonist7, immunosuppressive8 activity
and antiproliferative activity9 have been published (Fig. 1).
Fig. 1. Some N-benzothiazol-2-yl-carboxamides of pharmacological importance
Various methodologies were published for the synthesis of carboxamides possessing N-benzothiazol-2-
yl substituent. N-Substituted-2-aminobenzo[d]thiazoles, obtained via cyclization of 2-iodophenyl thiourea
intermediate resin, were acylated by various acyl halides and debenzylated.10 A high-yielding synthesis of N-
acyl 2-aminobenzothiazoles was carried out in NHC-catalysed direct oxidative amidation of aldehydes.11 An
efficient copper-mediated domino three-component approach was published for the synthesis of N-acyl-2-
aminobenzothiazoles from a 2,2’-aminophenyl disulphide derivative using the corresponding aryloyl chloride
as electrophile.12 Various benzothiazoles, among them N-acylated derivatives, were obtained as unexpected
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side- products in the synthesis of benzo-1,2,4-dithiazines.13 The efficiency of a copper catalysed biomimetic
route to N-heterocyclic carboxamides was also exemplified with benzothiazoles.14
Our preliminary experiences on palladium-catalysed aminocarbonylation encouraged us to investigate
the synthesis of benzothiazoles possessing acylamino functionality using 2-amino- or 2-
hydrazinobenzothiazoles as N-nucleophiles.15 In this way, after a detailed catalytic investigation a series of
benzamide-benzothiazole conjugates was synthesised.
2. Results and discussion
2.1. Aminocarbonylation of iodoaromatics in the presence of 2-aminobenzothiazole as N-nucleophile
2-Aminobenzothiazole (2) as N-nucleophile was applied for the aminocarbonylation of iodobenzene
(1a). in the presence of in situ generated palladium(0) catalysts. The reaction was completely chemoselective,
the corresponding carboxamide (3a) was formed exclusively (Scheme 1). Under the reaction conditions, the
catalyst precursor, Pd(OAc)2 underwent reduction to catalytically active Pd(0) species. The formation of the
low-ligated palladium(0) species is due to triphenylphosphine as reducing agent while it is oxidized to
triphenylphosphine oxide 16
Carrying out the optimization experiments with the parent iodobenzene (1a), the strong influence of the
reaction temperature was observed: the increasing temperature resulted in higher conversions both under
atmospheric and 40 bar carbon monoxide pressure (Figure 2). At 30 oC negligible activities were observed in
the pressure range investigated. It is worth noting that the influence of the temperature is especially high in
case of high pressure experiments: practically complete conversion was obtained even after 2 hours (Figure 2,
lower diagram). In order to achieve yields of practical importance, 70 oC reaction temperature has to be used.
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Figure 2. Conversions obtained in aminocarbonylation of 1a at various temperatures under 1 bar (upper
diagram) and 40 bar (lower diagram) CO pressure using nucleophile 2
Investigating the scope of the reaction, further 4-substituted iodobenzenes (1b-1m) (Scheme 1), as well
as 2-iodoanisole (1n), 2-iodothiophene (1o), 3-iodotoluene (1p), 3-iodobenzonitrile (1q), 3,5-
bis(trifluoromethyl)iodobenzene (1r) were aminocarbonylated.
O
N
I
N
S
N
CO
H
+
Pd(OAc)2 / PPh3
30 - 70 °C
H2N
S
X
X
1 - 40 bar
1a-1m
1a
2
3a-3m
Yield: 34 - 88%
1b
1c
1d)
1e
1f
1g
1h
X = H ( ), tBu ( ), CH3 ( ), OCH3 ( , Ph ( ), F ( ), Cl ( ), Br ( ),
COOH (1i), COOCH3 (1j), C(O)CH3 (1k), CF3 (1l), CN (1m)
Scheme 1. Aminocarbonylation of 4-substituted iodoaromatics (1a-1m) in the presence of 2-
aminobenzothiazole (2)
All experiments resulted in the formation of a single carboxamide product (3a-3r), i.e. the reaction is perfectly
chemoselective. The isolated yields obtained under optimised conditions (vide infra) are given in Figure 4.
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Regarding the reactivity of the substrates, the substituents in position-4 with both electron releasing (1b) and
electron withdrawing (1m) properties increase reactivity of the substrate. Considering the quite wide range of
4-substituted iodobenzenes (1a-1m) it can be stated that no linear relation between the reactivity of the
substrate and the Hammett substituent constants (σp) can be determined. Similar effect was found with 3-
substituted iodobenzenes possessing electron releasing (1p) and electron withdrawing (1q) groups (Figure 3).
Figure 3. Conversions obtained with various substrates under 1 bar (upper diagram) and at 40 bar CO pressure
(lower diagram) using nucleophile 2
The work-up of the reaction mixtures resulted in the isolated yields depicted in Figure 4. It is worth
noting that the composition of the eluent used in chromatographic work-up procedure was not optimised.
Therefore, in spite of the high conversion and chemoselectivity, moderate to good yields were obtained. All
compounds were fully characterised. It was revealed by NMR investigations carried out in DMSO that the
target carboxamides exist mainly in their tautomeric form, that is, the amide-imidic acid tautomerisation took
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place (Scheme 2). (As most characteristic feature the extremely large 1H NMR chemical shift of the NH proton
(δ= ca. 13 ppm) should be mentioned.
Figure 4. Carboxamide products isolated in palladium-catalysed aminocarbonylation (isolated yields in
brackets)
(reaction conditions: 1 mmol substrate (1a-1r), 1.2 mmol 2-aminobenzothiazole (2); 0.025 mmol of Pd(OAc)2,
0.05 mmol of PPh3, 0.5 mL of Et3N, 10 mL of DMF, 1 bar CO, 70 °C, 24 h; conversions were generally higher
than 98%, except substrates 1a-1c and 1f (conversion: 78-85%)
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Scheme 2. The amide–imidic acid tautomerization of the isolated N-benzothiazol-2-yl benzamides
2.2. Aminocarbonylation of iodoaromatics in the presence of 2-hydrazinobenzothiazole (4) as N-nucleophile
As above, 2-hydrazinobenzothiazole (4) was investigated as N-nucleophile in aminocarbonylation using 1a as
substrate under similar conditions. Although both nitrogen atoms of 4 might act as N-nucleophile in
aminocarbonylation (in other words, both nitrogen atom can be acylated) a single product was formed in all
cases. The detailed analytical characterisation revealed that surprisingly, only the nitrogen adjacent to C-2 was
acylated resulted in the formation of the corresponding carbohydrazide 5a (Scheme 3).
As above, the optimization experiments carried out with the parent iodobenzene (1a) under atmospheric CO
pressure showed that reaction temperatures higher than 30 oC had to be used to obtain conversions of synthetic
o
relevance. Reaction temperatures higher than 50 C provided practically complete conversions in acceptable
reaction time. However, the carbonylations carried out under 40 bar CO pressure revealed that the conversions
decreased dramatically. Close to complete conversion can be obtained at 70 oC only, however, the reactivity of
the substrate is definitely lower than that obtained under 1 bar (Figure 5). The formation of di- and
tricarbonylpalladium(0) complexes, blocking oxidative addition of the iodoarene substrate onto palladium(0)
species, might be an explanation for this unexpected behaviour.
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Figure 5. Conversions obtained at various temperatures under 1 bar (upper diagram) and 40 bar (lower
diagram) CO pressure using nucleophile 4
The substrates (1b-1r) mentioned above in 2.1. were reacted with 2-hydrazinobenzothiazole (4) (the hydrazine
analogue of 2) under similar conditions. That is, the carbohydrazides substituted at the α-nitrogen (N-
aminocarboxamide type compounds) were obtained exclusively (Scheme 3, .Figure 7).
Scheme 3. Aminocarbonylation of 4-substituted iodoaromatics (1a-1m) in the presence of 2-
hydrazinobenzothiazole (4)
Regarding the reactivity of various 4-substituted substrates in the presence of the hydrazine nucleophile (4),
the 4-cyanoiodobenzene (1m) showed the lowest reactivity under atmospheric CO pressure. However, all 4-
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substituents (for instance 1b and 1m, Figure 6) have increased reactivity compared to the parent iodobenzene
(1a). Similar influence of 3-substituents was observed (1p, 1q).
Figure 6. Conversions obtained with various substrates under 1 bar (upper diagram) and at 40 bar (lower
diagram) CO pressure using nucleophile 4
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Figure 7. Hydrazide products isolated in palladium-catalysed hydrazinocarbonylation (Scheme 3)
(reaction conditions: 1 mmol substrate (1a-1r), 1.2 mmol 2-hydrazinobenzothiazole (4); 0.025 mmol of
Pd(OAc)2, 0.05 mmol of PPh3, 0.5 mL of Et3N, 10 ml of DMF, 1 bar CO, 70 °C, 24 h; conversions were
higher than 98% in all cases).
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Conclusions
A novel synthetic method was given for the synthesis of two sets of aryl carboxamides possessing N-
benzothiazolyl substituent. It has been proved that iodoarenes undergo facile aminocarbonylation even under
mild conditions in the presence of 2-amino- and 2-hydrazinobenzothiazole as N-nucleophile. The new catalytic
procedure described for the synthesis of the above hybrides tolerates various functional groups, therefore no
functional group protection was necessary.
3. Experimental
3.1. General procedures
1H, 19F and 13C NMR spectra were recorded in DMSO on a Bruker Avance III 500 spectrometer at 500,
470.4 and 125.7 MHz, respectively. Chemical shifts δ are reported in ppm relative to DMSO (2.50 and 39.50
1
13
ppm for H and C, respectively). Elemental analyses were measured on a 1108 Carlo Erba apparatus. The
FT-IR spectra were taken in KBr pellets using an IMPACT 400 spectrometer (Nicolet) applying a DTGS
detector in the region of 400-4000 cm-1, the resolution was 4 cm-1. The amount of the samples was ca. 0.5 mg.
Mass spectrometry data have been obtained using a GC-MS system consisting of a Perkin Elmer AutoSystem
XL gas-chromatograph. Melting points are uncorrected and were measured with a Büchi apparatus. TLC
plates (silica gel on TLC Al foils with fluorescence indicator 254 nm) were purchased from Sigma-Aldrich.
The eluents used in thin-layer chromatography are specified below.
Substrates (iodoaromatics, 1a-1r) and nucleophiles (2 and 4) were purchased from Sigma-Aldrich and
were used without further purification.
It has to be noted that several compounds below (3a, 3c, 3d, 3e, 3f, 3g, 3h, 3l, 3m, 3o) have been
already synthesised. In general, good agreement with analytical details published for these compounds can be
observed. However, due to some missing data or partial characterization, all analytical details of the target
compounds will be given below.
3.2. Aminocarbonylation of iodoaromatics in the presence of nucleophiles 2 and 4 under atmospheric carbon
monoxide pressure
In a typical experiment Pd(OAc)2 (5.6 mg, 0.025 mmol), triphenylphosphine (13.1 mg, 0.05 mmol),
iodobenzene (1a) (110 µL, 1.0 mmol) (or an other iodoaromatics, 1b-1r) (1.0 mmol), nucleophile 2 (180.2 mg,
1.2 mmol) or 4 (198.3 mg, 1.2 mmol) and triethylamine (0.5 mL) were dissolved in DMF (10 mL) under argon
in a 100 mL three-necked flask equipped with a gas inlet, reflux condenser with a balloon (filled with argon) at
the top. The atmosphere was changed to carbon monoxide. The reaction was conducted for the given reaction
time upon stirring at 70 ˚C (either 50 °C or 30 °C) and analysed by GC-MS (internal standard: dodecane). The
cooled reaction mixture was then concentrated and evaporated to dryness under reduced pressure.
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Method A. (3b-3d, 3f, 3k, 3n-3p, 5n, 5r): The residue was dissolved in chloroform (15 mL) and washed
three times with water (30 mL). The organic phase was dried over Na2SO4, filtered and evaporated under
reduced pressure to a solid material. Aforesaid compounds were subjected to column chromatography
(Silicagel 60 (Merck), 0.063-0.200 mm), EtOAc/CHCl3 eluent mixtures (the exact ratios are specified in
Characterization for each compound; isolated yields are not optimized).
Method B. (3a, 3e, 3g-3j, 3l, 3m, 3q, 3r, 5a-5m, 5o-5q): Toluene (15 mL) was added to the residue, the
insoluble material (product) was filtered, washed with water on the filter and dried. The powder-like material
was dissolved in methanol, the palladium-black was filtered off and methanol was evaporated.
3.3. Aminocarbonylation of iodoaromatics in the presence of nucleophiles 2 and 4 under high (40 bar) carbon
monoxide pressure
In a typical experiment, Pd(OAc)2 (5.6 mg, 0.025 mmol), triphenylphosphine (13.1 mg, 0.05 mmol),
iodobenzene (1a) (110 µL, 1.0 mmol) (or another iodoaromatics, 1b-1r) (1.0 mmol), nucleophile 2 (180.2 mg,
1.2 mmol) or 4 (198.3 mg, 1.2 mmol) and triethylamine (0.5mL) were dissolved in DMF (10 mL) under argon
in a 100 mL autoclave. The atmosphere was changed to carbon monoxide and the autoclave was pressurized to
40 bar with carbon monoxide. The reaction was conducted for the given reaction time upon stirring at 70 ˚C
(either 50 °C or 30 °C) and analysed by GC-MS (internal standard: dodecane). The mixture was then
concentrated and evaporated to dryness and worked-up as described in Section 3.2.
3.4. Characterization of the products
N-(Benzothiazol-2-yl)benzamide (3a)10,11,12,13. Yield: 152.8 mg (60%), white powder, mp 190-191°C;
[Found: C, 66.26; H, 4.05; N, 10.88; C14H10N2OS requires C, 66.12; H, 3.96; N, 11.02%]; Rf (20% EtOAc,
80% CHCl3) 0.81; δH (500 MHz, DMSO) 12.91 (1H, br s, NH), 8.16 (2H, d, 7.6 Hz, CHortho(Ph)), 8.04 (1H, d,
7.9 Hz, CH(benzothiazole)), 7.81 (1H, d, 7.9 Hz, CH(benzothiazole)), 7.68 (1H, t, 7.4 Hz, CHpara(Ph)), 7.59
(2H, t, 7.6 Hz, CHmeta(Ph)), 7.49 (1H, t, 7.9 Hz, CH(benzothiazole)), 7.36 (1H, t, 7.9 Hz, CH(benzothiazole));
δC (125.7 MHz, DMSO) 166.4, 159.3, 149.0, 133.4, 132.4, 132.1, 129.1, 128.8, 126.7, 124.2, 122.2, 120.9. IR
(KBr ν (cm-1)) 3226 (NH), 1673 (CON); MS m/z (rel int.): 254 (26, M+), 226 (27), 149 (2), 105 (100), 77 (56).
N-(Benzothiazol-2-yl)-4-(tert-butyl)benzamide (3b). Yield: 245.6 mg (79%), orange needle crystal, mp
178-179 °C; [Found: C, 69.60; H, 5.98; N, 8.95; C18H18N2OS requires C, 69.65; H, 5.84; N, 9.02%]; Rf (20%
EtOAc, 80% CHCl3) 0.93; δH (500 MHz, DMSO) 12.84 (1H, br s, NH), 8.10 (2H, d, 8.2 Hz, CH(Ph)), 8.02
(1H, d, 7.9 Hz, CH(benzothiazole)), 7.79 (1H, d, 8.1 Hz, CH(benzothiazole)), 7.59 (2H, d, 8.2 Hz, CH(Ph)),
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7.49 (1H, t, 7.6 Hz, CH(benzothiazole)), 7.35 (1H, t, 7.6 Hz, CH(benzothiazole)), 1.33 (9H, s, CH3); δC (125.7
MHz, DMSO) 166.2, 159.3, 156.4, 149.0, 137.2, 132.0, 129.6, 128.7, 126.0, 124.1, 122.2, 120.8, 35.3, 31.3.
IR (KBr ν (cm-1)) 3226 (NH), 1676 (CON); MS m/z (rel int.): 310 (19, M+), 282 (10), 161 (100), 146 (10), 118
(14), 91 (10).
N-(Benzothiazol-2-yl)-4-methylbenzamide (3c)10,11,12. Yield: 177.7 mg (66 %), with solid, mp 193-194
°C; [Found: C, 67.36; H, 4.57; N, 10.25; C15H12N2OS requires C, 67.14; H, 4.51; N, 10.44%]; Rf (20% EtOAc,
80% CHCl3) 0.90; δH (500 MHz, DMSO) 12.81 (1H, br s, NH), 8.07 (2H, d, 8.1 Hz, CH(Ph)), 8.02 (1H, d, 7.9
Hz, CH(benzothiazole)), 7.79 (1H, d, 8.1 Hz, CH(benzothiazole)), 7.48 (1H, t, 7.6 Hz, CH(benzothiazole)),
7.38 (2H, d, 8.1 Hz, CH(Ph)), 7.35 (1H, t, 7.6 Hz, CH(benzothiazole)), 2.41 (3H, s, CH3); δC (125.7 MHz,
DMSO) 166.3, 159.3, 149.0, 143.7, 132.0, 129.7, 129.6, 128.8, 126.6, 124.1, 122.2, 120.8, 21.6. IR (KBr ν
(cm-1)) 3226 (NH), 1671 (CON); MS m/z (rel int.): 268 (23, M+), 240 (15), 149 (3), 119 (100), 91 (45), 65
(18).
N-(Benzothiazol-2-yl)-4-methoxybenzamide (3d)10,12. Yield: 243.3 mg (86%), pale brown solid, mp 196-
197 °C; [Found: C, 63.20; H, 4.41; N, 9.73; C15H12N2O2S requires C, 63.36; H, 4.25; N, 9.85%]; Rf (20%
EtOAc, 80% CHCl3) 0.87; δH (500 MHz, DMSO) 12.72 (1H, br s, NH), 8.16 (2H, d, 8.7 Hz, CH(Ph)), 8.01
(1H, d, 7.9 Hz, CH(benzothiazole)), 7.79 (1H, d, 8.1 Hz, CH(benzothiazole)), 7.48 (1H, t, 7.6 Hz,
CH(benzothiazole)), 7.34 (1H, t, 7.6 Hz, CH(benzothiazole)), 7.11 (2H, d, 8.7 Hz, CH(Ph)), 3.87 (3H, s, CH3);
δC (125.7 MHz, DMSO) 165.7, 163.4, 159.5, 149.0, 132.0, 130.9, 126.6, 124.4, 124.0, 122.1, 120.7, 114.4,
56.0. IR (KBr ν (cm-1)) 3230 (NH), 1665 (CON); MS m/z (rel int.): 284 (19, M+), 256 (4), 135 (100), 107 (8),
92 (11), 77 (17).
N-(Benzothiazol-2-yl)-[1,1’-biphenyl]-4-carboxamide (3e)17. Yield: 282.1 mg (85%), pale brown
powder, mp 236-237 °C; [Found: C, 72.54; H, 4.43; N, 8.30; C20H14N2OS requires C, 72.70; H, 4.27; N,
8.48%]; Rf (20% EtOAc, 80% CHCl3) 0.93; δH (500 MHz, DMSO) 12.92 (1H, br s, NH), 8.25 (2H, d, 8.2 Hz,
CH(Ph)), 8.03 (1H, d, 7.9 Hz, CH(benzothiazole)), 7.89 (2H, d, 8.2 Hz, CH(Ph)), 7.78-7.82 (3H, m, CH(Ph),
CH(benzothiazole)), 7.44-7.54 (4H, m, CH(Ph), CH(benzothiazole)), 7.36 (1H, t, 7.5 Hz, CH(benzothiazole));
δC (125.7 MHz, DMSO) 166.1, 159.3, 149.0, 144.8, 139.3, 132.0, 131.2, 129.6, 129.5, 128.9, 127.5, 127.3,
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126.7, 124.2, 122.2, 120.8. IR (KBr ν (cm-1)) 3226 (NH), 1675 (CON); MS m/z (rel int.): 330 (22, M+), 302
(11), 181 (100), 152 (52).
N-(Benzothiazol-2-yl)-4-fluorobenzamide (3f)10. Yield: 205.4 mg (75%), pale brown powder, mp 221-
222 °C; [Found: C, 61.59; H, 3.50; N, 10.20; C14H9N2OSF requires C, 61.75; H, 3.33; N, 10.29%]; Rf (20%
EtOAc, 80% CHCl3) 0.79; δH (500 MHz, DMSO) 12.89 (1H, br s, NH), 8.23 (2H, dd, JH-H 8.6 Hz, JH–F 5.5 Hz,
CH(Ph)), 8.02 (1H, d, 7.9 Hz, CH(benzothiazole)), 7.79 (1H, d, 8.0 Hz, CH(benzothiazole)), 7.48 (1H, t, 7.7
Hz, (benzothiazole)), 7.41 (2H, t, JH-H 8.6 Hz, JH–F 8.6 Hz, CH(Ph)), 7.35 (1H, t, 7.6 Hz, CH(benzothiazole));
δF (470.4 MHz, DMSO): -106.51 (br s, CF(Ph)); δC (125.7 MHz, DMSO) 165.3 (d, JC-F 251.2 Hz), 165.3,
159.2, 149.0, 132.0, 131.7 (d, JC-F 9.5 Hz), 129.0, 126.7, 124.2, 122.2, 120.8, 116.2 (d, JC-F 21.9 Hz). IR (KBr
ν (cm-1)) 3230 (NH), 1675 (CON), 1224 (CF); MS m/z (rel int.): 272 (24, M+), 244 (20), 149 (3), 123 (100),
95 (50), 75 (14).
N-(Benzothiazol-2-yl)-4-chlorobenzamide (3g)10,11,18. Yield: 98.7 mg (34%), pale brown powder, mp
234-235 °C; [Found: C, 58.11; H, 3.03; N, 9.46; C14H9N2OSF requires C, 58.23; H, 3.14; N, 9.70%]; Rf (20%
EtOAc, 80% CHCl3) 0.85; δH (500 MHz, DMSO) 12.98 (1H, br s, NH), 8.16 (2H, d, 8.3 Hz, CH(Ph)), 8.02
(1H, d, 7.8 Hz, CH(benzothiazole)), 7.79 (1H, d, 7.9 Hz, CH(benzothiazole)), 7.64 (2H, d, 8.3 Hz, CH(Ph)),
7,48 (1H, t, 7.6 Hz, CH(benzothiazole)), 7.35 (1H, t, 7.5 Hz, CH(benzothiazole)); δC (125.7 MHz, DMSO)
165.6, 159.2, 148.9, 138.2, 131.9, 131.3, 130.8, 129.2, 126.7, 124.2, 122.2, 120.9. IR (KBr ν (cm-1)) 3226
(NH), 1677 (CON), 1077(CCl); MS m/z (rel int.): 290 (9, M+), 288 (24, M+), 262 (9), 260 (24), 141 (34), 139
(100), 113 (14), 111 (44), 75 (20).
N-(Benzothiazol-2-yl)-4-bromobenzamide (3h)12,14. Yield: 190.6 mg (57%), pale brown powder, mp
250-251 °C; [Found: C, 50.34; H, 2.80; N, 8.22; C14H9N2OSBr requires C, 50.47; H, 2.72; N, 8.41%]; Rf (20%
EtOAc, 80% CHCl3) 0.86; δH (500 MHz, DMSO) 12.96 (1H, br s, NH), 8.07 (2H, d, 8.4 Hz, CH(Ph)), 8.02
(1H, d, 7.9 Hz, CH(benzothiazole)), 7.79 (3H, d, 8.1 Hz, CH(Ph), CH(benzothiazole)), 7.49 (1H, t, 7.6 Hz,
CH(benzothiazole)), 7.36 (1H, t, 7.5 Hz, CH(benzothiazole)); δC (125.7 MHz, DMSO) 165.7, 159.1, 149.0,
132.2, 131.6, 130.9, 127.3, 126.7, 124.3, 122.3, 121.0. IR (KBr ν (cm-1)) 3226 (NH), 1678 (CON); MS m/z
(rel int.): 334 (26, M+), 332 (25, M+), 306 (28), 304 (28), 185 (100), 183 (100), 157 (38), 155 (38), 76 (27).
15

ACCEPTED MANUSCRIPT
4-(Benzothiazol-2-ylcarbamoyl)benzoic acid (3i). Yield: 248.5 mg (83%), pale brown powder, mp above
390 °C; [Found: C, 60.24; H, 3.47; N, 9.27; C15H10N2O3S requires C, 60.39; H, 3.38; N, 9.39%]; Rf (20%
EtOAc, 80% CHCl3) 0.01; δH (500 MHz, DMSO) 13.21 (2H, br s, COOH; NH), 8.30 (2H, d, 8.1 Hz, CH(Ph)),
8.10 (2H, d, 8.1 Hz, CH(Ph)), 8.04 (1H, d, 8.3 Hz, CH(benzothiazole)), 7.80 (1H, d, 7.9 Hz,
CH(benzothiazole)), 7.50 (1H, t, 7.6 Hz, CH(benzothiazole)), 7.37 (1H, t, 7.5 Hz, CH(benzothiazole)); δC
(125.7 MHz, DMSO) 167.1, 166.2, 159.6, 148.3, 136.3, 134.8, 131.8, 129.9, 129.1, 126.8, 124.3, 122.3, 120.7.
IR (KBr ν (cm-1)) 3234 (NH), 2438 and 1895 (OH), 1678 (CO (acid), CON).
Methyl 4-(benzothiazol-2-ylcarbamoyl)benzoate (3j). Yield: 249.2 mg (80%), pale brown powder, mp
248-249 °C; [Found: C, 61.40; H, 3.90; N, 8.90; C16H12N2O3S requires C, 61.53; H, 3.87; N, 8.97%]; Rf (20%
EtOAc, 80% CHCl3) 0.73; δH (500 MHz, DMSO) 13.08 (1H, br s, NH), 8.25 (2H, d, 8.0 Hz, CH(Ph)), 8.12
(2H, d, 8.0 Hz, CH(Ph)), 8.04 (1H, d, 7.9 Hz, CH(benzothiazole)), 7.80 (1H, d, 8.0 Hz, CH(benzothiazole)),
7.49 (1H, t, 7.6 Hz, CH(benzothiazole)), 7.37 (1H, t, 7.5 Hz, CH(benzothiazole)), 3.91 (3H, s, CH3); δC (125.7
MHz, DMSO) 166.0, 165.9, 159.3, 148.8, 136.6, 133.5, 131.8, 129.7, 129.2, 126.8, 124.3, 122.3, 120.8, 52.9.
IR (KBr ν (cm-1)) 3230 (NH), 1714 (CO (ester)), 1674 (CON); MS m/z (rel int.): 312 (25, M+), 284 (31), 163
(100), 135 (20), 103 (14), 76 (11).
4-Acetyl-N-(benzothiazol-2-yl)benzamide (3k). Yield: 187.4 mg (63%), yellow powder, mp 211-212 °C;
[Found: C, 64.66; H, 4.01; N, 9.19; C16H12N2O2S requires C, 64.85; H, 4.08; N, 9.45%]; Rf (20% EtOAc, 80%
CHCl3) 0.54; δH (500 MHz, DMSO) 13.04 (1H, br s, NH), 8.25 (2H, d, 8.1 Hz, CH(Ph)), 8.11 (2H, d, 8.1 Hz,
CH(Ph)), 8.04 (1H, d, 7.9 Hz, CH(benzothiazole)), 7.81 (1H, d, 8.0 Hz, CH(benzothiazole)), 7.50 (1H, t, 7.6
Hz CH(benzothiazole)), 7.37 (1H, t, 7.5 Hz, CH(benzothiazole)), 2.66 (3H, s, CH3); δC (125.7 MHz,
DMSO)198.2, 165.9, 159.1, 148.9, 140.2, 136.2, 131.9, 129.4, 129.2, 128.8, 126.8, 124.3, 122.3, 121.0, 27.5.
IR (KBr ν (cm-1)) 3230 (NH), 1688 (CO (keto)), 1678 (CON); MS m/z (rel int.): 296 (26, M+), 268 (27), 177
(3), 147 (100), 119 (14), 104 (10), 91 (23), 76 (15).
N-(Benzothiazol-2-yl)-4-(trifluoromethyl)benzamide (3l)10. Yield: 220.6 mg (68%), pale brown powder,
mp 254-255 °C; [Found: C, 55.86; H, 2.59; N, 8.56; C15H9N2OSF3 requires C, 55.90; H, 2.81; N, 8.69%]; Rf
(20% EtOAc, 80% CHCl3) 0.88; δH (500 MHz, DMSO) 13.09 (1H, br s, NH), 8.32 (2H, d, 8.0 Hz, CH(Ph)),
8.03 (1H, d, 7.9 Hz, CH(benzothiazole)), 7.95 (2H, d, 8.0 Hz, CH(Ph)), 7.80 (1H, d, 8.0 Hz,
16

ACCEPTED MANUSCRIPT
CH(benzothiazole)), 7.49 (1H, t, 7.6 Hz, CH(benzothiazole)), 7.37 (1H, t, 7.6 Hz, CH(benzothiazole)); δF
(470.4 MHz, DMSO): -61.49 (s, CF3); δC (125.7 MHz, DMSO) 165.7, 159.4, 148.5, 136.5, 132.8 (q, JC-F 32.0
Hz), 131.8, 129.8, 126.8, 126.0 (q, JC-F 3.5 Hz), 124.3, 124.3 (q, JC-F 272.6 Hz), 122.3, 120.7. IR (KBr ν (cm-
1)) 3234 (NH), 1676 (CON), 1331, 1168 and 1119 (CF); MS m/z (rel int.): 322 (27, M+), 294 (31), 173 (100),
145 (71), 95 (9).
N-(Benzothiazol-2-yl)-4-cyanobenzamide (3m)10,12. Yield: 219.5 mg (79%), pale brown powder, mp
281-280 °C; [Found: C, 64.66; H, 3.40; N, 14.97; C15H9N3OS requires C, 64.50; H, 3.25; N, 15.04%]; Rf (20%
EtOAc, 80% CHCl3) 0.58; δH (500 MHz, DMSO) 13.02 (1H, br s, NH), 8.27 (2H, d, 8.2 Hz, CH(Ph)), 8.03-
8.06 (3H, m, CH(Ph), CH(benzothiazole)), 7.80 (1H, d, 8.0 Hz, CH(benzothiazole)), 7.50 (1H, t, 7.6 Hz,
CH(benzothiazole)), 7.37 (1H, t, 7.5 Hz, CH(benzothiazole)); δC (125.7 MHz, DMSO) 165.6, 159.0, 148.6,
136.6, 133.1, 131.8, 129.6, 126.8, 124.4, 122.4, 120.7, 118.6, 115.4. IR (KBr ν (cm-1)) 3230 (NH), 2229 (CN),
1676 (CON); MS m/z (rel int.): 279 (31, M+), 251 (37), 177 (6), 130 (100), 102 (69), 75 (14).
N-(Benzothiazol-2-yl)-2-methoxybenzamide (3n). Yield: 234.3 mg (82%), pale brown solid, mp 167-168
°C; [Found: C, 63.46; H, 4.18; N, 9.77; C15H12N2O2S requires C, 63.36; H, 4.25; N, 9.85%]; Rf (20% EtOAc,
80% CHCl3) 0.93; δH (500 MHz, DMSO) 12.07 (1H, br s, NH), 8.03 (1H, d, 7.9 Hz, CH(benzothiazole)),
7.78-7.81 (2H, m, CH(Ph), CH(benzothiazole)), 7.61 (1H, t, 7.8 Hz, CH(Ph)), 7.48 (1H, d, 7.6 Hz,
CH(benzothiazole)), 7.35 (1H, t, 7.6 Hz, CH(benzothiazole)), 7.26 (1H, d, 8.4 Hz, CH(Ph)), 7.16 (1H, t, 7.5
Hz, CH(Ph)), 3.97 (3H, s, CH3); δC (125.7 MHz, DMSO) 165.2, 158.1, 157.7, 149.0, 134.2, 132.1, 130.9,
126.7, 124.2, 122.2, 121.9, 121.2, 121.1, 112.8, 56.7. IR (KBr ν (cm-1)) 3277 (NH), 1666 (CON); MS m/z (rel
int.): 284 (17, M+), 253 (18), 135 (100), 92 (15), 77 (26).
N-(Benzothiazol-2-yl)thiophene-2-carboxamide (3o)10,12. Yield: 229.8 mg (88%), orange solid, mp 203-
204 °C; [Found: C, 55.50; H, 3.18; N, 10.65; C12H8N2OS2 requires C, 55.37; H, 3.10; N, 10.76%]; Rf (20%
EtOAc, 80% CHCl3) 0.79; δH (500 MHz, DMSO) 13.00 (1H, br s, NH), 8.30 (1H, br s, CH(thiophene)), 8.00-
8.03 (2H, m, CH(thiophene), CH(benzothiazole)), 7.77 (1H, d, 7.7 Hz, CH(benzothiazole)), 7.48 (1H, t, 7.6
Hz, CH(benzothiazole )), 7.35 (1H, t, 7.6 Hz, CH(benzothiazole)), 7.29 (1H, t, 4.3 Hz, CH(thiophene)); δC
(125.7 MHz, DMSO) 160.9, 158.9, 149.0, 137.5, 134.6, 131.9, 129.1, 126.7, 124.2, 122.3, 120.9. IR (KBr ν
(cm-1)) 3217 (NH), 1661 (CON); MS m/z (rel int.): 260 (28, M+), 232 (16), 149 (3), 111 (100), 83 (9).
17

ACCEPTED MANUSCRIPT
N-(Benzothiazol-2-yl)-3-methylbenzamide (3p). Yield: 222.9 mg (80 %), white solid, mp 175-176 °C;
[Found: C, 67.03; H, 4.60; N, 10.30; C15H12N2OS requires C, 67.14; H, 4.51; N, 10.44%]; Rf (20% EtOAc,
80% CHCl3) 0.81; δH (500 MHz, DMSO) 12.84 (1H, br s, NH), 8.03 (1H, d, 7.9 Hz, CH(benzothiazole)), 8.00
(1H, s, CH(Ph)), 7.95 (1H, d, 7.2 Hz, CH(Ph)), 7.80 (1H, d, 8.1 Hz, CH(benzothiazole)), 7.44-7.49 (3H, m,
CH(Ph)), CH(benzothiazole)), 7.35 (1H, t, 7.6 Hz, CH(benzothiazole)), 2.41 (3H, s, CH3); δC (125.7 MHz,
DMSO) 166.6, 159.3, 148.8, 138.5, 133.9, 132.4, 132.0, 129.3, 129.0, 126.6, 125.9, 124.1, 122.2, 120.8, 21.4.
IR (KBr ν (cm-1)) 3226 (NH), 1675 (CON); MS m/z (rel int.): 268 (25, M+), 240 (21), 149 (3), 119 (100), 91
(56), 65 (21).
N-(Benzothiazol-2-yl)-3-cyanobenzamide (3q). Yield: 147.8 mg (53%), pale brown powder, mp 198-199
°C; [Found: C, 64.54; H, 3.17; N, 14.90; C15H9N3OS requires C, 64.50; H, 3.25; N, 15.04%]; Rf (20% EtOAc,
80% CHCl3) 0.66; δH (500 MHz, DMSO) 13.05 (1H, br s, NH), 8.57 (1H, s, CH(Ph)), 8.41 (1H, d, 7.8 Hz,
CH(Ph)), 8.13 (1H, d, 7.6 Hz, CH(Ph)), 8.04 (1H, d, 7.8 Hz, CH(benzothiazole)), 7.78-7.81 (2H, m, CH(Ph),
CH(benzothiazole)), 7.50 (1H, t, 7.6 Hz, CH(benzothiazole )), 7.37 (1H, t, 7.6 Hz, CH(benzothiazole)); δC
(125.7 MHz, DMSO) 165.0, 159.2, 148.7, 136.5, 133.8, 133.5, 132.6, 131.8, 130.5, 126.8, 124.4, 122.4, 120.9,
118.6, 112.3. IR (KBr ν (cm-1)) 3234 (NH), 2233 (CN), 1676 (CON); MS m/z (rel int.): 279 (34, M+), 251
(30), 177 (8), 130 (100), 102 (65), 75 (13).
N-(Benzothiazol-2-yl)-3,5-bis(trifluoromethyl)benzamide (3r). Yield: 290.7 mg (75%), white powder,
mp 147-148 °C; [Found: C, 49.22; H, 8.17; N, 7.05; C16H8N2OSF6 requires C, 49.24; H, 8.07; N, 7.18%]; Rf
(20% EtOAc, 80% CHCl3) 0.95; δH (500 MHz, DMSO) 13.35 (1H, br s, NH), 8.77 (2H, s, CHortho(Ph)), 8.42
(1H, s, CHpara(Ph)), 8.02 (1H, d, 7.9 Hz, CH(benzothiazole)), 7.77 (1H, d, 7.9 Hz, CH(benzothiazole)), 7.50
(1H, t, 7.6 Hz, CH(benzothiazole)), 7.37 (1H, t, 7.5 Hz, CH(benzothiazole)); δF (470.4 MHz, DMSO): -61.45
(s, CF3); δC (125.7 MHz, DMSO) 164.6, 159.1, 148.6, 135.5, 131.1 (q, JC-F 33.4 Hz), 129.7, 126.9, 126.4,
124.4, 123.5 (q, JC-F 272.7 Hz), 122.5, 120.4. IR (KBr ν (cm-1)) 3243 (NH), 1669 (CON), 1279, 1190 and 1126
(CF); MS m/z (rel int.): 390 (36, M+), 371 (12), 362 (28), 241 (100), 213 (70), 177 (18), 144 (7), 69 (7).
N-(Benzothiazol-2-yl)benzohydrazide (5a). Yield: 205.6 mg (76%), white solid, mp 230-231 °C; [Found:
C, 62.46; H, 4.23; N, 15.44; C14H11N3OS requires C, 62.44; H, 4.12; N, 15.60%]; Rf (20% EtOAc, 80%
18

ACCEPTED MANUSCRIPT
CHCl3) 0.94; δH (500 MHz, DMSO) 8.04 (1H, d, 7.9 Hz, CH(benzothiazole)), 7.87 (1H, d, 8.1 Hz,
CH(benzothiazole)), 7.83 (2H, d, 7.5 Hz, CHortho(Ph)), 7.47-7.57 (4H, m, CHpara(Ph), CHmeta(Ph),
CH(benzothiazole)), 7.38 (1H, t, 7.5 Hz, CH(benzothiazole)), 5.83 (2H, s, NH2); δC (125.7 MHz, DMSO)
171.3, 161.6, 148.2, 134.6, 133.7, 131.2, 129.8, 128.0, 126.8, 124.5, 122.3, 121.5. IR (KBr ν (cm-1)) 3306 and
3212 (NH2), 1637 (CON); MS m/z (rel int.): 269 (25, M+), 164 (4), 105 (100), 77 (47).
N-(Benzothiazol-2-yl)-4-(tert-butyl)benzohydrazide (5b). Yield: 275.1 mg (85%), pale brown powder,
mp 226-227 °C; [Found: C, 66.56; H, 5.99; N, 12.75; C18H19N3OS requires C, 66.43; H, 5.88; N, 12.91%]; Rf
(10% EtOAc, 90% CHCl3) 0.98; δH (500 MHz, DMSO) 8.04 (1H, d, 7.9 Hz, CH(benzothiazole)), 7.88 (1H, d,
8.1 Hz, CH(benzothiazole)), 7.81 (2H, d, 8.2 Hz, CH(Ph)), 7.57-7.49 (3H, m, CH(Ph), CH(benzothiazole)),
7.38 (1H, t, 7.5 Hz, CH(benzothiazole)), 5.84 (2H, br s, NH2), 1.34 (9H, s, CH3); δC (125.7 MHz,
DMSO)171.2, 161.7, 154.2, 148.3, 133.8, 131.6, 130.0, 126.7, 124.7, 124.4, 122.2, 121.4, 35.1, 31.4. IR (KBr
ν (cm-1)) 3328 and 3212 (NH2), 1629 (CON); MS m/z (rel int.): 325 (8, M+), 310 (7), 161 (100), 146 (9), 118
(10), 91 (8).
N-(Benzothiazol-2-yl)-4-methylbenzohydrazide (5c). Yield: 206.5 mg (73%), pale brown solid, mp 218-
219 °C; [Found: C, 63.49; H, 4.70; N, 14.97; C15H13N3OS requires C, 63.58; H, 4.62; N, 14.83%]; Rf (10%
EtOAc, 90% CHCl3) 0.95; δH (500 MHz, DMSO) 8.03 (1H, d, 7.9 Hz, CH(benzothiazole)), 7.87 (1H, d, 8.1
Hz, CH(benzothiazole)), 7.78 (2H, d, 8.0 Hz, CH(Ph)), 7.50 (1H, t, 7.6 Hz, CH(benzothiazole)), 7.38 (1H, t,
7.5 Hz, CH(benzothiazole)), 7.30 (2H, d, 8.0 Hz, CH(Ph)), 5.82 (2H, s, NH2), 2.39 (3H, s, CH3); δC (125.7
MHz, DMSO) 171.1, 161.7, 148.3, 141.4, 133.8, 131.5, 130.2, 128.5, 126.7, 124.4, 122.2, 121.5, 21.6. IR
(KBr ν (cm-1)) 3310 and 3208 (NH2), 1635 (CON); MS m/z (rel int.): 283 (16, M+), 119 (100), 91 (38), 65
(15).
N-(Benzothiazol-2-yl)-4-methoxybenzohydrazide (5d). Yield: 240.2 mg (80%), brown powder, mp 219-
220 °C; [Found: C, 60.26; H, 4.20; N, 14.00; C15H13N3O2S requires C, 60.19; H, 4.38; N, 14.04%]; Rf (10%
EtOAc, 90% CHCl3) 0.91; δH (500 MHz, DMSO) 8.02 (1H, d, 7.6 Hz, CH(benzothiazole)), 7.95 (2H, d, 8.2
Hz, CH(Ph)), 7.87 (1H, d, 7.8 Hz, CH(benzothiazole)), 7.50 (1H, t, 7.3 Hz, CH(benzothiazole)), 7.37 (1H, t,
7.2 Hz, CH(benzothiazole)), 7.03 (2H, d, 8.2 Hz, CH(Ph)), 5.87 (2H, br s, NH2), 3.85 (3H, s, CH3); δC (125.7
19

ACCEPTED MANUSCRIPT
MHz, DMSO) 170.4, 161.9, 148.3, 133.8, 132.7, 126.7, 126.1, 124.4, 122.2, 121.4, 113.3, 55.9. IR (KBr ν
(cm-1)) 3306 and 3203 (NH2), 1617 (CON); MS m/z (rel int.): 299 (7, M+), 135 (100), 107 (7), 92 (9), 77 (15).
N-(Benzothiazol-2-yl)-[1,1’-biphenyl]-4-carbohydrazide (5e). Yield: 293.1 mg (85%), white powder, mp
273-274 °C; [Found: C, 69.33; H, 4.50; N, 12.02; C20H15N3OS requires C, 69.54; H, 4.38; N, 12.16%]; Rf
(10% EtOAc, 90% CHCl3) 0.98; δH (500 MHz, DMSO) 8.06 (1H, d, 7.8 Hz, CH(benzothiazole)), 7.97 (2H, d,
8.2 Hz, CH(Ph)), 7.89 (1H, d, 8.0 Hz, CH(benzothiazole)), 7.79 (4H, t, 8.8 Hz, CH(Ph)), 7.50-7.55 (3H, m,
CH(Ph), CH(benzothiazole)), 7.44 (1H, t, 7.4 Hz, CH(Ph)), 7.39 (1H, t, 7.6 Hz, CH(benzothiazole)), 5.89 (2H,
s, NH2); δC (125.7 MHz, DMSO) 170.9, 161.6, 148.3, 142.9, 139.8, 133.8, 133.4, 130.7, 129.5, 128.3, 127.7,
127.4, 126.2, 124.5, 122.3, 121.5. IR (KBr ν (cm-1)) 3309 and 3212 (NH2), 1635 (CON).
N-(Benzothiazol-2-yl)-4-fluorobenzohydrazide (5f). Yield: 274.9 mg (96%), pale brown solid, mp 234-
235 °C; [Found: C, 58.42; H, 3.35; N, 14.50; C14H10N3OSF requires C, 58.53; H, 3.51; N, 14.63%]; Rf (10%
EtOAc, 90% CHCl3) 0.87; δH (500 MHz, DMSO) 8.05 (1H, d, 7.8 Hz, CH(benzothiazole)), 7.96 (2H, dd, JH-H
8.8 Hz, JH-F 5.8 Hz, CH(Ph)), 7.88 (1H, d, 8.1 Hz, CH(benzothiazole)), 7.51 (1H, t, 7.4 Hz,
CH(benzothiazole)), 7.39 (1H, t, 7.5 Hz, CH(benzothiazole)), 7.34 (2H, dd, JH-H 8.8 Hz, JH-F 8.8 Hz, CH(Ph)),
5.87 (2H, br s, NH2); δF (470.4 MHz, DMSO): -108.98 (m, CF(Ph)); δC (125.7 MHz, DMSO) 170.2, 163.9 (d,
JC-F 249.0 Hz), 161.6, 148.2, 133.8, 132.8 (d, JC-F 8.9 Hz), 130.9 (d, JC-F 2.9 Hz), 126.8, 124.5, 122.3, 121.5,
115.0 (d, JC-F 21.8 Hz). IR (KBr ν (cm-1)) 3312 and 3212 (NH2), 1638 (CON), 1232 (CF); MS m/z (rel int.):
287 (22, M+), 164 (5), 123 (100), 95 (36).
N-(Benzothiazol-2-yl)-4-chlorobenzohydrazide (5g). Yield: 288.7 mg (95%), brown solid, mp 225-226
°C; [Found: C, 55.51; H, 3.24; N, 13.77; C14H10N3OSCl requires C, 55.36; H, 3.32; N, 13.83%]; Rf (10%
EtOAc, 90% CHCl3) 0.88; δH (500 MHz, DMSO) 8.05 (1H, d, 7.8 Hz, CH(benzothiazole)), 7.89 (3H, d, 7.8
Hz, CH(Ph), CH(benzothiazole)), 7.57 (2H, d, 8.0 Hz, CH(Ph)), 7.52 (1H, t, 7.5 Hz, CH(benzothiazole)), 7.39
(1H, t, 7.4 Hz, CH(benzothiazole)), 5.86 (2H, br s, NH2); δC (125.7 MHz, DMSO) 170.2, 161.5, 148.2, 136.1,
133.7, 133.4, 131.9, 128.1, 1268, 124.6, 122.3, 121.5. IR (KBr ν (cm-1)) 3323 and 3217 (NH2), 1615 (CON),
1094 (CCl); MS m/z (rel int.): 305 (8, M+), 303 (21, M+), 164 (7) 141 (34), 139 (100), 113 (11), 111 (33), 75
(12).
20

ACCEPTED MANUSCRIPT
N-(Benzothiazol-2-yl)-4-bromobenzohydrazide (5h). Yield: 269.7 mg (78%), pale brown solid, mp 232-
233 °C; [Found: C, 48.36; H, 2.76; N, 12.01; C14H10N3OSBr requires C, 48.29; H, 2.89; N, 12.07%]; Rf (10%
EtOAc, 90% CHCl3) 0.90; δH (500 MHz, DMSO) 8.04 (1H, d, 7.9 Hz, CH(benzothiazole)), 7.88 (1H, d, 8.0
Hz, CH(benzothiazole)), 7.79 (2H, d, 8.2 Hz, CH(Ph)), 7.70 (2H, d, 8.2 Hz, CH(Ph)), 7.51 (1H, t, 7.6 Hz,
CH(benzothiazole)), 7.39 (1H, t, 7.5 Hz, CH(benzothiazole)), 5.85 (2H, s, NH2); δC (125.7 MHz, DMSO)
170.3, 161.4, 148.2, 133.8, 133.7, 132.0, 131.0, 126.8, 124.9, 124.6, 122.3, 121.6. IR (KBr ν (cm-1)) 3323 and
3212 (NH2), 1614 (CON); MS m/z (rel int.): 349 (22, M+), 347 (21, M+), 185 (99), 183 (100), 164 (8), 157
(27), 155 (28), 109 (14), 76 (19).
4-(1-(Benzothiazol-2-yl)hydrazinecarbonyl)benzoic acid (5i). Yield: 211.9 mg (68%),pale brown solid,
mp 263-264 °C; [Found: C, 57.42; H, 3.66; N, 13.22; C15H11N3O3S requires C, 57.50; H, 3.54; N, 13.41%]; Rf
(10% EtOAc, 90% CHCl3) 0.04; δH (500 MHz, DMSO) 13.26 (1H, br s, COOH), 8.01-8.09 (3H, m, CH(Ph),
CH(benzothiazole)), 7.88-7.94 (3H, m, CH(Ph), CH(benzothiazole)), 7.52 (1H, t, 7.4 Hz, CH(benzothiazole)),
7.40 (1H, t, 7.4 Hz, CH(benzothiazole)), 5.86 (2H, s, NH2); δC (125.7 MHz, DMSO)170.7, 167.3, 161.3,
148.2, 138.8, 133.7, 132.8, 129.7, 128.9, 126.8, 124.6, 122.3, 121.6. IR (KBr ν (cm-1)) 3315 and 3217 (NH2),
3000 and 2545 (OH), 1688 (CO (acid)), 1639 (CON).
Methyl 4-(1-(benzothiazol-2-yl)hydrazinecarbonyl)benzoate (5j). Yield: 265.8 mg (81%), pale brown
powder, mp 247-248 °C; [Found: C, 51.80; H, 4.12; N, 12.75; C16H13N3O3S requires C, 51.71; H, 4.00; N,
12.84%]; Rf (10% EtOAc, 90% CHCl3) 0.79; δH (500 MHz, DMSO) 8.04-8.07 (3H, m, CH(Ph),
CH(benzothiazole)), 7.93 (2H, d, 8.3 Hz, CH(Ph)), 7.89 (1H, d, 8.1 Hz, CH(benzothiazole)), 7.52 (1H, t, 7.5
Hz, CH(benzothiazole)), 7.40 (1H, t, 7.5 Hz, CH(benzothiazole)), 5.86 (2H, s, NH2), 3.91 (3H, s, CH3); δC
(125.7 MHz, DMSO) 170.6, 166.2, 161.3, 148.2, 139.3, 133.7, 131.6, 129.9, 128.8, 126.8, 124.6, 122.3, 121.6,
52.9. IR (KBr ν (cm-1)) 3328 and 3217 (NH2), 1720 (CO (ester)), 1614 (CON); MS m/z (rel int.):. 327 (<1,
M+), 312 (24), 284 (28), 207 (9), 163 (100), 135 (19), 103 (15), 76 (12).
4-Acetyl-N-(benzothiazol-2-yl)benzohydrazide (5k). Yield: 249.8 mg (80%), pale brown solid, mp 244-
245 °C; [Found: C, 61.76; H, 4.38; N, 13.35; C16H13N3O2S requires C, 61.72; H, 4.21; N, 13.50%]; Rf (10%
EtOAc, 90% CHCl3) 0.73; δH (500 MHz, DMSO) 8.03-8.08 (3H, m, CH(Ph), CH(benzothiazole)), 7.93 (2H,
d, 8.2 Hz Hz, CH(Ph)), 7.89 (1H, d, 8.1 Hz, CH(benzothiazole)), 7.52 (1H, t, 7.6 Hz, CH(benzothiazole)), 7.40
21

ACCEPTED MANUSCRIPT
(1H, t, 7.6 Hz, CH(benzothiazole)), 5.86 (2H, br s, NH2), 2.66 (3H, s, CH3); δC (125.7 MHz, DMSO) 198.2,
170.7, 161.3, 148.2, 139.0, 138.4, 133.7, 129.8, 127.8, 126.8, 124.6, 122.3, 121.6, 27.4. IR (KBr ν (cm-1))
3315 and 3212 (NH2), 1685 (CO (keto)), 1637 (CON); MS m/z (rel int.): 311 (20, M+), 296 (10), 268 (10), 147
(100), 119 (12), 91 (18).
N-(Benzothiazol-2-yl)-4-(trifluoromethyl)benzohydrazide (5l). Yield: 259.8 mg (77%), pale brown solid,
mp 247-248 °C; [Found: C, 53.30; H, 3.18; N, 12.37; C15H10N3OSF3 requires C, 53.41; H, 2.99; N, 12.46%];
Rf (10% EtOAc, 90% CHCl3) 0.88; δH (500 MHz, DMSO) 8.07 (1H, d, 7.9 Hz, CH(benzothiazole)), 8.01 (2H,
d, 8.1 Hz, CH(Ph)), 7.90 (1H, d, 8.1 Hz, CH(benzothiazole)), 7.87 (2H, d, 8.1 Hz, CH(Ph)), 7.52 (1H, t, 7.4
Hz, CH(benzothiazole)), 7.40 (1H, t, 7.5 Hz, CH(benzothiazole)), 5.87 (2H, br s, NH2); δF (470.4 MHz,
DMSO) -61.36 (s, CF3); δC (125.7 MHz, DMSO) 170.3, 161.2, 148.2, 138.9, 133.7, 130.9 (q, JC-F 31.9 Hz),
130.3, 126.8, 125.0 (q, JC-F 3.6 Hz), 124.7, 124.4 (q, JC-F 268.1 Hz), 122.3, 121.6. IR (KBr ν (cm-1)) 3322 and
3212 (NH2), 1635 (CON); MS m/z (rel int.): 337 (42, M+), 173 (100), 164 (25), 145 (58), 109 (18).
N-(Benzothiazol-2-yl)-4-cyanobenzohydrazide (5m). Yield: 244.6 mg (83%), pale brown powder, mp
237-238 °C; [Found: C, 61.11; H, 3.50; N, 19.25; C15H10N4OS requires C, 61.21; H, 3.42; N, 19.04%]; Rf
(20% EtOAc, 80% CHCl3) 0.89; δH (500 MHz, DMSO) 8.05 (1H, d, 7.9 Hz, CH(benzothiazole)), 7.96 (4H, br
s, CH(Ph)), 7.89 (1H, d, 8.1 Hz, CH(benzothiazole)), 7.52 (1H, t, 7.6 Hz, CH(benzothiazole)), 7.40 (1H, t, 7.5
Hz, CH(benzothiazole)), 5.84 (2H, s, NH2); δC (125.7 MHz, DMSO) 170.0, 161.2, 148.2, 139.4, 133.7, 132.1,
130.2, 126.9, 124.7, 122.4, 121.6, 118.9, 113.3. IR (KBr ν (cm-1)) 3323 and 3217 (NH2), 2233 (CN), 1611
(CON); MS m/z (rel int.): 294 (37, M+), 280 (8), 251 (9), 164 (39), 130 (100), 109 (21), 102 (53).
N-(Benzothiazol-2-yl)-2-methoxybenzohydrazide (5n). Yield: 224.2 mg (75%), white solid, mp 177-178
°C; [Found: C, 60.02; H, 4.30; N, 13.95; C15H13N3O2S requires C, 60.19; H, 4.38; N, 14.04%]; Rf (20%
EtOAc, 80% CHCl3) 0.88; δH (500 MHz, DMSO) 8.05 (1H, d, 7.9 Hz, CH(benzothiazole)), 7.85 (1H, d, 8.1
Hz, CH(benzothiazole)), 7.51 (1H, t, 7.7 Hz, CH(benzothiazole)), 7.47 (1H, t, 7.5 Hz, CH(Ph)), 7.36-7.40 (2H,
m, CH(Ph), CH(benzothiazole)), 7.12 (1H, d, 8.4 Hz, CH(Ph)), 7.04 (1H, t, 7.5 Hz, CH(Ph)), 5.64 (2H, s,
NH2), 3.81 (3H, s, OCH3); δC (125.7 MHz, DMSO) 171.0, 161.0, 156.3, 148.2, 133.5, 131.5, 128.4, 126.8,
125.7, 124.5, 122.3, 121.5, 120.5, 111.6, 56.2. IR (KBr ν (cm-1)) 3310 and 3208 (NH), 1655 (CON); MS m/z
(rel int.): 299 (11, M+), 135 (100), 92 (10), 77 (20).
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ACCEPTED MANUSCRIPT
N-(Benzothiazol-2-yl)thiophene-2-carbohydrazide (5o). Yield: 250.8 mg (91%), brown solid, mp 256-
257 °C; [Found: C, 52.39; H, 3.10; N, 15.05; C12H9N3OS2 requires C, 52.35; H, 3.29; N, 15.26%]; Rf (10%
EtOAc, 90% CHCl3) 0.94; δH (500 MHz, DMSO) 8.21 (1H, d, 3.0 Hz, CH(thiophene)), 8.00-8.05 (2H, m,
CH(thiophene), CH(benzothiazole)), 7.87 (1H, d, 8.1 Hz, CH(benzothiazole)), 7.50 (1H, t, 7.5 Hz,
CH(benzothiazole)), 7.37 (1H, t, 7.5 Hz, CH(benzothiazole)), 7.26 (1H, t, 4.4 Hz, CH(thiophene)), 6.17 (2H, s,
NH2); δC (125.7 MHz, DMSO) 163.0, 161.0, 148.3, 137.9, 137.5, 133.9, 132.3, 127.2, 126.7, 124.4, 122.2,
121.5. IR (KBr ν (cm-1)) 3315 and 3203 (NH2), 1618 (CON); MS m/z (rel int.): 275 (28, M+), 164 (5), 111
(100), 83 (7).
N-(Benzothiazol-2-yl)-3-methylbenzohydrazide (5p). Yield: 195.1 mg (69%), pale brown solid, mp 172-
173 °C; [Found: C, 63.66; H, 4.77; N, 14.75; C15H13N3OS requires C, 63.58; H, 4.62; N, 14.83%]; Rf (10%
EtOAc, 90% CHCl3) 0.91; δH (500 MHz, DMSO) 8.05 (1H, d, 7.9 Hz, CH(benzothiazole)), 7.88 (1H, d, 8.0
Hz, CH(benzothiazole)), 7.62-7.67 (2H, m, CH(Ph)), 7.51 (1H, t, 7.5 Hz, CH(benzothiazole)), 7.35-7.41 (3H,
m, CH(Ph), CH(benzothiazole)), 5.82 (2H, br s, NH2) 2.39 (3H, s, CH3); δC (125.7 MHz, DMSO) 171.4,
161.6, 148.3, 137.2, 134.6, 133.8, 131.8, 130.2, 127.8, 127.0, 126.7, 124.5, 122.2, 121.5, 21.4. IR (KBr ν (cm-
1)) 3288 and 3208 (NH2), 1657 (CON); MS m/z (rel int.): 283 (9, M+), 268 (13), 240 (10), 119 (100), 91 (51),
65 (18).
N-(Benzothiazol-2-yl)-3-cyanobenzohydrazide (5q). Yield: 244.8 mg (83%), pale brown powder, mp
236-237 °C; [Found: C, 61.34; H, 3.50; N, 19.25; C15H10N4OS requires C, 61.21; H, 3.42; N, 19.04%]; Rf
(10% EtOAc, 90% CHCl3) 0.78; δH (500 MHz, DMSO) 8.32 (1H, s, CH(Ph)), 8.14 (1H, d, 7.7 Hz, CH(Ph)),
8.07 (1H, d, 7.8 Hz, CH(benzothiazole)), 8.02 (1H, d, 7.7 Hz, CH(Ph)), 7.90 (1H, d, 8.0 Hz,
CH(benzothiazole)), 7.73 (1H, t, 7.7 Hz, CH(Ph)), 7.53 (1H, t, 7.5 Hz, CH(benzothiazole)), 7.41 (1H, t, 7.5
Hz, CH(benzothiazole)), 5.88 (2H, br s, NH2); δC (125.7 MHz, DMSO) 169.5, 161.2, 148.2, 135.9, 134.6,
134.2, 133.7, 133.5, 129.5, 126.9, 124.7, 122.4, 121.6, 118.8, 111.2. IR (KBr ν (cm-1)) 3318 and 3212 (NH2),
2229 (CN), 1624 (CON); MS m/z (rel int.): 294 (39, M+), 280 (9), 251 (7), 164 (41), 130 (100), 109 (19), 102
(50).
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ACCEPTED MANUSCRIPT
N-(Benzothiazol-2-yl)-3,5-bis(trifluoromethyl)benzohydrazide (5r). Yield: 329.7 mg (81%), white solid,
mp 214-215 °C; [Found: C, 47.56; H, 2.38; N, 10.26; C16H9N3OSF6 requires C, 47.41; H, 2.24; N, 10.37%]; Rf
(10% EtOAc, 90% CHCl3) 0.92; δH (500 MHz, DMSO) 8.53 (2H, s, CH(Ph)), 8.32 (1H, s, CH(Ph)), 8.08 (1H,
d, 8.0 Hz, CH(benzothiazole)), 7.92 (1H, d, 8.1 Hz, CH(benzothiazole)), 7.53 (1H, t, 7.7 Hz,
CH(benzothiazole)), 7.41 (1H, t, 7.6 Hz, CH(benzothiazole)), 5.91 (2H, s, NH2); δF (470.4 MHz, DMSO) -
61.23 (s, CF3); δC (125.7 MHz, DMSO) 168.5, 161.0, 148.1, 137.5, 133.7, 130.5 (br s), 130.1 (q, JC-F 31.7 Hz),
126.9, 124.8, 124.5 (br s), 123.6 (q, JC-F 273.0 Hz), 122.4, 121.7. IR (KBr ν (cm-1)) 3310 and 3221 (NH2),
1637 (CON), 1276, 1170 and 1130 (CF); MS m/z (rel int.): 405 (68, M+), 386 (13), 241 (80), 213 (64), 164
(100), 109 (55).
Acknowledgement: The authors thank the Hungarian Scientific Research Fund (K113177) for the
financial support, as well as Johnson Matthey for the generous gift of Pd(OAc)2. This work was supported by
the GINOP-2.3.2-15-2016-00049 grant, as well as by the European Social Fund Grant no.: EFOP-3.6.1.-16-
2016- 00004 entitled by Comprehensive Development for Implementing Smart Specialization Strategies at the
University of Pécs.
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