Syntheses and reactivity of alkyl 1-[ N-(2-chloro-5-nitro-phenyl)- benzimidoyl] thioureas

Article abstract of DOI:10.1080/17415993.2011.629094

A series of new alkyl 1-[N-(2-chloro-5-nitro-phenyl)-benzimidoyl] thioureas 3a-h were prepared from benzamides 1a-c. Benzimidoyl thioureas 3a-e afforded 5-nitro-2-phenyl-benzothiazole 5a-c under basic conditions via thiourea-isothiourea rearrangement and SNAr. A mechanistic rationalization supported by the direct formation of benzothioamide 8 and bis-benzimidoyl sulfide 9 derivatives from the reaction of imidoyl isothiocyanate 2 with bulky amines was supported.

Full text of DOI:10.1080/17415993.2011.629094

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Syntheses and reactivity of alkyl 1-[N-
(2-chloro-5-nitro-phenyl)-benzimidoyl]
thioureas
Walid Fathalla a , Ibrahim. A.I. Ali b , Jaromir Marek c & Pavel
Pazdera d
a Department of Mathematics and Physical Sciences, Faculty of
Engineering, Port Said University, Port Said, Egypt
b Department of Chemistry, Faculty of Science, Suez Canal
University, Ismailia, Egypt
c Laboratory of Functional Genomics and Proteomics, Institute of
Experimental Biology, Masaryk University, Brno, Czech Republic
d Centre for Syntheses at Sustainable Conditions and Their
Management, Faculty of Science, Masaryk University, Brno, Czech
Republic
Published online: 05 Dec 2011.
To cite this article: Walid Fathalla , Ibrahim. A.I. Ali , Jaromir Marek & Pavel Pazdera (2012):
Syntheses and reactivity of alkyl 1-[N-(2-chloro-5-nitro-phenyl)-benzimidoyl] thioureas, Journal of
Sulfur Chemistry, 33:1, 49-63
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Journal of Sulfur Chemistry
Vol. 33, No. 1, February 2012, 49–63
Syntheses and reactivity of alkyl
1-[N-(2-chloro-5-nitro-phenyl)-benzimidoyl] thioureas†
Walid Fathallaa*, Ibrahim. A.I. Alib, Jaromir Marekc and Pavel Pazderad
aDepartment of Mathematics and Physical Sciences, Faculty of Engineering, Port Said University, Port Said,
Egypt; bDepartment of Chemistry, Faculty of Science, Suez Canal University, Ismailia, Egypt; cLaboratory of
Functional Genomics and Proteomics, Institute of Experimental Biology, Masaryk University, Brno, Czech
Republic; dCentre for Syntheses at Sustainable Conditions and Their Management, Faculty of Science,
Masaryk University, Brno, Czech Republic
(Received 4 April 2011; final version received 20 September 2011)
A series of new alkyl 1-[N-(2-chloro-5-nitro-phenyl)-benzimidoyl] thioureas 3a–h were prepared from
benzamides 1a–c. Benzimidoyl thioureas 3a–e afforded 5-nitro-2-phenyl-benzothiazole 5a–c under basic
conditions via thiourea–isothiourea rearrangement and SNAr. A mechanistic rationalization supported by
the direct formation of benzothioamide 8 and bis-benzimidoyl sulfide 9 derivatives from the reaction of
imidoyl isothiocyanate 2 with bulky amines was supported.
Cl
H
R2
S
O2N
R1
N
N
S
N
R1
N
H
O2N
5a-c
3a-h
Keywords: thiourea–isothiourea rearrangement; SNAr reaction; benzimidoyl thiourea; benzothiazole
1. Introduction
Several heterocyclic thioureas have been reported as a new class of potent non-nucleoside
inhibitors of human immunodeficiency virus type 1 reverse transcriptase (NNRTIs) such as
phenethylthiazolyl-thiourea derivatives (1–4).
Thiourea is an important building block of a number of heterocycles such as pyrimidines (5),
pyridines (6) and thiazoles (7, 8). Compounds containing the benzothiazole nucleus belong
to an important class of heterocycles which are known to possess important pharmaceutical
antitumor (9, 10) and anticancer activities (11–13). A variety of methods for the syntheses of
*Corresponding author. Email: walid3369@yahoo.com
†Dedicated to Professor El-Said Ismail Faculty of Science, Suez Canal University, for his 65th birthday
ISSN 1741-5993 print/ISSN 1741-6000 online
© 2012 Taylor & Francis
http://dx.doi.org/10.1080/17415993.2011.629094
http://www.tandfonline.com

50 W. Fathalla et al.
2-arylbenzothiazoles have been developed (14–16). The most common methods for syntheses
involve direct condensation of aldehydes with 2-aminothiophenol in the presence of various cat-
alysts or the oxidation of thiobenzanilides (17). Recently, we have explored the reactivity of
N-(2-cyanophenyl)benzimidoyl isothiocyanate with primary amines, secondary amines, anilines,
amino heterocycles and amino acids. These studies have led to a number of interesting quinazoline
derivatives (18–23). The formation of these compounds was tentatively explained by a multi-step
domino reaction.
2. Results and discussion
In view of these facts, we have found it desirable to synthesize a series of alkyl 1-[N-(2-chloro-
5-nitro-phenyl)-benzimidoyl] thioureas 3 containing alkyl or aryl substituents and to induce
S-chemoselective intramolecular nucleophilic aromatic substitution to afford benzothiadiazepine
derivatives 4 (Scheme 1) (24). The very reactive starting compound 3 was successfully pre-
pared from N-(2-chloro-5-nitro-phenyl)-benzamide (1) in a one-pot strategy. The amide 1 was
transformed by the action of phosphorous pentachloride into benzimidoyl chloride that sub-
sequently reacted with potassium thiocyanate to give N-(2-chloro-5-nitro-phenyl)-benzimidoyl
isothio-cyanate (2). The isothiocyanate 2 was used without further isolation or purification (to
avoid polymerization and destruction of this very reactive compound). The in situ-generated imi-
doyl isothiocyanate 2 reacted with one equivalent of amines and anilines in one-pot strategy to
furnish the desired benzimidoyl thioureas 3 in very good yields. We further explored the pos-
sibility of intramolecular cyclization under basic conditions to benzothiadiazepine derivative 4.
Heating benzimidoyl thiourea 3a–c (R=Ar) in DMF in the presence of triethyl amine gave 5-
nitro-2-phenyl-benzothiazole 5a instead. The use of benzimidoyl thiourea 3a–c (R=Ar) with an
aromatic side chain proved to be mandatory since employment of benzimidoyl thiourea 3f–h
Cl
N
Cl
N
Cl
N
R2NH2
1. PCl5
H
R2
S
H
O2N
R1
O2N
R1
N
O2N
2. KSCN
H
N
C
S
N
H
O
R1
3a-h
1a-c
2a-c
NaH or NEt3
no reacton
R2= alkyl
NEt3
R2
NH
S
N
R1
S
N
R2= aryl
N
O2N
O2N
5a-c
4
R1
3
a
b
R1
H
R2
3
e
f
R1
R1
R2
1, 2, 5
-
a
b
c
C6H5
Cl
H
H
CH3
Cl
C6H5
-
-
H
4-CH3C6H4
C6H5CH2
-
-
c
H
4-CH3OC6H4
g
h
H
H
CH3(CH2)3
-
-
d
CH3
C6H5
(CH3)2CHCH2
Scheme 1. Sequential syntheses of benzothiazole 5a–c from the corresponding benzamide 1a–c.

Journal of Sulfur Chemistry 51
with aliphatic side chain gave no reaction or poor yields. Consequently, we used this new method
to synthesize benzothiazole 5a–c from the corresponding benzamide 1a–c (R1 = H, CH3, Cl)
(25, 26). The synthetic procedures for the formation of 3a-h and 5a–c reported herein have the
advantage of one-pot synthesis in addition to operational simplicity and availability giving a series
of very interesting compounds with promising biological activities.
The structures of compounds 3a–h were assigned by 1H NMR, 13C NMR and mass spectral
1
data. The mass spectrum of 3b displayed its molecular ion peak at m/z = 424. The H-NMR
spectrum of 3b in CDCl3 showed three singlets for CH3 (δ = 2.36 ppm) and NH (δ = 13.35 and
8.21 ppm) groups along with multiplets for the aromatic protons. The significant downfield shifts
of the NH protons are due to intra- and intermolecular hydrogen bond interactions (18–20, 27).
All the isolated thioureas 3a–h exhibited similar 1H NMR spectral pattern with the NH protons at
similar chemical shifts and they adopt a rather interesting folded conformation (vide infra). The
13
=
C NMR spectrum of 3b reveals carbon signals at δ = 178.49 and 21.31 ppm assigned to C S
and CH3 groups, respectively.
A single-crystal X-ray diffraction study confirmed the identities of compounds 3a–h. ORTEP
diagrams of 3g and 3h are shown in Figures 1 and 3, respectively. The hydrogen bond interactions
and the folded conformation of benzimidoyl thiourea derivatives alluded to above are also evident
from an examination of these X-ray crystal structures shown in Figures 1 and 2.
The crystallographic analysis of 3g suggests that the crystal packing is determined by
N–H. . .N=C and N–H. . .S=C interactions. These intra- and intermolecular hydrogen bond
interactions show a bond distance of 2.01 and 2.67Å, respectively (Figures 1–4 and Appendix 1).
The structures of compounds 5a–c were assigned by 1H NMR, 13C NMR and physicochemical
1
analysis. Thus, the H NMR spectrum of 5a exhibited signals at δ 8.90, 8.26, 8.19–8.09, 8.00
and 7.55–7.39 ppm, respectively, due to aromatic protons. The 13C NMR spectrum of 5a exhib-
ited quaternary carbon signals at 171.76, 154.21, 147.27, 141.85 and 132.92, respectively. The
structural assignment of 5-nitro-2-phenyl-benzothiazole (5a) was corroborated by X-ray crystal-
lographic analysis. The molecular structure and labeling scheme used for 5a are shown in Figure 5.
The structure of 5a shows that the phenyl ring bonded at C2 is almost coplanar with the C2–N3
Figure 1. ORTEP plot of 3g from the X-ray crystal structure.

52 W. Fathalla et al.
Figure 2. ORTEP plot of 3h from the X-ray crystal structure.
Figure 3. ORTEP plot of 5a from the X-ray crystal structure.
bond as verified by torsion angle values and the crystal packing pattern (Appendix 1, Table 12
and Figures 6 and 7).
The reaction of N-(2-chloro-5-nitro-phenyl)-benzimidoyl isothiocyanate (2) with bulk amines:
tert-butyl amine, iso-propyl amine, sec-butyl amine and cyclohexyl amine were principally
expected to give the thioureas 3. We found now that the reaction of isothiocyanate 2 with the
above-mentioned nucleophiles gave different products, i.e. thioamide 8 (NH2R2 = iso-propyl

Journal of Sulfur Chemistry 53
Figure 4. ORTEP plot of 9 from the X-ray crystal structure.
Figure 5. ORTEP plot of 5a from the X-ray crystal structure.
Figure 6. Packing diagram pattern of 5a.

54 W. Fathalla et al.
Figure 7. Packing diagram pattern of 5a.
amine or sec-butyl amine), bis benzimidoyl sulfide 9 (NH2R2 = tert-butyl amine), benzamidine
10 and the expected thiourea 3i (NH2R2 = cyclohexyl amine) by different reaction pathways
(Scheme 2). The attempted intramolecular cyclization of thioamide 8 in the presence of NaH
failed to give the benzothiazole 5.
1
The structure of compound 8 was assigned by H NMR, 13C NMR and physicochemical
analysis. The 1H NMR spectrum of 8 exhibited an aromatic proton at at δ 9.51 ppm attributed to
proton H6 of the phenyl ring, which implies an anisotropy caused by the adjacent thiocarbonyl
1
group (28, 29). The H NMR spectrum of 8 also shows an exchangeable signal at δ 8.54 ppm
corresponding to the NH group.
The 1H and 13C NMR spectra of 9, 3i and 10 showed distinct resonances in agreement with
the proposed structure as expressed in the experiment part. The structural assignment of 9 was
corroborated by X-ray crystallographic analysis.An ORTEP diagram and packing diagram pattern
of 9 are shown in Figures 8–10, respectively.
A mechanistic rationalization for the benzimidoyl thiourea reactivity and the resulting
rearrangement is given in Scheme 3.
A first step: N3-deprotonation of the thiourea 3 and the subsequent sulfur attack at the
electrophilic imidoyl carbon atom afforded the four-membered ring intermediate 11 (30). The
intramolecular hydrogen atom transfer in the first step provides a rationale for why R2 must

Journal of Sulfur Chemistry 55
Cl
Cl
N
H
O2N
O2N
N
N
+
NH
N
H
S
NH2
3i
10
Cl
N
Cl
NH2
O2N
NO2
O2N
N
N C S
S
N
2
Cl
9
NH2
or
NH2
Cl
NaH
S
H
O2N
N
N
O2N
H
S
5a
8
Scheme 2. Reaction of N-(2-chloro-5-nitro-phenyl)-benzimidoyl isothiocyanate (2) with bulk
amines.
be aromatic not aliphatic. The hydrogen atom migration together with the four-membered ring
opening afforded the isothiourea intermediate 12. Thioureas are normally characterized by a high
reluctance to undergo alterations to isothioureas (24, 31, 32). This thiourea–isothiourea con-
version is promoted by a remarkable electrophilic activity at the imidoyl carbon atom induced
by the electron-withdrawing groups on the aromatic ring. In the next step, a base-assisted
deprotonation of another proton from N3 followed by sulfur–carbon bond rupture gives the
intermediate 13. Finally, sulfur attack at the C–Cl bond via SNAr reaction gives the product 5
(Scheme 3).
The reaction of benzimidoyl isothiocyanate 2 with bulk amines gave good evidence for our
rational mechanism by tracking the reaction intermediates. The reaction of N-(2-chloro-5-nitro-
phenyl)-benzimidoyl isothiocyanate (2) with bulk amines were principally expected to give the
thioureas 3, which subsequently was converted to intermediate 11. The formation of the four-
membered ring intermediate 11 provides an excellent branching point for the formation of all
products. Its conceivable that as the size of R2 gets larger (NH2R2 = iso-propyl amine or sec-
butyl amine), it promotes the −[2 + 2] reaction to give the thioamide derivative 8 as an alternative
reaction pathway. This happens to reduce the steric interactions between R2 and either the NH or
S atom on 11 (30).
Thioamide 8 is capable of nucleophilic attack at the imidoyl carbon of isothiourea 12. This result
was obtained by the reaction of benzimidoyl isothiocyanate 2 with tert-butyl amine. Similarly,
cyclohexyl amine reacted with intermediate 12 to afford benzamidine 10.

56 W. Fathalla et al.
Figure 8. ORTEP plot of 5a from the X-ray crystal structure 9.
Figure 9. Packing diagram pattern of 9.
3. Conclusion
We reported herein the formation and reactivity of a series of benzimidoyl thiourea deriva-
tives. Benzimidoyl thioureas 3 were prepared by the reaction of N-(2-chloro-5-nitro-phenyl)-
benzimidoyl isothiocyanate with amines and anilines. Moreover, we have presented a facile novel

Journal of Sulfur Chemistry 57
Figure 10. Packing diagram pattern of 9.
S
Cl
N
R1
S
NH
N
O2N
R2
C
N
+
O2N
5
-
R2= C6H5, 4-CH3C6H4-, 4-CH3OC6H4
13
R1=H, CH3, Cl
Cl
Cl
Cl
R2NH2
H
R2
S
H
S
R2
O2N
R1
NH
S
O2N
R1
N
N
O2N
N
N
2
NH
N
NH
H
N R2
H+
12
R1
11
3
R2NH2
-[2+2]
O2N
Cl
N
Cl
Cl
N
N
12
NH
O2N
H
R2
C
+
O2N
N
N
S
R2HN
H
S
NO2
9
10
8
R2= iso-propyl amine,
sec-butyl amine
Cl
R2= tert-butyl amine
R2= cyclo-hexyl amine
Scheme 3. Mechanistic rationalization for the benzimidoyl thiourea reactivity.
route for the formation of benzothiazole by heating benzimidoyl thiourea derivatives containing
an aryl substituent under basic conditions. Benzothiazole was formed due to the capability of
benzimidoyl thiourea to rearrange and subsequent intramolecular cyclization via nucleophilic
aromatic substitution reaction.

58 W. Fathalla et al.
4. Experimental
4.1. General procedures
Solvent were purified and dried in the usual way. The boiling range of the petroleum ether used
was 40–60◦C.Analysis of the reaction mixtures and purity control of the products were carried out
by TLC on Silufole UV-254. Elemental analyses were performed on a Flash EA-1112 instrument
at the Microanalytical Laboratory, Faculty of Science, Suez Canal University, Ismailia, Egypt.
Melting points were determined on a Buchi 510 melting-point apparatus and the values are
uncorrected. 1H and 13C NMR spectra were recorded at 300 and 75.5 MHz, respectively (DRX 500
AvanceBruker)inCDCl3 solutionwithtetramethylsilaneasaninternalstandard. X-raycrystaldata
and structure refinement of compounds 3g, 3h, 5a and 9 were collected with a KUMA KM-4 kappa
four-circle diffractometer. The structure was solved by direct methods using SHELXS86 (33) and
refined on F2 for all reflections using SHELXl93 (34). Crystals suitable for X-ray determination
were obtained in the form of white prisms by recrystallization from CHCl3/petroleum ether at
room temperature. The crystallographic data for 3g, 3h, 5a and 9 have been deposited with the
Cambridge Crystallographic Data Center as supplementary publications number CCDC 815032-
815034 and 815036. The molecular structure, bond lengths, angles, packing diagrams and crystal
structure refinement data can be found in Supplementary data, Appendix 1. Mass spectra were
determined (electron impact, 70 eV) with a Fisons TRIO 1000 and GC 8000 series instrument.
The starting compounds 1 were prepared according to the described methods (35).
4.2. Synthesis of N-(2-chloro-5-nitro-phenyl)-benzimidoyl isothiocyanate (2)
A mixture of N-(2-chloro-5-nitro-phenyl)-benzamide (1) (0.5 g, 2.25 mmol) and phosphorous
pentachloride (0.5 g, 2.4 mmol) was refluxed in dry toluene for 8 h. The solvent was removed
under reduced pressure to give a brownish colored oil of N-(2-chloro-5-nitro-phenyl)-benzimidoyl
chloride which was not further purified. To a solution of this crude oil in dry acetone, a solution
of potassium thiocyanate (0.22 g, 2.25 mmol) in dry acetone was added portion-wise with stirring
and cooling at −5◦C for 2 h. The precipitated potassium chloride was filtered off, thus leaving an
acetone solution of N-(2-chloro-5-nitro-phenyl)-benzimidoyl isothiocyanate (2).
4.3. General procedure for the synthesis of alkyl
1-[N-(2-chloro-5-nitro-phenyl)-3-benzimidoyl] thioureas 3
The appropriate aromatic and non-bulky aliphatic primary amine (2.25 mmol) solution in acetone
was added portion-wise to an in situ-generated benzimidoyl isothiocyanate (2, 2.25 mmol) solu-
tion in acetone. The reaction mixture was stirred at room temperature for 24 h. The precipitated
benzimidoyl thiourea 3 was filtered off and recrystallized from ethyl alcohol. Spectral data are
given below.
4.3.1. 1-[N-(2-Chloro-5-nitro-phenyl)-benzimidoyl]-3-phenyl thiourea (3a)
1
From aniline and 1a. Colorless crystals (0.62 g, 67%); mp 155–156◦C. H NMR (300 MHz,
CDCl3): δ 13.44 (1H, s, N-H), 8.31 (1H, s, N-H), 7.69–7.85 (1H, m, Ar-H), 7.78–7.61 (3H, m,
Ar-H), 7.45–7.33 (8H, m, Ar-H), 7.16–7.04 (1H, m, Ar-H). 13C-NMR (CDCl3): δ 178.56 (C9S),
159.18 (Cq), 156.07 (Cq), 144..39 (Cq) , 138.15 (Cq), 135.81 (Cq), 131.85 (CHAr), 131.67 (Cq),
134.78 (CHAr), 129.59 (CHAr), 129.14 (CHAr), 127.51 (CHAr), 124.35 (CHAr), 121.16 (CHAr),
120.31 (CHAr). Anal. Calcd. For C20H15ClN4O2S (410.9): C, 58.46; H, 3.68, Cl, 8.63, N, 13.64,
S, 7.80; Found: C, 58.39; H, 3.61, N, 13.57.

Journal of Sulfur Chemistry 59
4.3.2. 1-[N-(2-Chloro-5-nitro-phenyl)-benzimidoyl] 3-(4-methyl phenyl) thiourea (3b)
From p-toluidine and 1a. Colorless crystals (0.79 g, 83%); mp 170–171◦C. 1H NMR (300 MHz,
CDCl3): δ 13.35 (1H, s, N-H), 8.21 (1H, s, N-H), 7.71 (1H, d, J = 8.0 Hz, Ar-H), 7.77 (2H, d,
J = 8.0 Hz, Ar-H), 7.51–7.18 (9H, m, Ar-H), 2.36 (3H, s, CH3). 13C-NMR (CDCl3): δ 178.49
(C9S), 158.01 (Cq), 146.85 (Cq), 145.29 (Cq), 136.89 (Cq), 135.63 (Cq), 134.55 (Cq), 131.39
(CHAr), 130.54 (Cq), 129.69 (CHAr), 129.61 (CHAr), 127.56 (CHAr), 124.25 (CHAr), 119.75
(CHAr), 118.48 (CHAr), 21.31 (CH3). MS, m/z (Ir/%): 427 (0.1), 424 (2), 391 (1), 317 (2), 277
(18), 276 (31), 275 (11), 261 (31), 259 (36), 240 (13), 228 (11), 219 (8), 194 (12), 166 (7), 151 (8),
152 (23), 149 (100), 121 (4), 109 (18), 104 (83), 91 (88), 77 (39), 62 (25), 51 (23). Anal. Calcd.
For C21H17ClN4O2S (424.9): C, 59.36; H, 4.03, Cl, 8.34, N, 13.19, S, 7.55; Found: C, 59.31; H,
4.03, N, 13.11.
4.3.3. 1-[N-(2-Chloro-5-nitro-phenyl)-benzimidoyl] 3-(4-methoxy phenyl) thiourea (3c)
From p-anisdine and 1a. Colorless crystals (0.73 g, 74%); mp 158–159◦C. 1H NMR (300 MHz,
CDCl3): δ 13.44 (1H, s, N-H), 8.32 (1H, s, N-H), 7.85 (1H, d, J = 8.0 Hz, Ar-H), 7.81–7.59 (4H,
m, Ar-H), 7.46–7.25 (7H, m, Ar-H), 3.86 (3H, s, OCH3). 13C-NMR (CDCl3): δ 178.56 (C9S),
159.47 (Cq), 156.07 (Cq), 144.39 (Cq), 138.15 (Cq), 135.81 (Cq), 134.55 (Cq), 131.85 (CHAr),
131.67 (Cq), 129.59 (CHAr), 129.14 (CHAr), 127.13 (CHAr), 124.35 (CHAr), 121.02 (CHAr),
116.56 (CHAr), 114.48 (CHAr), 55.75 (OCH3). Anal. Calcd. For C21H17ClN4O3S (440.9): C,
57.21; H, 3.89, Cl, 8.04, N, 12.71, S, 7.27; Found: C, 57.09; H, 3.74, N, 12.48.
4.3.4. 3-Phenyl-1-[N-(2-chloro-5-nitro-phenyl)-4-methylbenzimidoyl] thiourea (3d)
From aniline and 1b. Colorless crystals (0.58g, 61%); mp 176–177◦C. δ 13.24 (1H, s, N-H),
8.22 (1H, s, N-H), 7.79 (1H, d, J = 8.0 Hz, Ar-H), 7.63–6.99 (11H, m, Ar-H), 2.29 (3H, s, CH3).
13C-NMR (CDCl3): δ 178.59 (C=S), 159.47 (Cq), 156.07 (Cq), 145.31 (Cq), 136.97 (Cq), 135.89
(Cq), 134.55 (Cq), 131.81 (CHAr), 129.70 (Cq), 129.34 (CHAr), 129.66 (CHAr), 127.51 (CHAr),
124.22 (CHAr), 119.35 (CHAr), 116.99 (CHAr), 21.38 (CH3). Anal. Calcd. For C21H17ClN4O2S
(424.9): C, 59.36; H, 4.03; Cl, 8.34; N, 13.19; S, 7.55; Found: C, 59.16; H, 3.84; N, 12.88.
4.3.5. 3-Phenyl-1-[N-(2-chloro-5-nitro-phenyl)-4-chlorobenzimidoyl] thiourea (3e)
1
From aniline and 1c. Colorless crystals (0.72 g, 72%); mp 184–185◦C. H NMR (300 MHz,
CDCl3): δ 13.59 (1H, s, N-H), 8.29 (1H, s, N-H), 7.79 (1H, d, J = 8.0 Hz, Ar-H), 7.57–7.45
(4H, d, J = 8.0 Hz, Ar-H), 7.38–7.08 (7H, m, Ar-H). 13C-NMR (CDCl3): δ 179.09 (C9S), 159.12
(Cq), 146.85 (Cq), 145.13 (Cq), 137.22 (Cq), 135.91 (Cq), 131.39 (CHAr), 130.58 (Cq), 130.31
(Cq), 129.69 (CHAr), 129.23 (CHAr), 127.84 (CHAr), 125.84 (CHAr), 119.75 (CHAr), 117.98
(CHAr). Anal. Calcd. For C20H14Cl2N4O2S (445.3): C, 53.94; H, 3.17; Cl, 15.92; N, 12.58; S,
7.20; Found C, 53.63; H, 2.82; N, 12.11.
4.3.6. 3-Benzyl-1-[N-(2-chloro-5-nitro-phenyl)-benzimidoyl] thiourea (3f)
From benzyl amine and 1a. Colorless crystals (0.82 g, 86%); mp 215–216◦C. 1H NMR (300 MHz,
CDCl3): δ 11.53 (1H, s, N–H), 8.33 (1H, s, N–H), 7.74 (1H, d, J = 8.0 Hz, Ar–H), 7.45–7.23
(12H, m, Ar–H), 4.97 (2H, d, J = 4.8 Hz, CH2). 13C-NMR (CDCl3): δ 180.20 (C9S), 157.89
(Cq), 146.64 (Cq), 145.40 (Cq), 136.57 (Cq), 134.42 (Cq), 134.55 (Cq), 131.69 (CHAr), 131.29
(Cq), 130.39 (CHAr), 129.47 (CHAr), 128.70 (CHAr), 119.54 (CHAr), 118.36 (CHAr), 50.18

60 W. Fathalla et al.
(CH2). Anal. Calcd. For C21H17ClN4O2S (424.9): C, 59.36; H, 4.03; Cl, 8.34; N, 13.19; S, 7.55;
Found: C, 59.21; H, 3.97; N, 13.01.
4.3.7. 3-Butyl-1-[N-(2-chloro-5-nitro-phenyl)-benzimidoyl] thiourea (3g)
From n-butyl amine and 1a. Colorless crystals (0.38 g, 43%); mp 182–183◦C. 1H NMR (300 MHz,
CDCl3): δ 11.43 (1H, s, N-H), 8.12 (1H, s, N-H), 7.47 (1H, d, J=8.0 Hz, Ar-H), 7.40–7.16 (7H,
m, Ar-H), 3.65 (2H, q, J = 6.7 Hz, CH2), 1.68–1.54 (2H, m, CH2), 1.42–1.31 (2H, m, CH2), 0.91
(3H, t, J = 6.7 Hz, CH3). 13C-NMR (CDCl3): δ 179.77 (C9S), 157.89 (Cq), 146.78 (Cq), 145.64
(Cq), 136.57 (Cq), 134.30 (Cq), 134.55 (Cq), 131.59 (CHAr), 131.45 (Cq), 130.39 (CHAr), 129.69
(CHAr), 128.68 (CHAr), 119.44 (CHAr), 118.35 (CHAr), 45.99 (CH2), 30.46 (CH2) 20.36 (CH2)
13.84 (CH3). Anal. Calcd. For C18H19ClN4O2S (390.9): C, 55.31; H, 4.90; Cl, 9.07; N, 14.33; S,
8.20; Found: C, 55.13; H, 4.87; N, 14.26.
4.3.8. 3-Isobutyl 1-[N-(2-chloro-5-nitro-phenyl)-benzimidoyl] thiourea (3h)
From iso-butyl amine and 1a. Colorless crystals (0.50 g, 57%); mp 158–159◦C. 1H NMR
(300 MHz, CDCl3): δ 11.56 (1H, s, N-H), 8.20 (1H, s, N-H), 7.76 (1H, d, J = 8.0 Hz, Ar-H),
7.40–7.16 (7H, m, Ar-H), 3.75 (2H, q, J = 6.6 Hz, CH2), 2.14–2.02 (1H, m, CH), 1.03 (6H, t,
J = 6.7 Hz, 2CH3). 13C-NMR (CDCl3): δ 179.98 (C9S), 157.85 (Cq), 146.63 (Cq), 145.64 (Cq),
136.55 (Cq), 134.55 (Cq), 131.79 (CHAr), 131.45 (Cq), 130.41 (CHAr), 129.69 (CHAr), 128.68
(CHAr), 119.94 (CHAr), 118.45 (CHAr), 53.88 (CH2), 28.16 (CH), 19.75 (CH3). Anal. Calcd.
For C18H19ClN4O2S (390.9): C, 55.31; H, 4.90; Cl, 9.07; N, 14.33; S, 8.20; Found: C, 55.28; H,
4.81; N, 14.27.
4.4. Preparation of 5-nitro-2-aryl-benzothiazole
A mixture of the appropriate aryl 1-[N-(2-chloro-5-nitro-phenyl)-benzimidoyl] thioureas 3
(2.25 mmol) and triethyl amine (2.50 mmol) was refluxed in dry DMF for 4 h. The reaction mixture
was evaporated and poured over cold water, extracted with CH2Cl2 and washed with NaHCO3.
The organic layer was dried over Na2SO4, filtered evaporated and the residue was crystallized
from ethanol.
4.4.1. 5-Nitro-2-phenyl-benzothiazole (5a)
From 3a. Colorless crystals (0.49 g, 86%); mp 201–202◦C. 1H NMR (300 MHz, CDCl3): δ 8.90
(1H, s, Ar-H), 8.26 (1H, d, J = 8.0 Hz, Ar-H), 8.19–8.09 (2H, m, Ar-H), 8.00 (1H, d, J = 8.0 Hz,
Ar-H), 7.55–7.39 (3H, m, Ar-H). 13C-NMR (CDCl3): δ 171.76 (Cq), 154.21 (Cq), 147.27 (Cq),
141.85 (Cq), 132.92 (Cq), 132.22 (CHAr), 129.49 (CHAr), 128.06 (CHAr), 122.21 (CHAr),
119.85 (CHAr), 118.82 (CHAr). Anal. Calcd. For C13H8N2O2S (256.3): C, 60.93; H, 3.15; N,
10.93; S, 12.51 Found: C, 60.84; H, 3.01; N, 10.78.
From 3b. Colorless crystals (0.40 g, 69%).
From 3c. Colorless crystals (0.36 g, 64%).
4.4.2. 5-Nitro-2-(4-methylphenyl)-benzothiazole (5b)
From 3d. Colorless crystals (0.38 g, 62%); mp 185–186◦C. 1H NMR (300 MHz, CDCl3): δ 8.78
(1H, s, Ar-H), 8.23 (1H, d, J=8.0 Hz, Ar-H), 8.19–8.97 (5H, m, Ar-H), 2.48 (3H, s, CH3). 13C-
NMR (CDCl3): δ 169.87 (Cq), 154.38 (Cq), 146.13 (Cq), 141.84 (Cq), 132.31 (CHAr), 131.48

Journal of Sulfur Chemistry 61
(Cq), 129.49 (CHAr), 127.21 (CHAr), 122.07 (CHAr), 119.97 (CHAr), 118.62 (CHAr), 21.43
(CH3). Anal. Calcd. For C14H10N2O2S (270.3): C, 62.21; H, 3.73; N, 10.36; S, 11.86; Found: C,
62.15; H, 3.69; N, 10.44
4.4.3. 5-Nitro-2-(4-chlorophenyl)-benzothiazole (5c)
From 3e. Colorless crystals (0.31 g, 53%); mp 213–214◦C. 1H NMR (300 MHz, CDCl3): δ 8.91
(1H, s, Ar-H), 8.24 (1H, d, J = 8.0 Hz, Ar-H), 8.14–8.01 (5H, m, Ar-H). 13C-NMR (CDCl3):
δ 168.45 (Cq), 154.01 (Cq), 135.85 (Cq), 132.92 (Cq), 131.22 (CHAr), 129.23 (CHAr), 127.19
(CHAr), 122.85 (CHAr), 118.97 (CHAr). Anal. Calcd. For C13H7ClN2O2S (290.7): C, 53.71; H,
2.43; Cl, 12.19; N, 9.64; S, 11.03 Found: C, 53.65; H, 2.36; N, 9.60.
4.5. Reaction of benzimidoyl isothiocyanate 2 with bulk primary amines
The appropriate amine (tert-butyl amine, iso-propyl amine, sec-butyl amine) (2.25 mmol) solu-
tion in acetone was added portion-wise to an in situ-generated benzimidoyl isothiocyanate (2,
2.25 mmol) solution in acetone. The reaction mixture was stirred at room temperature for 24 h,
poured over H2O and extracted with CH2Cl2, dried over Na2SO4 and evaporated. The resultant
residue was crystallized from ethyl alcohol.
4.6. N-(2-Chloro-5-nitro-phenyl)-thiobenzamide (8)
From iso-propyl amine. Colorless crystals (0.58 g, 88%); mp 131–132◦C. H NMR (300 MHz,
1
CDCl3): δ 9.51 (1H, s, Ar-H), 8.54 (1H, s, N-H), 8.03–7.92 (3H, m, Ar-H), 7.68–7.46 (4H, d,
J = 8.0 Hz, Ar-H). 13C-NMR (CDCl3): δ 165.48 (Cq), 147.55 (Cq), 135.93 (Cq), 133.91 (Cq),
133.03 (CHAr), 129.74 (CHAr), 129.34 (CHAr), 129.10 (Cq), 127.38 (CHAr), 119.30 (CHAr),
116.46 (CHAr). MS, m/z (Ir/%): 294 (1), 261 (31), 259 (100), 257 (4), 215 (18), 213 (31), 210
(3), 126 (2), 121 (6), 109 (13), 105 (6), 90 (15), 77 (12), 51 (25). Anal. Calcd. For C13H9ClN2O2S
(292.7): C, 53.34; H, 3.10; Cl, 12.11; N, 9.57; S, 10.95; Found: C, 53.24; H, 2.91; N, 9.38.
From sec-butyl amine. 0.43 g, 65%.
4.7. Bis-[Nꢀ-(2-chloro-5-nitrophenyl)benzimidoyl] sulfide (9)
1
From tert-butyl amine. Colorless crystals (0.61 g, 47%); mp 135–136◦C. H NMR (300 MHz,
CDCl3): δ 7.98 (2H, d, J = 8.0 Hz, Ar-H), 7.63–7.30 (14H, d, J = 8.0 Hz, Ar-H). 13C-NMR
(CDCl3): δ 155.08 (Cq), 147.06 (Cq), 136.45 (Cq), 133.91 (Cq), 132.04 (CHAr), 130.99 (CHAr),
128.96 (CHAr), 129.56 (Cq), 128.75 (CHAr), 120.60 (CHAr), 116.09 (CHAr). Anal. Calcd. For
C26H16Cl2N4O4S (551.4): C, 56.63; H, 2.92; Cl, 12.86; N, 10.16; S, 5.82; Found: C, 56.56; H,
2.84; N, 10.03.
4.8. Reaction of benzimidoyl isothiocyanate 2 with cyclohexyl amine
Cyclohexyl amine (2.25 mmol) solution in acetone was added portion-wise to an in situ-
generated benzimidoyl isothiocyanate (2, 2.25 mmol) solution in acetone. The reaction mixture
was stirred at room temperature for 24 h, poured over H2O and extracted with CH2Cl2, dried
over Na2SO4 and evaporated. The resultant residue was separated by column chromatography
(ethyl acetate: petroleum ether 1:3 eluent) to give 3-cyclohexyl N-(2-chloro-5-nitro-phenyl)-
benzimidoyl] thiourea (3g) and N-(2-chloro-5-nitro-phenyl)-Nꢀ-cyclohexyl-benzamidine (10).
Spectral data are given below.

62 W. Fathalla et al.
4.9. 3-Cyclohexyl 1-[N-(2-chloro-5-nitro-phenyl)-benzimidoyl] thiourea (3i)
Colorless crystals (0.42 g, 45%); mp 168–169◦C. 1H NMR (300 MHz, CDCl3): δ 11.41 (1H, s,
N-H), 8.24 (1H, s, N-H), 7.48 (1H, d, J = 8.0 Hz, Ar-H), 7.47–7.16 (7H, m, Ar-H), 4.64–4.57
(1H, m, CH), 2.44–2.27 (2H, m, CH2), 1.91–1.71 (4H, m, 2CH2), 1.59–1.33 (4H, m, 2CH2). 13C-
NMR (CDCl3): δ 178.34 (C9S), 157.90 (Cq), 146.82 (Cq), 145.65 (Cq), 134.47 (Cq), 133.01 (Cq),
131.65 (CHAr), 131.49 (Cq), 130.41 (CHAr), 129.52 (CHAr), 128.95 (CHAr), 127.48 (CHAr),
119.47 (CHAr), 118.41 (CHAr), 54.73 (CH), 31.86 (CH2), 25.71 (CH2), 24.48 (CH2). Anal.
Calcd. For C20H21ClN4O2S (416.9): C, 57.62; H, 5.08; Cl, 8.50; N, 13.44; S, 7.69; Found: C,
57.45; H, 4.93; N, 13.36.
4.10. N-(2-Chloro-5-nitro-phenyl)-Nꢀ-cyclohexyl-benzamidine (10)
Yellowish crystals (0.41 g, 51%); mp 122–123◦C. H NMR (300 MHz, CDCl3): δ 7.95 (1H, d,
1
J = 8.0 Hz, Ar-H), 7.66–7.45 (3H, m, Ar-H), 7.32–7.18 (4H, m, Ar-H), 4.78–4.67 (1H, m, CH),
4.01 (1H, s, N-H), 2.34–2.08 (1H, m, CH2), 2.34–2.08 (1H, m, CH2), 2.34–2.08 (2H, m, CH2),
1.74–1.22 (8H, m, 2CH2). 13C-NMR (CDCl3): δ 158.39 (Cq), 150.23 (Cq), 146.85 (Cq), 135.95
(Cq), 134.75 (Cq), 133.94 (CHAr), 130.01 (CHAr), 129.80 (CHAr), 129.36 (CHAr), 128.82
(CHAr), 119.31 (CHAr), 116.76 (CHAr), 50.61(CH), 33.24 (CH2), 26.19 (CH2), 25.21 (CH2).
Anal. Calcd. For C19H20ClN3O2 (357.8): C, 63.77; H, 5.63; Cl, 9.91; N, 11.74; Found: C, 63.68;
H, 5.47; N, 11.51.
Acknowledgement
We would like to thank Dr Mustafa Aly Faculty of Science, Port-Said University, Egypt for technical support.
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