Study of the acylation reaction of 2(3H)-benzothiazolones in the mixture of ZnCl2-DMF

Article abstract of DOI:10.1080/10426500214558

The use of polyphosphoric acid and the complex AlCl₃-DMF in 6-acylation of 2(3H)-benzothiazolones previously have been reported. Instead of the frequently used AlCl₃ as a catalyst in the Friedl-Crafts reactions, we conducted the acyl

Full text of DOI:10.1080/10426500214558

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Study of the Acylation Reaction of 2(3H)-
Benzothiazolones in the Mixture of ZnCl 2 -DMF
a
a
Faouzi Guenadil & Houcine Aichaoui
a
Laboratoire de Chimie Pharmaceutique, Institut de Chimie , Université Badji Mokhtar ,
Algérie
Published online: 27 Oct 2010.
To cite this article: Faouzi Guenadil & Houcine Aichaoui (2002) Study of the Acylation Reaction of 2(3H)-Benzothiazolones
in the Mixture of ZnCl 2 -DMF, Phosphorus, Sulfur, and Silicon and the Related Elements, 177:11, 2633-2638, DOI:
10.1080/10426500214558
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Phosphorus, Sulfur and Silicon, 2002, Vol. 177:2633–2638
Copyright �C 2002 Taylor & Francis
1
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DOI: 10.1080/10426500290110856
STUDY OF THE ACYLATION REACTION OF
2
(3H)-BENZOTHIAZOLONES IN THE
MIXTURE OF ZnCl -DMF
2
Faouzi Guenadil and Houcine Aichaoui
Laboratoire de Chimie Pharmaceutique, Institut de Chimie,
Universit e´ Badji Mokhtar, Alg e´ rie
(Received January 3, 2002; accepted February 19, 2002)
The use of polyphosphoric acid and the complex AlCl -DMF in
3
6
-acylation of 2(3H)-benzothiazolones previously have been reported.
Instead of the frequently used AlCl as a catalyst in the Friedl-Crafts
3
reactions, we conducted the acylation of 2(3H)-benzothiazones using
zinc chloride as a catalyst in DMF as solvent and acid chlorides or
anhydrides as acylating agents.
Keywords: AlCl
3
-DMF; 2(3H)-benzothiazolone; 6-acyl-2(3H)-benzothi-
-DMF
zolones; acylation reaction; polyphosphoric acid; ZinCl
2
INTRODUCTION
The use of the complex of aluminum chloride-N,N-dimethylformamide
in Friedl-Crafts reaction was previously reported.1 This process was
� 4
2
applied to the Haworth reaction of 2(3H)-benzoxazolones and to the
synthesis of various serotonin receptor ligands.5 When the AlCl3-DMF
reagent was applied as a catalyst in the acylation reaction of 2(3H)-
benzothiazolones using acid halides or anhydrides, the acylation prod-
,6
7
ucts are obtained in good yields (Scheme 1, Method b). The polyphos-
phoric acid as solvent and catalyst was also applied using carboxylic
8
acids or anhydrides (Scheme 1, Method a). However, the (PPA) method
was not found as satisfactory as the AlCl3-DMF complex in the case
7
of halogeno or dicarboxylic acids. The products were not formed or
obtained only in low yields. The regioselectivity for position 6 of 2(3H)-
benzothiazolones was observed and extended to other compounds by
1
7
the use of high-field H-NMR .
Address correspondence to Faouzi Guenadil, Laboratoire de Chimie Pharmaceu-
tique, Institut de Chimie, Universite Badji Mokhtar, Bp.: 12 Annaba, Algiers. E-mail:
guendouda@yahoo.fr
2
633

2
634
F. Guenadil and H. Aichaoui
The 6-acyl-2(3H)-benzothiazolones such as the 6-acyl-benzo-
xazolones have interesting analgesic, anti-inflammatory, antiepilep-
9
tic and antiviral properties. Instead of the frequently used AlCl3
as catalyst in Friedl-Crafts reactions, we conducted the acylation
of 2(3H)-benzothiazolones using zinc chloride as catalyst in N,N-
1
0
dimethylformamide as solvent and acid chlorides or anhydrides as
acylating agent (Scheme 1, Method c). With this method we obtained
the corresponding 6-acyl-2(3H)-benzothiazolones in good yields and we
optimized the conditions of their synthesis.
SCHEME 1
RESULTS AND DISCUSSION
The essential problem in the Friedl-Crafts acylation is the complexation
of 2(3H)-benzothiazolone by Lewis acids such as ZnCl2. The substrate
became therefore highly deactivated in this electrophilic aromatic sub-
1
1
stitution process. In view to this problem, the first study involved
the determination of the zinc chloride/2(3H)-benzothiazolone ratio. The
DMF/2(3H)-benzothiazolone ratio was kept constant at 3. The acylation
in the present case was found to proceed with a satisfactory rate and
yield only, when this ratio was in the range of 8–10.
The treatment of 2(3H)-benzothiazolone at the temperatures used
7
in the case of AlCl3-DMF for the acid halides, and anhydrides, gave
a negative result. We have not observed any reactivety of zinc chlo-
ride in these temperatures. After these results, the second part was
the optimisation of the temperatures in order to obtain the acylation
�
products. The optimum was at 125–130 C for the aliphatic and at
1
�
40–145 C for the aromatic and heterocyclic chlorides. In the case of
anhydrides we have study the succinic anhydride. The mixture was
�
treated at 120–125 C for 6 h. Under these conditions we have iso-
lated only the starting material and the corresponding acid was not
formed. This failure is probably due to the degradation of succinic an-
hydride.
Under these conditions, the 6-acyl-derivatives were obtained in ex-
cellent yields in the range of 53–87% (Table I). The structures of

Study of the Acylation Reaction
2635
TABLE I Yields and Mp of the Compounds c
R1
R2
Time (h)
�
Cryst. solvent Yields (%) m.p. ( C)
H
CH3
H
CH3
H
CH3
H
CH3
CH3
CH3
CH3
CH3
CH2CH3
CH2CH3
C6H5
1,30
1,30
1,40
1,40
2
2
2
2
18
6
Ethanol
Ethanol
Ethanol
Propanol
Toliol
Ethanol
Ethanol
Ethanol
Ethanol
/
68
73
63
66
82
87
53
58
63
0
189–191
145–146
204–205
177–178
216–218
147–148
223–224
223–225
176–178
/
C6H5
2-C4H3S
2-C4H3S
3-C5H4N
CH2 H2 COOH
6
-acyl-2(3H)-benzothiazolones were confirmed by IR, and 1H-NMR
spectroscopy and were compatible with the products obtained with
AlCl3-DMF. The precise position of acylation was unequivocally con-
firmed by x-ray single-crystal diffraction in the case of 6-benzoyl-2(3H)-
1
2
benzothiazolone, and was extended to other compounds by use of high
1
7
field H-NMR .
The reactivity of 2(3H)-benzothiazolones in this reaction appears to
be parallel to that in the mixture AlCl3-DMF at different temperatures
and the ZnCl2-DMF method (Scheme 1, Method c), provides good yields
with aliphatic, aromatic, and heterocyclic chlorides. The comparative
yields obtained by the aluminum chloride-N,N-dimethylformamide (B)
and zinc chloride-N,N-dimethylformamide (c) methods, for similar com-
pounds are summarized in Table II.
TABLE II Comparative Yields Obtained by the AlCl
Method
3
-DMF and ZnCl
ZnCl2-DMF
2
-DMF
AlCl3-DMF
Method
Temp
Time
(h)
Yields
(%)
Temp
Time
(h)
Yields
(%)
R1
R2
( C)
�
( C)
�
H
H
H
H
CH3
CH3
CH3
CH3
CH2CH3
C6H5
2-C4H3S
2-C4H3S
3-C5H4N
CH2 CH2 COOH
75–80
75–80
95–100
95–100
95–100
85–90
90–95
3,30
3
4,30
4,30
4,30
28
61
60
83
57
62
71
59
125–130
125–130
140
140–145
140–145
140–145
120–125
1,30
1,40
2
2
2
68
63
82
53
58
63
0
18
6
6

2
636
F. Guenadil and H. Aichaoui
CONCLUSION
The results of this study indicate that the reactivity of 2(3H)-
benzothiazolones in zinc chloride-N,N-dimethylformamide is par-
allel to that in aluminium chloride-N,N-dimethylformamide. At
different temperatures, 2(3H)-benzothiazolones react with acids
chlorides in the presence of a large excess of zinc chloride (8–10
equi) to give 6-acyl-2(3H)-benzothiazolones in excellent yields (53–
8
7%).
EXPERIMENTAL
Melting points were determined using an Electrothermal melting point
apparatus and are uncorrected. The IR spectra were recorded on a
Shimadzu 40 (KBr pellets). H-NMR spectra were recorded us-
ing a Bruker 80 MHz spectometer with TMS as internal stan-
dard. The compounds were pure according to TLC (ethylacetate-
cyclohexane, 3/2, v/v). The following examples demonstrate the
procedure.
General Procedure for the Reaction of
2
(3H)-Benzothiazolones with Aliphatic Acids Chlorides
Method (C)
Dimethyl formamide (0.039 mmol, 2.8 ml), was added to zinc chlo-
ride (0.117 mmol, 16 g). The mixture was stirred and maintained at
�
7
5 C, and 2(3H)-benzothiazolones (0.013 mmol), and acid chlorides
(
1
0.02 mmol) were added. The reaction mixture was warmed at 125–
�
30 C for 1 h 40 min. After cooling the complex was decomposed by
addition of ice water and 5 ml of 0.1N HCl. The resulting mixture
was stirred for 1 h, filtered, and the filtrate washed with water and
recrystallized.
6
-Acetyl-2(3H)-benzothiazolone. IR (KBr, � cm 1); 3160, (–NH), 1695,
�
1
1
660, (C O); H-NMR (80 MHz, DMSO D6, � in ppm); 2.55 (s, 3H), 7.19
(
sd ,, 11 HH ,, NJ H=) .8 .4 Hz), 7.88 (dd, 1H, J = 1.6, 8.4 Hz), 8.23 (s, 1H), 12.20
(
6
-Propanoyl-2(3H)-benzothiazolone. IR (KBr, � cm 1); 3160, (–NH),
�
1
1
685, 1655, (C O); H-NMR (80 MHz, DMSO D6, � in ppm); 1.08
(
t, 3H), 3.01 (q, 2H), 7.18 (d, 1H, J = 8.4 Hz), 7.86 (d, 1H, J = 8.4 Hz),
8
.20 (d, 1H, J = 1.6 Hz), 12.24 (s, 1H, NH).

Study of the Acylation Reaction
2637
General Procedure for the Reaction of
2
(3H)-Benzothiazolones with Aromatic Acids Chlorides
Method (B)
Dimethyl formamide (0.039 mmol, 2.8 ml), was slowly added to alu-
minium chloride (0.117 mmol). The mixture was stirred and maintained
�
at 45 C, and 2(3H)-benzothiazolones (0.013 mmol) and acids chlorides
(
1
0.0195 mmol) were added. The reaction mixture was warmed at 95–
00 C for 4 h 30 min. After cooling, it was poured into ice water. The
�
resulting mixture was stirred for 1 h, filtered and the filtrate washed
with water and recrystallized.
Method (C)
Dimethyl formamide (0.037 mmol, 2.8 ml), was added to zinc chlo-
ride (0.117 mmol, 16 g). The mixture was stirred and maintained
�
at 75 C, and 2(3H)-benzothiazolone or 3-methyl-2(3H)-benzoxazolone
(
0.013 mmol), and acids chlorides (0.02 mmol) were added. The reaction
�
mixture was warmed at 140–145 C for 2 h. After cooling the complex
was decomposed by addition of ice water and 5 ml of 0.1 N HCl. The
resulting mixture was stirred for 1 h, filtered, and the filtrate washed
with water and recrystallized.
6
-Benzoyl-2(3H)-benzothiazolone. IR (KBr, � cm 1); 3190, (–NH),
�
1
1
680, 1635, (C O); H-NMR (80 MHz, DMSO-D6, � in ppm); 7.23 (d, 1H,
J = 8.4 Hz), 7.58 (m, 6H), 8.00 (d, 1H, J = 1.6 Hz), 12 (s, 1H, NH).
-(2-Thinoyl)-2(3H)-benzothiazolone. IR (KBr, � cm 1); 3140, (–NH),
�
6
1
1
735, 1620, (C O); H-NMR (80 MHz, DMSO-D6, � in ppm); 7.29
(
m, 2H), 7.82 (m, 2H), 8.02 (m, 2H), 12 (s, 1H, NH).
-Methyl-6-(2-thinoyl)-2(3H)-benzothiazolone. IR (KBr, � cm 1);
�
3
1
1
7
3
1
660, 1620, (C O); H-NMR (80 MHz, DMSO-D6, � in ppm); 3.50 (s, 3H),
.30 (d, 1H, J = 8.28 Hz), 7.40 (dd, 1H, J = 5, 3.6 Hz), 7.70 (d, 1H, J =
.6 Hz), 7.88 (dd, 1H, J = 8.28, 1.5 Hz), 8.06 (d, 1H, J = 5 Hz) 8.18 (d,
H, J = 1.5 Hz).
3
-Methyl-6-nicotinoyl-2(3H)-benzothiazolone (Method C). Dimethyl
formamide (0.039 mmol, 2.8 ml), was added to zinc chloride
�
(
0.117 mmol, 16 g). The mixture was stirred and maintained at 75 C,
and 3-methyl-2(3H)-benzothiazolone (0.013 mmol, 2, 16 g), and nicoti-
noyl chloride hydrochloride (0.02 mmol) were added. The reaction mix-
�
ture was warmed at 140–145 C for 18 h. After cooling the complex was
decomposed by addition of ice water. The resulting mixture was stirred
for 1 h, filtered, and the filtrate washed with water and recrystallized

2
638
F. Guenadil and H. Aichaoui
from ethanol. IR (KBr, � cm� 1); 1670, 1635, (C O); H-NMR (80 MHz,
1
DMSO-D6, � in ppm); 3.49 (s, 3H), 7.40 (d, 1H, J = 8.2 Hz), 7.60 (m, 1H),
7
.80 (m, 1H), 8.10 (m, 2H), 8.80 (m, 1H), 8.87 (d, 1H, J = 1.6 Hz).
4
-Oxo-4-(3-methyl-2(3H)-benzothiazolon-6yl) butyric acid (Method
B). Dimethyl formamide (0.039 mmol, 2.8 ml), was slowly added to alu-
minium chloride (0.2 mmol). The mixture was stirred and maintained
�
at 45 C, and 3-methyl-2(3H)-benzothiazolone, and succinic anhydride
(
�
0.02 mmol) were added. The reaction mixture was warmed at 90–95 C
for 6 h. After cooling the complex was decomposed by addition of ice wa-
ter. The resulting mixture was stirred for 1 h, filtered, and the filtrate
�
washed with water and recrystallized from ethanol. M.p. = 226–227 C:
�
1
1
IR (KBr, � cm ); 3290 (OH), 1730, 1680, 1660, (C O); H-NMR (80
MHz, (DMSO-D6, � in ppm); 2.54 (t, 2H), 3.25 (t, 2H), 3.48 (s, 3H), 7.33
(
d, 1H, J = 8.4 Hz), 7.89 (d, 1H, J = 1.6 Hz), 8.32 (dd, 1H, J = 8.4, 1.6
Hz), 12.19 (s, 1H, OH).
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