Synergistic promoting effect of ball milling and KF–alumina support as a green tool for solvent-free synthesis of 2-arylidene-benzothiazinones

Article abstract of DOI:10.1080/17415993.2016.1163699

A solvent-free procedure is developed for the reaction of benzothiazinones with benzaldehyde derivatives, where the solid KF–Al₂O₃ support and ball milling synergistically leads to a green and efficient synthesis of several 2-arylide

Full text of DOI:10.1080/17415993.2016.1163699

Journal of Sulfur Chemistry
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Synergistic promoting effect of ball milling and
KF–alumina support as a green tool for solvent-
free synthesis of 2-arylidene-benzothiazinones
Ali Sharifi, Mohammad Ansari, Hossein Reza Darabi & M. Saeed Abaee
To cite this article: Ali Sharifi, Mohammad Ansari, Hossein Reza Darabi & M. Saeed Abaee
(2016): Synergistic promoting effect of ball milling and KF–alumina support as a green tool
for solvent-free synthesis of 2-arylidene-benzothiazinones, Journal of Sulfur Chemistry, DOI:
10.1080/17415993.2016.1163699
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Date: 21 April 2016, At: 12:40

JOURNAL OF SULFUR CHEMISTRY, 2016
http://dx.doi.org/10.1080/17415993.2016.1163699
Synergistic promoting effect of ball milling and KF–alumina
support as a green tool for solvent-free synthesis of
2-arylidene-benzothiazinones
Ali Sharifi, Mohammad Ansari, Hossein Reza Darabi and M. Saeed Abaee
Department of Organic Chemistry and Natural Products, Chemistry and Chemical Engineering Research
Center of Iran, Tehran, Iran
ABSTRACT
ARTICLE HISTORY
Received 15 January 2016
Accepted 6 March 2016
A solvent-free procedure is developed for the reaction of benzoth-
iazinones with benzaldehyde derivatives, where the solid KF–Al2O3
support and ball milling synergistically leads to a green and effi-
cient synthesis of several 2-arylidene-benzothiazinones. Therefore, a
cooperative effect of the solid support and ball milling leads to excel-
lent yields of the target dienes, while the catalyst can be recycled for
subsequent reactions without significant loss of its activity.
KEYWORDS
2-arylidene-
benzothiazinones;
4-benzothiazin-3-ones; ball
milling; KF–alumina; green
chemistry
1. Introduction
Considerable effort has been devoted in recent decades by synthetic chemists to design
and develop green processes.[1] This has led to increasing use of environmentally cleaner
solvents, reagents, and catalysts [2] and as a result an everyday growth has been witnessed
in the development of solvent-free procedures [3,4] and solid-supported synthesis.[5,6]
Nowadays, solid-support catalyzed reactions constitute a very powerful synthetic tool in
organic chemistry.[7] In specific, potassium fluoride on alumina (KF–Al2O3) has been
used as a very popular system since KF–Al2O3 possesses a mild basic character, exhibits
increased reactivity and selectivity in its reactions, and requires no special work-up
conditions.[8,9]
On another green chemistry front, many investigations have been carried out in a search
for new energy source for activation of reactants for various transformations. This has led
to the development of useful synthetic methods involving the adoption of microwave [10]
CONTACT Ali Sharifi
sharifi@ccerci.ac.ir
Supplemental data for this article can be accessed here. http://dx.doi.org/10.1080/17415993.2016.1163699
© 2016 Informa UK Limited, trading as Taylor & Francis Group

2
A. SHARIFI ET AL.
Scheme 1. Optimization of the conditions for the synthesis of 3a.
and ultrasonic [11,12] techniques. Another rapidly growing alternative energy sources has
been ball milling,[13,14] a method which provides the required energy via mechanical
grinding of the reactants in solid form and has succeeded in emerging as a green method
for conducting different synthetic reactions.[13,15]
The 2-arylidene-benzothiazinones constitute a class of heterocyclic compounds which
are significant for their antimalarial,[16] medicinal,[17,18] aldose reductase inhibition,[19]
and anti-bacterial [20] properties. In addition, they have potential as precursors in con-
structing more complex heterocyclic structures via dipolar [21] and Diels-Alder cycloaddi-
tion reactions,[22] further simultaneously being useful for the synthesis of larger benzoth-
iazepine rings.[23] Perhaps the most efficient and straightforward route for the synthesis
of these dienes goes through the Knoevenagel condensation of the respective benzothiazi-
nones with aromatic aldehydes,[24,25] although they have also been obtained via ring con-
traction of 1,4-thiazepin-5-one [26,27] or Horner–Wadsworth–Emmons reactions.[28,29]
In continuation of our investigations to develop environmentally attractive synthetic
procedures [30,31] and in the framework of our studies on heterocyclic systems,[32,33]
we here report a synergistic phenomenon caused by concurrent use of KF–alumina
support and ball milling which promotes the solvent-free synthesis of a group of (Z)-2-
arylidene-benzothiazinone derivatives 3, as shown in Scheme 1 for the reaction between
benzothiazinones 1 and aromatic aldehydes 2 to produce dienes 3.
2. Results and discussion
Initially the condensation of 1a with benzaldehyde 2a was chosen as the model reaction
to optimize the conditions (Table 1). A 1.0:1.0 solvent-free mixture of the two reactants
was shaken at 20 Hz in a ball mill reactor for 70 min gave no products (Entry 1). Addition
of 1.0 mmol of either alumina (Entry 2) or KF (Entry 3) to this mixture produced 18% or
25% of 3a, respectively, after the same time period. When both KF and alumina were used
together the yield increased to 40% (Entry 4), while the same mixture without ball milling
gave only 20% of 3a (Entry 5), indicating the crucial effect of ball milling in the process.
For further optimization of the conditions for the synthesis of 3a, we examined the
influence of ball milling, catalyst, and the time on the reaction progress, as summarized
in Table 2. Thus, an improved yield for 3a was observed when the reaction was carried
out at a frequency of 30 Hz (Table 2, Entry 1). Variation in the catalyst amount indicated
that 1.5 mmol of KF–alumina is the optimum amount (Entries 2–5). Similarly, the best
ratio for 1a/2a was determined to be 1.0:1.5 (Entries 6 and 7). Under the optimized ratio
of the reactants and the reagent (1.0:1.5:1.5), the optimum reaction time at 30 Hz was
demonstrated to be 50 min (Entries 6–9).

JOURNAL OF SULFUR CHEMISTRY
3
Table 1. Study the effect of catalyst on solvent-free synthesis of 3a.
Entry
Catalyst
Time (min)
Yield (%)a,b
1
2
3
4
5
None
Alumina
KF
KF–alumina
KF–alumina
70
70
70
–
18
25
40
20
70
70b
aIsolated yield.
bNo ball milling.
Table 2. Optimization of the synthesis of 3a.
Entry
1a:2a:catalyst
Time (min)
Yield (%)a
1
2
3
4
5
6
7
8
9
1.0:1.0:1.0
1.0:1.0:0.8
1.0:1.0:1.2
1.0:1.0:1.5
1.0:1.0:2.0
1.0:1.5:1.5
1.0:2.0:1.5
1.0:1.5:1.5
1.0:1.5:1.5
50
50
50
50
50
50
50
25
40
47
42
55
57
57
92
70
51
62
aIsolated yield.
To extend the scope of the reaction, we then applied the optimized conditions to various
substrates, as summarized in Table 3. Besides the reaction with benzaldehyde (Entry 1),
1a reacted with p-methoxybenzaldehyde as well to produce 3b (Entry 2). The N-Me
substituted benzothiazinone derivative 1b also reacted successfully under the optimized
conditions to efficiently produce products 3c–3g (Entries 3–7). This was also the case for
the reactions of the unsubstituted reactant 1c with 2a-b (Entries 8 and 9). In all cases, NMR
spectroscopy verified the structure of the products.
The reusability of the catalyst was studied next, where the recovered KF–Al2O3 was
reused several times in the reaction between 1a and 2a (Figure 1). For this reason, the
suspension of the reaction mixture in ethyl acetate was filtered to separate the catalyst.
The recovered catalyst was then dried and reactivated in a microwave oven (360 watt) for
5 min before being reused in the subsequent runs and without any makeup. As a result, it
could be reused for four runs with only showing a gradual decrease in its activity after each
recovery.
3. Conclusion
In summary, a versatile benign route to product 3 is developed which under solvent-free
conditions leads to high yields of 2-arylidene-benzothiazinones. The attractive features of
the procedure are the mild reaction conditions, the use of acid-free reagents, and to overall
very low waste generation. These make the method a useful and attractive green addition
to the literature archive for the preparation of the target compounds. For a more direct
comparison, some previously reported conditions used to produce compounds similar to
those reported here are presented in Table 4.

4
A. SHARIFI ET AL.
Table 3. Evaluation of the reaction scope.
Entry
1
Reactants
Product
Time (min) Yield (%)a
Mp (°C)
1a + C6H5CHO
50
65
50
92
90
92
71–73 (this work)
2
3
1a + p-MeOC6H4CHO
110–112 (this work)
1b + C6H5CHO
86–88 [28]
4
5
6
7
1b + p-MeC6H4CHO
1b + p-MeOC6H4CHO
1b + p-ClC6H4CHO
60
60
65
65
90
88
87
85
138–139 [28]
101–104 (this work)
120–122 (this work)
109–111 [28]
1b + C6H5CH = CHCHO
(Continued)

JOURNAL OF SULFUR CHEMISTRY
5
Table 3. Continued.
Entry
8
Reactants
Product
Time (min)
55
Yield (%)a
87
Mp (°C)
1c + C6H5CHO
201–203 [28]
207–210 [28]
9
1c + p-MeOC6H4CHO
80
90
aIsolated yield.
Figure 1. The reusability of the catalyst for the synthesis of 3a.
Table 4. Comparison of the present procedure with some other recent methods.
Entry
1
Method
Condition (Reference)
Yield%
50–94
Knoevenagel condensation
(i) SO2Cl2, CH2Cl2 (2–5 h);
(ii) triethyl phosphite, reflux (28 h);
(iii) C2H5OH, NaOEt [28]
2
3
4
Ring contraction
Horner-Wadsworth-Emmons reaction
Knoevenagel condensation
C5H5N, SOCl2, rt (2d), 55°C (4 h) [26]
DMF, NaOMe (excess), 125°C, 3 h [24]
KF–Alumina, Ball mill, rt, 45 min (This work)
14
69
87–92
4. Experimental design
Reactions were monitored by thin-layer chromatography (TLC). FT-IR spectra were
recorded using KBr disks on a Bruker Vector-22 infrared spectrometer and absorptions
were reported as wave numbers (cm−1). NMR spectra were obtained on an FT-NMR
Bruker Ultra Shield™ (500 MHz) as CDCl3 solutions and the chemical shifts were expressed

6
A. SHARIFI ET AL.
as δ units with Me4Si as the internal standard. Mass spectra were obtained on a Finnigan
Mat 8430 apparatus at ionization potential of 70 eV. Elemental analyses were performed
by a Thermo Finnigan Flash EA 1112 instrument. Compounds 1 were prepared using
available methods. All other chemicals were purchased from commercial sources and were
freshly used after being purified by standard procedures.
4.1. Typical synthesis of 3
A 5 mL stainless steel vial was charged with a derivative of benzothiazinones 1 (1.0 mmol),
benzaldehyde 2a (1.5 mmol) and KF–alumina (0.24 g) together with a 10 mm stainless steel
ball. The vial was sealed with a Teflon® gasket. The reaction was shaken at 30 Hz in an oscil-
latory ball mill for the appropriate length of time. After completion of the reaction, based
on TLC monitoring, the crude reaction mixture was diluted with ethyl acetate (10 mL) and
filtered to separate the catalyst. The filtrate was concentrated under reduced pressure and
the residue was purified by column chromatography using silica gel and EtOAc/hexanes
mixture (1/10) as the eluent. The identity of known products was confirmed by compar-
ison of their spectroscopic data with those available in the literature. New products were
1
characterized by H NMR, 13C NMR, IR, CHN and mass spectra and their purity was
confirmed by elemental analysis.
4.2. Spectral data of new products
4.2.1. (Z)-4-Benzyl-2-benzylidene-2H-benzo[b][1,4]thiazin-3(4H)-one (3a)
1
Yellow solid; 71–73 mp°C; IR (KBr) 3032, 1632, 1583, 1485, 1439 cm−1; H NMR
(500 MHz, CDCl3) δ 8.03 (s, 1H), 7.71 (d, J = 7.5 Hz, 2H), 7.50 (t, J = 7.5 Hz, 2H),
7.44–7.38 (m, 3H), 7.32–7.29 (m, 4H), 7.11–7.09 (dt, J = 1.5, 7.5 Hz, 1H), 7.05 (d,
J = 7.5 Hz, 1H), 7.00 (d, J = 7.5 Hz, 1H), 5.41 (s, 2H); 13C NMR (125 MHz, CDCl3) δ
162.6, 137.2, 136.9, 135.6, 135.2, 130.7, 129.4, 129.3, 128.8, 127.6, 127.4, 126.7, 126.6, 124.0,
121.0, 119.8, 117.9, 49.8; MS (70 ev) m/z 343 (M+), 252, 224, 102, 91, 77; Anal. Calcd for
C22H17NOS: C, 76.94; H, 4.99; S, 9.34. Found: C, 76.59%; H, 4.78%; S, 9.15%.
4.2.2. (Z)-4-Benzyl-2-(4-methoxybenzylidene)-2H-benzo[b][1,4]thiazin-
3(4H)-one (3b)
1
Yellow solid; 110–112 mp°C; IR (KBr) 3039, 2339, 1622, 1492, 1292 cm−1; H NMR
(500 MHz, CDCl3) δ 7.91 (s, 1H), 7.66 (d, J = 8.5 Hz, 2H), 7.34 (dd, J = 8.0, 8.0 Hz,
2H), 7.25 (m, 4H), 7.07 (t, J = 8.0 Hz, 1H), 6.99–6.92 (m, 4H), 5.35 (s, 2H), 3.86 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 163.1, 160.6, 137.4, 137.0, 135.5, 132.6, 129.3, 128.0,
127.6, 127.4, 126.7, 126.6, 123.9, 120.0, 118.2, 117.9, 114.4, 55.8, 49.8; Anal. Calcd for
C23H19NO2S: C, 73.97; H, 5.13; S, 8.59. Found: C, 74.115; H, 4.995; S, 8.75%.
4.2.3. (Z)-2-(4-Methoxybenzylidene)-4-methyl-2H-benzo[b][1,4]thiazin-3
(4H)-one (3e)
Yellow solid; 101–104 mp°C; IR (KBr) 2954, 2312, 1631, 1495 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.83 (s, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.25–7.19 (m, 2H), 7.03–6.98 (m, 2H),
6.95 (d, J = 8.5, 2H), 3.83 (s, 3H), 3.53 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 163.4,
160.5, 138.1, 135.1, 132.5, 127.9, 127.4, 126.7, 123.7, 119.9, 118.3, 116.9, 114.3, 55.7, 33.2;

JOURNAL OF SULFUR CHEMISTRY
7
MS (70 ev) m/z 297 (M+), 264, 190, 159, 136, 108; Anal. Calcd for C17H15NO2S: C, 68.66;
H, 5.08; S, 10.78. Found: C, 68.89%; H, 4.92%; S, 10.84%.
4.2.4. (Z)-2-(4-Chlorobenzylidene)-4-methyl-2H-benzo[b][1,4]thiazin-3(4H)-one (3f)
Yellow solid; mp 120–122°C; IR (KBr) 3429, 2904, 1643, 1471 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.84 (s, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.5 Hz, 2H), 7.28–7.24 (m,
2H), 7.10–7.03 (m, 2H), 3.57 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 162.6, 137.8, 135.1,
133.8, 133.6, 131.9, 129.1, 128.7, 127.6, 126.8, 123.9, 119.2, 117.1, 33.3; MS (70 ev) m/z 301
(M+), 268, 190, 136; Anal. Calcd for C16H12ClNOS: C, 63.68; H, 4.01; S, 10.62. Found: C,
63.81%; H, 4.11%; S, 10.75%.
Acknowledgement
Authors would like to thank the Analytical Chemistry Department for conducting some of the
analysis experiments.
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