Solvent-free synthesis of benzothiazolines in the presence of alumina

Article abstract of DOI:10.1080/00397910701490048

o-Aminothiophenol reacted with ketones and β-keto esters in the presence of alumina under mild and solvent-free conditions to afford the corresponding benzothiazolines in high yields. Alumina can be reused for subsequent reactions without any loss of the

Full text of DOI:10.1080/00397910701490048

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Solvent‐Free Synthesis of Benzothiazolines in
the Presence of Alumina
Mitsuo Kodomari a , Akihito Satoh a , Ryo Nakano a & Tadashi Aoyama b
a Department of Applied Chemistry , Shibaura Institute of Technology ,
Koto‐ku, Tokyo, Japan
b Department of Materials and Applied Chemistry , College of Science and
Technology, Nihon University , Chiyoda‐ku, Tokyo, Japan
Published online: 05 Oct 2007.
To cite this article: Mitsuo Kodomari , Akihito Satoh , Ryo Nakano & Tadashi Aoyama (2007)
Solvent‐Free Synthesis of Benzothiazolines in the Presence of Alumina, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:19, 3329-3335, DOI:
10.1080/00397910701490048
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Synthetic Communicationsw, 37: 3329–3335, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701490048
Solvent-Free Synthesis of Benzothiazolines
in the Presence of Alumina
Mitsuo Kodomari, Akihito Satoh, and Ryo Nakano
Department of Applied Chemistry, Shibaura Institute of Technology,
Koto-ku, Tokyo, Japan
Tadashi Aoyama
Department of Materials and Applied Chemistry, College of Science and
Technology, Nihon University, Chiyoda-ku, Tokyo, Japan
Abstract: o-Aminothiophenol reacted with ketones and b-keto esters in the presence of
alumina under mild and solvent-free conditions to afford the corresponding benzothia-
zolines in high yields. Alumina can be reused for subsequent reactions without any loss
of the activity.
Keywords: alumina, benzothiazolines, heterocycles, ketones, solvent-free synthesis
INTRODUCTION
Benzothiazoline derivatives are important compounds and useful intermedi-
ates in organic synthesis and pharmaceutical chemistry. Benzothiazolines con-
stitute an important class of multidentate ligands, and some As,[1] Sb,[2] Ga,
and In[3] derivatives of benzothiazolines have been reported, in which these
ligands behave as bifunctional tridente ligands. 1,4-Benzothiazines are
prepared by ring-expansion of benzothiazolines.[4,5] There are many
methods for preparing benzothiazolines. The most common method is the con-
densation of o-aminothiophenol with carbonyl compounds in the presence of
p-toluenesulfonic acid[4] and a Lewis acid such as Ga(OTf)3.[6] Other methods
Received in Japan January 1, 2007
Address correspondence to M. Kodomari, Department of Applied Chemistry,
Shibaura Institute of Technology, Toyosu, Koto-ku, Tokyo 135-8548, Japan. E-mail:
kodomari@sic.shibaura-it.ac.jp
3329

3330
M. Kodomari et al.
include the reaction of 2,20-dinitrodiphenyl disulfide with ketones in the
presence of TiCl4/Sm[7] and SmI2/HMPA.[8] However, most of these
methods involve harsh conditions such as use of acid or toxic catalysts and
moderate to high thermal conditions as well as long reaction time. In recent
years, solvent-free organic synthesis using inorganic supports has become a
popular method[9] and attracted immense interest as an environmentally
benign methodology, because it often leads to high yields, clean reactions,
and shorter reaction times. Herein we describe the solvent-free synthesis of
benzothiazolines in the presence of alumina.
Ketones were reacted with o-aminothiophenol in the presence of
p-toluenesulphonic acid in refluxing benzene for 14–24 h to afford the corre-
sponding benzothiazolines.[4] In contrast, similar reactions proceeded readily
in the presence of neutral alumina under solvent-free and mild conditions to
give the benzothiazolines in high yields.
For instance, the reaction of acetophenone with o-aminothiophenol was
carried out at 808C for 1 h in the presence of neutral alumina under solvent-
free conditions to give 2-methyl-2-phenylbenzothiazoline in 90% yield
(Scheme 1), whereas the same reaction was carried out in the presence of
p-toluenesulphonic acid in refluxing benzene for 14 h to give 72% yield of
the product. Among different supports tested, neutral and acidic alumina
were the most adaptable support for the synthesis of 2-methyl-2-phenylben-
zothiazoline because comparatively higher yield is achieved under the same
conditions. Silica gel and montmorillonite K10 were ineffective. Therefore,
neutral alumina was used in all subsequent experiments. The amount of
neutral alumina was critical for achieving high yield of products within a
short time; thus, 3 g of neutral alumina versus a mixture of 2 mmol of
ketone and 3 mmol of o-aminothiophenol gave optimum yield (Table 1).
The reactions of various ketones with o-aminothiophenol were carried out
in the presence of neutral alumina under solvent-free conditions. These results
are shown in Table 2.
The reactivity of aliphatic ketones was strongly influenced by their steric
factors. The reaction of methyl propyl ketone and cyclohexanone with o-ami-
nothiophenol was successfully carried out at room temperature, whereas the
reaction of methyl isopropyl ketone and methyl t-butyl ketone was hard to
proceed at room temperature. However, these reactions were carried out at
808C to give the products in high yields (Table 2, entries 3–5 and 15). The
reactivity of aromatic ketones was lower than that of aliphatic ketones.
Acetone was reacted with o-aminothiophenol at room temperature to afford
Scheme 1.

Solvent-Free Synthesis of Benzothiazolines
3331
Table 1. Reaction of o-aminothiophenol with acetophenone in the pre-
sence of various inorganic supports under solvent-free conditionsa
Inorganic support
Yieldb (%)
None
15
91
Alumina (neutral)
Alumina (basic)
Alumina (acidic)
Silica gel
34
86
17
14
Montmorillonite K 10
Molecular sieve 5A
Trace
aAll reaction were carried out using 2 mmol of acetophenone, 3 mmol
of o-aminothiophenol, and 3 g of a support.
bIsolated yield.
the product in high yield. In contrast, acetophenone did not react at room
temperature, but when the reaction was carried out at 808C, the product was
obtained in high yield (Table 2, entries 1 and 6). a-Diketones were also
reacted with o-aminothiophenol to give the corresponding benzothiazolines
in good yields (Scheme 2).
Although b-keto esters react with o-aminothiophenol under solvent-free
and microwave irradiation conditions to give 2-substituted benzothiazoles,[10]
and under similar conditions using basic alumina as support give benzothia-
zines,[11] the same reactions were carried out in the presence of neutral
alumina under solvent-free conditions give the corresponding benzothiazo-
lines in high yields, and benzothiazoles and benzothiazines were not
formed. Aliphatic b-keto esters readily reacted with o-aminothiophenol at
room temperature, whereas aromatic b-keto esters required higher reaction
temperature (Table 3, entry 7).
b-Diketones are allowed to react with o-aminothiophenol in ethanol or
dimethyl sulfoxide (DMSO) under reflux to afford benzothiazines.[12]
Similar reactions were carried out in the presence of neutral alumina under
solvent-free conditions to give a mixture of benzothiazolines and benzothia-
zines. In contrast, the same reactions were performed without alumina under
similar conditions to give the benzothiazolines in high yields (Scheme 3).
For example, the reaction of 2,4-pentandione with o-aminothiophenol
was carried out without alumina at 508C for 3 h to give 2-(acetonyl)-2-methyl-
benzothiazoline in 95% yield, whereas the same reaction was performed in the
presence of neutral alumina under similar conditions to give a mixture of
2-(acetonyl)-2-methylbenzothiazoline (31%) and 2-acetyl-3-mehyl-ben-
zothiazine (51%).

3332
M. Kodomari et al.
a
Table 2. Reaction of o-aminothiophenol with ketones in the presence of Al2O3
Yield
(%)b
Entry
Reactant
R1
Ra
8C/h
Product
1
2
1a
1b
1c
1d
1e
1f
CH3
CH3
CH3
CH3
CH3
CH3
Ph
RT/0.5
RT/0.5
RT/0.5
80/1.0
88/1.0
80/0.5
80/0.5
80/3.0
80/6.0
RT/0.5
RT/0.5
80/0.5
80/0.5
RT/0.5
2a
2b
2c
2d
2e
2f
84
81
82
85
88
95
86
69
85
85
87
91
87
87
CH3CH2
CH3CH2CH2
(CH3)2CH
(CH3)3C
CH3
3
4
5
6
7
1g
1h
1i
CH3CH2CH2
(CH3)2CH
Ph
Ph
Ph
2g
2h
2i
8
9
Ph
CH3
10
11
12
13
14
1j
PhCH2CH2
CH3CH2
CH3CH2CH2
PhCH2
2j
1k
1l
CH3CH2
CH3CH2CH2
PhCH2
2k
2l
1m
1n
2m
2n
15
1o
RT/0.5
2o
91
aAll reactions were carried out using 2 mmol of ketone, 3 mmol of o-aminothio-
phenol, and 3 g of A2O3.
bIsolated yield.
In summary, we have developed a simple, convenient method for the
synthesis of benzothiazolines from the reaction of various ketones and
b-keto esters with o-aminothiophenol in the presence of neutral alumina
under solvent-free conditions. Alumina can be easily recovered from the
reaction mixture by simple filtration and reused for subsequent reactions
without any loss of the activity.
Scheme 2. 5a (R1 ¼ R2 ¼ CH3CH2): 84%; 5b (R1 ¼ CH3, R2 ¼ Ph): 73%.

Solvent-Free Synthesis of Benzothiazolines
3333
Table 3. Reaction of o-aminothiophenol with b-diketones and b-keto estersa
Yield
(%)b
Entry
Reactant
R1
R2
8C/h
Product
1c
2c
3
3a
3b
3c
3d
3e
3f
CH3
CH3
CH3
CH3
CH3
CH3
C6H5
50/3
80/3
RT/1
RT/1
RT/1
RT/1
80/1
4a
4b
4c
4d
4e
4f
95
84
87
91
90
80
66
CH3CH2O
(CH3)3CO
C6H5CH2O
4
5
6
CH3CH2CH2 CH3CH2O
C6H5 CH3CH2O
7
3g
4g
aAll reactions were carried out using 2 mmol of b-diketone or b-keto ester and 3 g of
Al2O3 under solvent-free conditions.
bIsolated yield.
cThe reaction was carried out without Al2O3.
Scheme 3.
EXPERIMENTAL
IR spectra were recorded on Horiba FT-710 spectrometer in KBr with absorp-
tions in cm21. 1H NMR spectra were recorded on a Jeol JNM-LA 300, and TMS
was used as internal standard. Mass spectra were recorded on a Jeol 600H at
70 eV. Neutral alumina for column chromatography (MP Biochemicals, MP
Alumina N-Super 1) was used as a solid support without any treatment.
Products were characterized by comparison of their spectroscopic data (1H
NMR, IR, and mass) and melting points with those reported in the literature.
General Procedure for the Synthesis of 2,2-Disubstituted
Benzothiazolines
2,2-Dimethylbenzothiazoline (2a)
A mixture of acetone (0.116 g, 2 mmol), o-amonothiophenol (0.375 g,
3 mmol), and neutral alumina (3 g) was stirred at room temperature for

3334
M. Kodomari et al.
30 min under a nitrogen atmosphere. The products were extracted with
chloroform. The extract was filtered, and the filtrate was concentrated under
reduced pressure to leave the crude product. The product was purified by
column chromatography on silica gel (hexane–chloroform ¼ 3:1) to give 2,2-
dimethylbenzothiazoline (0.277 g, 84% yield). Mp 44–458C (lit.[5] 45–468C).
1
IR: nmax 3378, 2965, 1583, 1473, 1305, 755 cm21. H NMR (CDCl3):
d1.55 (s, 6H, 2 ꢀ CH3), 4.32 (bs, 1H, NH), 6.57–6.71(m, 2H, ArH), 6.85–
7.02 (m, 2H, ArH).
2-Isopropyl-2-methylbenzothiazoline (2d)
IR: nmax 3359, 2964, 1583, 1465, 1118, 1022, 740 cm21. 1H NMR (CDCl3): d
1.04 (q, J ¼ 6.8 Hz, 6H, 2 ꢀ CH3), 1.62 (s, 3H, CH3), 2.08–2.18 (m, 1H, CH),
3.95 (s, 1H, NH), 6.57–6.72 (m, 2H, ArH), 6.85–7.03 (m, 2H, ArH). HRMS
(TOF-Cl) found m/z: 194.0996; calcd. for C11H16NS (MHþ): 194.0997.
2-Methyl-2-phenylbenzothiazoline (2f)
1
IR: nmax 3344, 3062, 2975, 1579, 1462, 1259, 1120, 1022 cm21. H NMR
(CDCl3): d 2.04 (s, 3H, CH3), 4.27 (s, 1H, NH), 6.70–6.78 (m, 2H, ArH),
6.90–7.02 (m, 2H, ArH), 7.20 (m, 3H, ArH), 7.60–7.64 (m, 2H, ArH).
HRMS (TOF-Cl) found m/z: 228.0842; calcd. for C14H14NS (MHþ):
228.0841.
2-(Acetonyl)-2-methylbenzothiazoline (4a)
1
IR: nmax 3334, 1706, 1581, 1473, 1118, 744 cm21. H NMR (CDCl3): d1.79
(s, 3H, CH3), 2.16 (s, 3H, CH3), 3.03 (d, J ¼ 17 Hz, 1H, CH2), 3.28
(d, J ¼ 17 Hz, 1H, CH2), 5.04 (s, 1H, NH), 6.58–6.72 (m, 2H, ArH),
6.88–7.03 (m, 2H, ArH). HRMS (TOF-Cl) found m/z: 208.0790; calcd. for
C11H14NOS (MHþ): 208.0790.
2-Methyl-2-benzoyl-benzothiazoline (5b)
IR: nmax 3341, 3306, 1677, 1471, 1259, 1022, 743 cm21, 1H NMR (CDCl3): d
2.01 (s, 3H, CH3), 5.47 (s, 1H, NH), 6.74–6.80 (m, 2H, ArH), 6.94–7.02
(m, 2H, ArH), 7.42–7.58 (m, 3H, ArH), 8.02–8.05 (m, 2H, ArH). HRMS
(TOF-Cl) found m/z: 256.0798; calcd. for C15H14NOS (MHþ): 256.0790.
REFERENCES
1. Durgashanker, R.; Audhesh, K.; Singh, Y. Synthesis and characterisation of some
new organoarsenic(V) Schiff bases derivatives derived from bifunctional tridentate
benzothiazolines. Main Group Metal Chem. 2006, 29, 65.

Solvent-Free Synthesis of Benzothiazolines
3335
2. Sharma, P. K.; Rai, A. K.; Singh, Y. Triphenylantimony(V) derivatives of 2,2-dis-
ubstituted benzothiazoline ligands: Synthetic and spectroscopic studies.
Phosphorus, Sulfur Silicon Relat. Elem. 2006, 181, 2147.
3. Agrawal, M.; Trandon, J. P.; Mehrotra, R. C. Synthesis of some new gallium and
indium complexes with some sulfer containing ligands. J. Inorg. Nucl. Chem.
1981, 43, 1070.
4. Liso, G.; Trapani, G.; Latrofa, A.; Marchini, P. Oxidative ring-expansion of
benzothiazolines into 1,4-benzothiazines. J. Heterocyclic. Chem. 1981, 18, 279.
5. Chioccara, F.; Prota, G. A novel route to 4H-1,4-benzothiazines by ring-expansion
of 2,3-dihydro-1,3-benzothiazoles. Synthesis 1977, 876.
6. Prakash, G. K. S.; Mathew, T.; Panja, C.; Vaghoo, H.; Venkataraman, K.;
Olah, G. A. Efficient one-pot synthesis of fluorinated benzimidazolines, benzothia-
zolines, benzoxazolines, and dihydrobenzoxazinones using gallium(III) triflate as a
catalyst. Org. Lett. 2007, 9, 179.
7. Zhong, W.; Chen, X.; Zhang, Y. Low-valent titanium induced simultaneous
reduction of nitro group and S-S bond in nitrodisulfides: A novel method for the
synthesis of benzothiazolines, benzothiazoles and 2,3-dihydro-1,5-benzothiaze-
pines. Synth. Commun. 2000, 30, 4451.
8. Chen, X. Y.; Zhong, W. H.; Zhang, Y. M. Simultaneous reduction of nitro group
and S-S bond in nitrodisulfides by samarium diiodide: A new approach to ben-
zothiazolines. Chin. Chem. Lett. 2000, 11, 387.
9. Tanaka, K. Solvent-Free Organic Synthesis; Wiley-VCH: Weinheim, 2003.
10. Kamila, S.; Zhang, H.; Biehi, E. R. One-pot synthesis of 2-aryl- and 2-alkylben-
zothiazoles under microwave irradiation. Heterocycles 2005, 65, 2119.
11. Paul, S.; Gupta, R.; Loupy, A.; Rani, B.; Dandia, A. Dry media synthesis of 4H-
1,4-benzothiazines under microwave irradiation using basic alumina as solid
support. Synth. Commun. 2001, 31, 711.
12. Alyea, E. C.; Malek, A. Reaction products of 2-aminobenzenethiol with some
b-diketones. J. Heterocyclic. Chem. 1985, 22, 1325.