Effect of nitro-substituton on the photochemistry of 3-piperidino-1,2-benzisothiazole derivatives: A mechanistic investigation

Article abstract of DOI:10.3987/COM-09-11889

Photochemical isomerization of 3-piperidino-1,2-benzisothiazole (BIT)-benzothiazole (BT) was investigated. In particular, the effect of nitro-substitution on the benzene ring was selectively examined for the parent, 5-nitro-, and 7-nitro-derivatives. 3-Piperidino-BIT and nitro-3-piperidino-BIT isomerized irreversibly to the corresponding 2-piperidino-BT, and this reaction mechanism was investigated using density-functional theory (DFT) and time-dependent (TD)-DFT calculations. These calculations showed that this isomerization goes through an azirine intermediate. In addition, excitation wavelength effect demonstrates that isomerization occurs from the upper excited state of nitro-derivatives. The HOMO-LUMO transition has charge-transfer and photoinactive characters.

Full text of DOI:10.3987/COM-09-11889

HETEROCYCLES, Vol. 81, No. 3, 2010
659
HETEROCYCLES, Vol. 81, No. 3, 2010, pp. 659 - 674. © The Japan Institute of Heterocyclic Chemistry
Received, 18th December, 2009, Accepted, 29th January, 2010, Published online, 1st February, 2010
DOI: 10.3987/COM-09-11889
EFFECT OF NITRO-SUBSTITUTON ON THE PHOTOCHEMISTRY OF
3-PIPERIDINO-1,2-BENZISOTHIAZOLE
MECHANISTIC INVESTIGATION
DERIVATIVES:
A
Hiroharu Tanikawa, Kazuhiro Ishii, Shun Kubota, Takashi Sasanuma, Shiki
Yagai, Akihide Kitamura, and Takashi Karatsu*
Department of Applied Chemistry and Biotechnology, Graduate School of
Engineering, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba, 263-8522,
Japan, e-mail address: karatsu@faculty.chiba-u.jp
Abstract – Photochemical isomerization of 3-piperidino-1,2-benzisothiazole
(BIT)–benzothiazole (BT) was investigated. In particular, the effect of
nitro-substitution on the benzene ring was selectively examined for the parent,
5-nitro-, and 7-nitro-derivatives. 3-Piperidino-BIT and nitro-3-piperidino-BIT
isomerized irreversibly to the corresponding 2-piperidino-BT, and this reaction
mechanism was investigated using density-functional theory (DFT) and
time-dependent (TD)-DFT calculations. These calculations showed that this
isomerization goes through an azirine intermediate. In addition, excitation
wavelength effect demonstrates that isomerization occurs from the upper excited
state of nitro-derivatives. The HOMO-LUMO transition has charge-transfer and
photoinactive characters.
INTRODUCTION
Benzisothiazoles (BIT) and benzothiazoles (BT) skeletons are often found in pharmaceutically and
agriculturally active chemicals, and possess key functions. For example, ziprasidone (as Zeldox from
Pfizer), which has a BIT skeleton, is approved by US-FDA,1 and is now being used as an antipsychotic
drug. Riluzole (as Rilutek from Sanofi-Aventis), which has a BT skeleton, is an authorized medicine for
amyotrophic lateral sclerosis (ALS).2 The BT structured KIF-230 (as Benthiavalicarb from Kumiai
Chemicals) is also used as an antifungal agricultural chemical.3 If BIT–BT photoisomerization is found to
occur, this reaction could become a valuable tool in the synthesis of BIT and BT derivatives with similar
substituents, while they are currently synthesized by completely separate methods.

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HETEROCYCLES, Vol. 81, No. 3, 2010
Five-membered aromatic compounds containing of two heteroatoms, such as isothiazoles–thiazoles,4-7 or
isooxazoles–oxazoles,4-7 have been studied in depth and are known to undergo reversible
photoisomerization. However, the photochemical behavior of their condensed ring analogues has not been
widely studied. This study focuses on the increasingly important photochemical BIT–BT isomerization
reaction, while, partial photoisomerization has been observed during photostability testing of
ziprasidone,8 better understanding and control of this reaction should be very important in the design of
new drugs.
Our preliminary paper9 deals with 3-piperidino-5-nitrobenzisothiazole derivatives because of their highly
selective photochemical reactions (Fig.1, 1a). The nitro-group does not often feature in biological
processes; however, compounds involving a nitro group are easy to detect, and allow conversion to
various functional groups, such as amines, imines, amides, and halides. In this paper, to clarify the
function of the nitro-groups in the photochemical reactivity of 1a, photoreaction of 1b (R1=H, R2=NO2)
and 1c (R1=H, R2=H) for the photochemical isomerization of 3-piperidinobenzisothiazole to
piperidinobenzothiazole were studied using density functional theory (DFT) and time-dependent
(TD)-DFT.
Figure 1. Photochemical isomerization of 3-peperidino-1,2-benzisothiazole derivatives (1a-c) to
benzothiazole derivatives (2a-c)
RESULTS AND DISCUSSION
When a solution of 1b in acetonitrile (3 mL, 3.9  10−4 M) purged by argon was exposed to a 400 W
Xe-arc lamp through a quartz cuvette using UV30 glass filter (> 300 nm), no photochemical reactions
were observed. However, using a low-pressure mercury lamp (254 nm) for 24 h, UV–Vis absorption
analyses showed clear isosbestic points at 255 and 377 nm. 254 nm-Photolysis of 1b gave 2b in 46%
yield (Figure 2). Reverse phase HPLC analysis of reaction mixture showed 2b as the only separable
product. Spectral identification of the BIT and BT structures were difficult, however, the 4, 6, and 7
positions proton signals were slight shifted to the higher magnetic field after the isomerization (1a→2a, 
=8.79→8.31 (H4), 8.30→7.91 (H6), 7.89→7.65 (H7), see details in experimental section) indicating a

HETEROCYCLES, Vol. 81, No. 3, 2010
661
decreasing electron density in the benzene ring of BT compared to that of BIT (i.e., due to BIT→BT
isomerization). The spectral data of 2b were identical to those of the separately synthesized substance,
7-nitro-2-piperidino-1,3-benzothiazole. Noticeably, irradiation of 2b did not produce 1b. Therefore, the
BIT→BT isomerization is one-way, and not reversible.
4
3.5
0 h
3
2.5
24 h
2
1.5
1
0.5
0
200 250 300 350 400 450 500 550 600
Wavelength (nm)
Figure 2. Absorption spectral change of 1b by irradiation of 254 nm light in MeCN (3.9×10-4 M)
Photoreactions of 1b were also examined in methanol and n-hexane purged by argon (1.5  10−4 M), as
shown in Figure 3. The isomerization cleanly produced 2b as the sole photo-product. The reaction was
accelerated two-fold in methanol. On the other hand, photoirradiation of 1b produced in several
inseparable products in n-hexane. This reaction was also examined under oxygen-saturated acetonitrile.
The complete spectral change of 1b to 2b under oxygen was identical to that under argon. Therefore, we
conclude that this reaction was not quenched by oxygen and may occur via a electronically
singlet-excited state (S1) with a short lifetime.
To supplement our findings, we conducted two control experiments. No isomerization was observed
when 1a was irradiated with light of wavelength greater than 300 nm (irradiation was performed using a
500W Xe arc lamp with UV30 HOYA glass filter). The reaction of 1a was also examined in the presence
of trifluoroacetic acid (TFA) for protonating the amino group. However, TFA had no effect on the
photochemical isomerization reaction. From the results of solvent effect, we expected that the
isomerization proceeds through polar intermeadiate which has charge transfer nature from piperidino
nitrogen to the nitrobenzisothiazole moiety, however, no effect was observed by protonation of the
piperidino nitrogen to reduce electron donating character.
Figure 4 shows the absorption spectral change of 1c in acetonitrile after 10 h of irradiation. The initial
spectrum of 1c changed cleanly to the product spectrum, with isosbestic points at 220, 252, 306 nm
(Figure 4a). The spectrum of the product is absolutely consistent with the spectrum of 2c synthesized

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HETEROCYCLES, Vol. 81, No. 3, 2010
separately (Figure 4b).
Irradiation of 1a, 1b, and 1c induced BIT BT isomerization. However, irradiation of 2a, 2b, and 2c
induced no BTｖ→BIT isomerization. Therefore, this isomerization proceeded as BIT BT one-way
isomerization. The absorption maxima of BT derivatives usually locate at shorter wavelengths than the
corresponding BIT derivatives, and therefore, lowest excitation energies of 2a and 2c are expected to be
higher than that of the primary azirine–type intermediate (spiroazacyclopropene) IM1 except in the case
of 2b.
2.5
4
3.5
3
0 h
2 h
0 h
2
14 h
2.5
2
1.5
1
1.5
1
0.5
0
0.5
0
200 250 300 350 400 450 500 550 600
Wavelength (nm)
200 250 300 350 400 450 500 550 600
Wavelength (nm)
Figure 3. Absorption spectra change of 1b by irradiation of 254 nm light in MeOH (left) and in
n-hexane (right), 1.5×10-4 M
0 h
0 h
10 h
2c prepared
10 h
separately
Figure 4. Absorption spectra change of 1c by irradiation of 254 nm light in MeCN
Figure 5 shows a plausible isomerization mechanism proposed in our preliminary paper, and Figure 6
shows an energy diagram of the reactants, products, and possible reaction intermediates appearing in
Figure 5. This reaction mechanism is proposed on the basis of the reported isothiazole–thiazole

HETEROCYCLES, Vol. 81, No. 3, 2010
663
photoisomerization via an azirine (IM1) after the breakage of the S–N bond.5a The reaction may generate
Dewar benzisothiazole (IM2), isomerizes to azirine (IM1), and finally gives 2. This reaction may
proceeds stepwise from S1 of 1→IM2→IM1, or from S1 of 1 to IM3→IM2→IM1. Alternatively, this
reaction may proceeds directly from S1 of 1→IM1 by skipping some steps in the formation of IM1. In
addition, the step involving N−S bond dissociation is unclear, since there are no experimental data.
Recently, similar reaction mechanisms have been reported in the study of Sipos et al.5c There is a
possibility that this reaction proceeds through electrocyclic ring closure, and sigmatropic shift of sulfur
atom around the four sides of azetine ring (IM2, IM3, IM4).5b
N
N
N
N
R1
R1
R1
R1
h
N
N
N
N
S
S
S
S
R2
R2
R2
R2
IM1
IM2
S1 of 1
1
R1
n-Bu
R1
N
S
N
S
N
N
N
S
N
R2
R2
R2
IM4
IM5
R1
IM3
R1
N
S
N
N
S
N
R2
R2
2
3
Figure 5. Plausible mechanism of the photochemical isomerization of 1a, 1b, or 1c
Figure 6 indicates energetic aspect of this mechanism. The reaction initiates from a S1 of 1a, 1b, and 1c,
generated by UV irradiation. S1 state energies of 1a, 1b, and 1c calculated from the longest absorption
band maxima of UV absorption spectra are 68.1, 71.9, and 92.0 kcal mol–1 higher than the values
calculated for the corresponding ground-state reactants, respectively. The S1 of 1a, 1b, or 1c forms azirine
(IM1, 52.1, 60.3 and 39.8 kcal mol-1 for a, b, and c, respectively), or a Dewar-type isomer (IM2, 51.4,
61.6 and 41.3 kcal mol-1 for a, b, and c, respectively). Other isomeric intermediates (IM3-IM5) may not
be formed because they have higher energies than those of IM1 and IM2, and also S1 energies of 1a and
1b. Relative energy differences E of the corresponding reactant and product were 12.5, 12.1, and 23.1
kcal mol−1, for 1a-2a, 1b-2b, and 1c-2c, respectively, by DFT calculation (Figure 6) indicating these
reactions exothermic.
The effect of the nitro-group on the BIT→BT photoisomerization was considered. The yields of
isomerization of 3-piperadino-BIT to BT achieved are summarized in Table 1. BIT→BT

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HETEROCYCLES, Vol. 81, No. 3, 2010
photoisomerization yield of 1c was the highest (91%), and 1b was the lowest (46%). 1c has no
nitro-group as a substituent, and no absorption at the wavelength longer than 350 nm (Figure 7c).
Therefore, the S1 state of 1c is 92 kcal mol−1 above the ground state. In 1b, an introduction of a
nitro-group at 7-position of BIT brought a significant red-shift in the absorption spectra, and the tail
reached to 550 nm. The longest absorption maximum was 407 nm, and this corresponds to S1 of 1b,
located 71.9 kcal mol−1 higher than the ground state.
Figure 6. Relative energies calculated by DFT method for the reactant (1), product (2), and
intermediates (IM) considered in the photoisomerization
1c has no absorption longer than 350 nm. Calculated oscillator strength at 318 nm was 0.074, and this
transition is ascribed to HOMO→LUMO transition. In energy diagram of 1c, S1 locates much higher in

HETEROCYCLES, Vol. 81, No. 3, 2010
665
energy than other intermediates. However, once 1c generates azirine intermediate (IM1), it is difficult to
isomerize to IM3-5 by the reason of energetic requirement.
Compound 3 is another possible photoproduct. We have reported that an irradiation of
3-n-butylamino-5-nitrobenzisothiazole (1d) is the only case obtaining 3-type product
(3-amino-6-nitrobenzoisothiazole: 3e) through the isomerization to 3d and dealkylation giving 3e (Figure
7).9 This product 3d (N and S atom positions were inversed by the typical expecting product 2d) was not
isolable, and a control experiment showed 1e did not give 3e. This reaction is useful to introduce a
nitro-group to 6-position in the benzothiazole skeleton. However, we could not observe this type of
photoproducts from the photoreaction of 1a and 1b. Formation of 3d requires sulfur-atom migration
along the isothiazole ring (the second row, IM4, IM3, and IM5 in Figure 5) which is an energetically
unfavorable (endothermic) process (Figure 6). In the case of 1c, it is hard to exclude this reaction, because
3d corresponds to 2c in case of no nitro-substituent.
Figure 7. Photochemical reaction of 1d produced 3e through the photoreaction of 3d
Table 1 summarizes the substituents, isomerization yield, and the energy difference between the
singlet-excited state and the reaction intermediates in the BIT→BT isomerization. BIT→BT
isomerization yields increase with the increase in exothermicity from the singlet-excited state of the
reactant to the azirine IM1. Higher exothermicity (S1 of 1a and 1c to corresponding IM1) (52.2 and 16.0
kcal mol−1) leads to higher yields (91 and 87%, respectively), and lower exothermicity (11.6 kcal mol−1)
leads to a lower yield (46%). This may be explained by the Hammond’s hypothesis that higher
exothermic reaction requires smaller activation energy.
The electronic transitions of the ground state to low-lying eight singlet-excited states obtained by
TD-DFT method are shown in Table 2, and their energies and oscillator strengths are superimposed in the
absorption spectra (Figure 8). Figure 9 shows molecular orbitals involving in the transition. The longest
wavelength transition is predominantly ascribed to HOMO–LUMO transition (weight of HOMO–LUMO

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HETEROCYCLES, Vol. 81, No. 3, 2010
is nearly 70%). The transition energies appeared lower in energy than the observed absorption bands for
1a and 1b, but appeared in the same position for 1c. Transition in the higher energies of 1a and 1b are
mostly from occupied molecular orbitals (MO) lower than HOMO to LUMO. Molecular orbital analysis
showed that HOMO–LUMO transition of 1a-b has a charge-transfer (CT) character. HOMO mainly
localized at piperidino–nitrogen atom (N1’) and isothiazole moiety (S, N2, C3, and C9), and LUMO
localized at nitro moiety as seen in HOMO–LUMO in left and center column of Figure 9.
Table 1. Reaction yield and exothermicity from singlet excited state of reactant to intermediates
Reaction
R1 R2
2
ES1–EIM (kcal mol-1)
yield
87%
IM1
16.0
11.6
52.2
IM2
16.7
10.3
50.7
IM3
6.0
IM4
-17.0
-16.7
20.5
IM5
-16.2
-15.9
20.5
1a → 2a
1b → 2b
1c → 2c
NO2 H
H
H
NO2 46%
91%
0.1
H
39.6
Table 2. Electronic transition of ground state to singlet-excited state of 1a, 1b, and 1c calculated by
TD-DFT method.
f: oscillator
strength
Compounds
Main Transition
(MO #)
(69→70)
Weight of config.

max/nm
1a: 5NO2
Entry 1
HOMO →LUMO
HOMO-3 →LUMO
HOMO →LUMO+1
HOMO-1 →LUMO
HOMO-6 →LUMO
HOMO-2 →LUMO
HOMO →LUMO+2
HOMO-4 →LUMO
0.68
0.60
0.64
0.64
0.61
0.59
0.51
0.55
437
333
328
306
290
285
269
252
0.060
0.000
0.041
0.036
0.001
0.175
0.009
0.000
2
3
4
5
6
7
8
(66→70)
(69→71)
(68→70)
(63→70)
(67→70)
(69→72)
(65→70)
1b: 7NO2
Entry 1
HOMO →LUMO
HOMO-3 →LUMO
HOMO-1 →LUMO
HOMO-2 →LUMO
HOMO-6 →LUMO
HOMO →LUMO+1
HOMO-4 →LUMO
HOMO →LUMO+2
(69→70)
(66→70)
(68→70)
(67→70)
(63→70)
(69→71)
(65→70)
(69→72)
0.68
0.48
0.58
0.51
0.55
0.52
0.45
0.69
476
334
321
305
292
289
272
264
0.064
0.003
0.007
0.004
0.064
0.064
0.001
0.023
2
3
4
5
6
7
8
1c:
Entry 1
HOMO →LUMO
(58→59)
0.66
318
0.074
2
3
4
HOMO →LUMO+1
HOMO →LUMO+3
HOMO-1 →LUMO
(58→60)
(58→62)
(57→59)
0.55
0.37
0.42
275
269
255
0.023
0.024
0.008

HETEROCYCLES, Vol. 81, No. 3, 2010
667
5
6
7
8
HOMO-1 →LUMO
HOMO →LUMO+4
HOMO →LUMO+5
HOMO →LUMO+5
(57→59)
(58→63)
(58→64)
(58→64)
0.48
0.60
0.53
0.44
252
237
234
233
0.003
0.013
0.023
0.124
1.2
0.2
(a)
1.0
0.15
0.1
0.05
0
0.8
0.6
0.4
0.2
0.0
200
250
(b)
300
350
400
450
500
550
Wavelength / nm
0.8
0.07
0.06
0.05
0.04
0.03
0.02
0.01
0
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
200
250
(c)
300
350
400
450
500
550
Wavelength / nm
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
0.14
0.12
0.1
0.08
0.06
0.04
0.02
0
200
250
300
350
400
450
500
550
Wavelength / nm
Figure 8. Absorption spectra of (a) 1a, (b) 1b and (c) 1c in acetonitrile, and their oscillator strengths
calculated by TD-DFT method

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HETEROCYCLES, Vol. 81, No. 3, 2010
On the other hand, transitions of 1c are more complicated. Most transitions have a character from HOMO
to LUMO or MOs higher than LUMO (i.e. LUMO + n, n = 1, 3, or 5). The LUMO of 1c has the same
nature as LUMO + 1 of 1a and 1b (Figure 8). These LUMO + 1 and LUMO of 1c orbitals have an
anti-bonding -orbital character of the S–N bond of the isothiazole ring. Therefore, the isomerization may
proceed through these excitations and the following band dissociation of S-N. Characteristic transitions
having high oscillator strengths are HOMO–(LUMO +1) transition (those are entry 3 of 1a [328 nm] and
entry 6 of 1b [289 nm]), and the HOMO–LUMO transition of 1c. These transitions have an
intramolecular charge transfer nature from piperidino- to nitro-groups as mentioned above. No
isomerization was observed by the excitation of the longest absorption band of 1a and 1b. These results
were consistent with the above results, and the LUMO orbital is the origin of photo-inactiveness by
irradiation at longest wavelength absorption band. In photochemistry, upper excited state usually
undergoes internal deactivation to the lowest excited state known as Kasha’s rule. However,
photoisomerization of 1a and 1b may occur through higher excited state. The lifetime of this higher
excited state is expected to be very short. Therefore photoisomerization was unaffected by oxygen.
Figure 9. Molecular orbitals of 1a, 1b, and 1c obtained by TD-DFT B3LYP/6-31++G(d) method

HETEROCYCLES, Vol. 81, No. 3, 2010
669
In conclusion, we described in this paper the photochemical isomerization mechanisms of the parent,
5-nitro- and 7-nitro-substituted 3-piperidino-1,2-benzisothazole–benzothiazole derivatives on the basis of
experimental and DFT calculated investigations. These isomerizations proceeded from BIT to BT cleanly
one-way, and proceeded selectively through the singlet-excited state. In addition, excitation wavelength
effect demonstrates that isomerization occurs as a result of excitation to the upper excited state of
nitro-derivatives. The HOMO–LUMO transition of nitro-derivatives is inactive due to the charge-transfer
nature from piperidino nitrogen and isothiazole ring to the nitrobenzo moiety assigned by MOs. This
isomerization initiates from the excited states having dissociative S-N bond character (LUMO of parent,
and LUMO+1 of nitro-derivatives), and goes through an azirine intermediate.
EXPERIMENTAL
1
Instrumentation: H NMR and 13C NMR spectra were recorded on JEOL JNM-LA 400 and Bruker
AVANCE 300. Mass spectra (FAB or GC-MS) were recorded on a JEOL JMS-AX500 double focusing
mass spectrometer or Shimadzu PARVUM 2 GC-mass spectrometer. Elemental analysis was performed
on Parkin-Elmer 2400. GC analyses were performed on an FID-GC equipped with a 15 m × 3 m phenyl
silicon based capillary column. UV-Vis absorption spectra were recorded on a JASCO V570
spectrophotometer.
Irradiation procedure: 3-Piperidino-1,2-benzisothiazole derivatives were dissolved in MeCN or other
solvent used, the resulting solution was allowed into a quartz cuvette and purged by argon, then
irradiation was performed by a 1-kW high pressure mercury lamp or 400-W Xe-lamp using appropriate
glass filters.
Materials preparation:
2,2’-Dithiobis[5-nitrobenzoic acid]10: To a dry EtOH (50 mL) solution of 2-chloro-5-nitrobenzoic acid
(5.14 g, 25 mmol), potassium t-butoxide (2.89 g, 25.0 mmol) was added portion wise to the stirred
solution under nitrogen atmosphere at ambient temperature. Resulting mixture was added to dry EtOH
(25 mL), and refluxed for 15 min. A solution of sodium sulfide (9.31 g, 12.6 mmol) and sulfur (0.44 g,
13.8 mmol) in water (150 mL) was added slowly to the reaction vessel and resulting solution was
refluxed for 10 h. After cooling to room temperature, the reaction mixture was acidified to pH 3-4 with
hydrochloric acid. The resulting solids were collected by suction filtrations, washed with water, and dry
under vacuum to give 2,2’-dithiobis[5-nitrobenzoic acid], (4.31 g, 10.8 mmol, yield 87.0%) as pale
yellow powder.
1H NMR 400MHz (DMSO-d6), = 8.51 (1H, d, J = 2.7Hz, H4), 8.16 (1H, dd, J = 8.9, 2.7 Hz, H6), 7.67
(1H, d, J = 8.9, H7).
5-Nitro-1,2-benzoisothiazole-3(2H)-one10: A mixture of 2,2’-dithiobis[5-nitrobenzoic acid] (4.04 g, 10.0

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HETEROCYCLES, Vol. 81, No. 3, 2010
mmol), thionyl chloride (4.39 g, 59.3 mmol), and DMF (72 L) in CH2Cl2 (50 mL) was refluxed. Then,
evaporation of solvents gave crude oil. A mixture of the crude oil and bromine (2.0 mL, 38.9 mmol) in
CH2ClCH2Cl (50 mL) was stirred for 20 min at room temperature and then heated at reflux for 4 h. The
residue remaining after evaporation of solvent was dissolved in CH2ClCH2Cl (50 mL) at 0 °C in an ice
bath, and was added 25 % ammonium hydroxide (25 mL) to the reaction mixture at the same temperature.
The solution was stirred at 0 °C for 20 min and at ambient temperature for 16 h. After cooling to 0 °C, the
reaction mixture was acidified to pH 3-4 with hydrochloric acid. The resulting solids were collected by
suction
filtrations,
washed
with
water,
and
dried
under
vacuum
to
give
5-nitro-1,2-benzoisothiazole-3(2H)-one (3.62 g, 18.4 mmol, yield 92.3%) as pale yellow plates.
1H NMR 400MHz (DMSO-d6),  = 8.60 (1H, d, J = 2.0Hz, H4), 8.40 (1H, dd, J = 8.9, 2.0 Hz, H6), 8.28
(1H, d, J = 8.9, H7).
3-Methoxy-5-nitro-1,2-benzisothiazole10: 5-Nitro-1,2-benzoisothiazole-3(2H)one (1.02 g, 5.1 mmol)
was dissolved in dry DMF (15 mL). Potassium carbonate (1.07 g, 7.7 mmol) and then methyl iodide (1.7
mL, 25.9 mmol) was added to the stirred solution of 5-nitro-1,2-benzoisothiazole-3(2H)-one under
nitrogen atmosphere at room temperature and for the reaction mixture was stirred over night. The reaction
mixture was poured into ice-water (50 mL), and acidified to pH 3-4 with hydrochloric acid. The aqueous
mixture was extracted with three portions of 90 mL EtOAc, combined organic layer was washed with
water and brine, dried over Na2SO4, and evaporated to give the crude oil. Purification by chromatography
on silica gel eluting with CH2Cl2-hexane (1:1) to give 3-methoxy-5-nitro-1,2-benzisothiazole (421 mg,
yield 39.3%) as yellow powder.
1H NMR 400MHz (CDCl3),  = 8.79 (1H, d, J = 2.2Hz, H4), 8.37 (1H, dd, J = 8.9, 2.7 Hz, H6), 7.89 (1H,
d, J = 8.9, H7), 4.24 (3H, s, -OCH3). GC-MS m/z: 210.
3-Chloro-5-nitro-1,2-benzisothiazole10: A mixture of 3-methoxy-5-nitro-1,2-benzisothiazole (3.53 g,
17.7 mmol), phosphorus oxychloride (14 mL, 148 mmol), and tributylamine (4.3 mL, 17.3 mmol) are
stirred at 115 °C for 6 h, and ambient temperature for over night. The reaction mixture was poured into
ice-water (50 mL), and the aqueous mixture was extracted with three portions of 90 mL CH2Cl2.
Combined organic layer was washed with water and saturated aqueous NaHCO3, dried over anhydrous
Na2SO4, and evaporated, to give crude oil. Purification by chromatography on silica gel eluting with
CH2Cl2 to give 3-chloro-5-nitro-1,2-benzisothiazole, (3.10 g, yield 81.8%) as orange color plates.
1H NMR 400MHz (CDCl3),  = 8.93 (1H, d, J = 2.0Hz, H4), 8.47 (1H, dd, J = 8.9, 2.0 Hz, H6), 8.08 (1H,
dd, J = 8.9, 0.5 Hz, H7).
3-Chloro-1,2-benzisothiazole: 3-Chloro-1,2-benzisothiazole was prepared by a similar method with
3-chloro-5-nitro-1,2-benzisothiazole. Purification by distillation of brown oil (bp 95–98 °C /9 mmHg),

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gave the product (6.97 g, yield 46.4%) as colorless solid.
1H NMR 400MHz (CDCl3),  = 8.04 (1H, ddd, J = 8.1, 1.0, 1.0 Hz, H4), 7.92 (1H, ddd, J = 8.3, 1.0, 1.0
Hz, H7), 7.61 (1H, ddd, J = 8.3, 7.1, 1.0 Hz, H6), 7.53 (1H, ddd, J = 8.1, 7.1, 1.0 Hz, H5).
3-Chloro-7-nitro-1,2-benzisothiazole: A mixture of 3-chloro-1,2-benzisothiazole (2.26 g, 13.3 mmol)
dissolved in 96% sulfuric acid (8 mL) was cooled over ice-water bath. Finely powdered potassium nitrate
(1.23 g, 12.2 mmol) dissolved in 96% sulfuric acid (4 mL) was slowly added portion wise to the stirred
solution of 3-chloro-1,2-benzisothiazole at 0 °C and kept at 0 °C with stirring for 3 h. Resulting mixture
was poured into ice cold water (150 mL). The resulting solids were collected by suction filtration, washed
with water, and dried under vacuum. Purification by chromatography on silica gel eluting with
CHCl3–hexane (7:3) to give 3-chloro-7-nitro-1,2-benzisothiazole (429 mg, yield 15.0%) as pale yellow
powder.
1H NMR 400MHz (CDCl3),  =8 .59 (1H, dd, J = 7.9Hz, H6), 8.40 (1H, dd, J = 5.8 Hz, H4), 7.77 (1H, dd,
J = 7.9 Hz, H5). GC-MS m/z 263.
5-Nitro-3-piperidino-1,2-benzisothiazole (1a)9: A mixture of piperidine (6.00 mL, 101 mmol) and
3-chloro-5-nitro-1,2-benzisothiazole (310 mg, 1.40 mmol) was refluxed with stirring for overnight, and
excess piperidine was evaporated off, to give a crude oil. The mixture was partitioned between CH2Cl2
(30 mL) and water (30 mL), the aqueous layer was extracted with CH2Cl2 (2 × 30 mL), and the combined
organic layers were washed with water (20 mL), dried over anhydrous Na2SO4, and evaporated, to give
the crude oil. Purification by chromatography on silica gel eluting with CHCl3, and crystallization from
CH2Cl2–hexane to give 1a (121 mg, yield 32.8%) as orange color plates.
1H NMR 400MHz (CDCl3),  =8.79 (1H, d, J = 2.4 Hz, H4), 8.30 (1H, dd, J = 9.0, 2.0 Hz, H6), 7.89 (1H,
d, J = 9.0 Hz, H7), 3.53 (4H, t, J = 5.4 Hz, -NCH2-), 1.86-1.84 (4H, m, -CH2-), 1.72-1.65 (2H, m, -CH2-).
GC-MS m/z: 263. Anal. Calcd for C12H13N3O2S: C, 54.74; H, 4.98; N, 15.96. Found: C, 54.56; H, 4.83; N,
16.03.
3-Piperidino-1,2-benzisothiazole (1c)9: 1c was prepared according to a similar method to prepare 1a.
Purification by chromatography on silica gel eluting with hexane–EtOAc (9:1) to give 1c (456 mg, yield
70.8%) as colorless oil.
1H NMR 400MHz (CDCl3),  = 7.91 (1H, dd, J = 8.0, 1.0 Hz, H4), 7.80 (1H, dd, J = 8.3, 1.0 Hz, H7),
7.46 (1H, td, J = 8.3, 1.0 Hz, H6), 7.35 (1H, td, J = 8.0, 1.0 Hz, H5), 3.49-3.46 (4H, t, J = 5.5 Hz,
-NCH2-), 1.83-1.76 (4H, m, -CH2-), 1.72-1.65 (2H, m, -CH2-). GC-MS m/z: 218. Anal. Calcd for
C12H14N2S: C, 66.02; H, 6.46; N, 12.83. Found: C, 66.33; H, 6.21; N, 13.08.
7-Nitro-3-piperidino-1,2-benzisothiazole (1b)9: 1b was prepared by a similar method to prepare 1a.
Purification by silica gel chromatography eluting with CHCl3 and by crystallization from EtOH gave 1b

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(58.5 mg, yield 49.4%) as red crystals.
1H NMR 400MHz (CDCl3),  = 8.46 (1H, dd, J = 7.1Hz, H6), 8.25 (1H, dd, J = 7.1Hz, H4), 7.56 (1H, t, J
= 7.9, H5), 3.49 (4H, t, J = 5.7 Hz, -NCH2-), 1.67-1.84 (6H, m, -CH2-). GC-MS m/z: 263. Anal. Calcd for
C12H13N3O2S: C, 54.74; H, 4.98; N, 15.96. Found: C, 54.64; H, 4.88; N, 15.98.
5-Nitro-3-piperidino-1,3-benzthiazole (2a)9: A mixture of piperidine (4.0 mL, 68 mmol) and
2-chloro-5-nitro-1,3-benzothiazole (420 mg, 1.90 mmol) was refluxed with stir for 2 h, and excess
piperidine was evaporated to give crude oil. The mixture was partitioned between CH2Cl2 (30 mL) and
water (30 mL), the aqueous layer was extracted with CH2Cl2 (30 mL), and the combined organic layers
were washed with water (20mL), dried over anhydrous Na2SO4, and evaporated, to give the crude yellow
solid. Purification by chromatography on silica gel eluting with CHCl3 to give 2a (408 mg, yield 81.5%)
as yellow plates.
1H NMR 400MHz (CDCl3), = 8.31 (1H, d, J = 2.2 Hz, H4), 7.91 (1H, dd, J = 8.6, 2.2 Hz, H6), 7.65 (1H,
d, J = 8.6 Hz, H7), 3.65 (4H, m, -NCH2-), 1.73 (6H, m, -CH2-). GC-MS m/z: 263. Anal. Calcd for
C12H13N3O2S: C, 54.74; H, 4.98; N, 15.96. Found: C, 54.66; H, 4.88; N, 15.75.
3-Piperidino-1,3-benzthiazole (2c)9: A mixture of piperidine (1.06 g, 21.5 mmol) and sodium
bicarbonate (2.10 g, 25.0 mmol) in 2-propanol (88 mL) was refluxed with stirring for 1 h. A solution of
2-chloro-1,3-benzothiazole (1.06 g, 6.25 mmol) in 2-propanol (5.0 mL) was added slowly into the stirred
solution at ambient temperature. The mixture was refluxed for 24 h. The excess piperidine was removed
by evaporation, to give a crude oil. The mixture was partitioned between CH2Cl2 (30 mL) and water (30
mL), the aqueous layer was extracted with CH2Cl2 (30 mL), and the combined organic layers were
washed with water (20 mL), dried over anhydrous Na2SO4, and evaporated, to give the crude yellow solid.
Purification by crystallization from CH2Cl2 / hexane gave 2c (866 mg, yield 63.5%) as pale yellow plates.
1H NMR 400MHz (CDCl3), = 7.58 (1H, dd, J = 8.0, 1.0 Hz, H4), 7.53 (1H, dd, J = 8.0, 1.0 Hz, H7),
7.27 (1H, ddd, J = 8.0, 8.0, 1.0 Hz, H6), 7.04 (1H, ddd, J = 8.0, 8.0, 1.0 Hz, H5), 3.61-3.59 (4H, m,
-NCH2-), 1.71-1.69 (6H, m, -CH2-). GC-MS m/z: 218. Anal. Calcd for C12H14N2S: C, 66.02; H, 6.46; N,
12.83. Found: C, 65.98; H, 6.28; N, 12.94.
7-Nitro-3-piperidino-1,3-benzthiazole (2b): A solution of 1b in MeCN (3 mL, 3.9 × 10-4 M) under
argon was exposed to a low pressure mercury lamp (254 nm) for 24 h, giving the product with
quantitative yield. Purification by crystallization from CHCl3, gave 2b (yield 46%) as colorless powder.
1H NMR 400MHz (CDCl3), = 8.02 (1H, dd, J = 11.0, 1.1 Hz, H4), 7.78 (1H, dd, J = 11.0, 1.1 Hz, H6),
7.41 (1H, dd, J = 11.0, 11.0 Hz, H5), 3.93-3.65 (4H, m, -NCH2-), 1.76-1.68 (6H, m, -CH2-). GC-MS m/z:
263.
Computational method: Quantum chemical calculations were performed for all examined

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673
2-piperidino-1,2-benzisothiazoles, 1,3-benzothiazoles, and intermediates. Molecular geometries were
fully optimized by using density functional theory (DFT) with standard B3LYP functional and 6-31G*
basis set, applying the Spartan-’06 Win.11 All the calculations were performed for the compounds with
absolute configuration. The ground states geometries optimized in this manner gave relative energies of
the compounds. Excited-state energies, oscillator strengths of the transitions, and molecular orbitals
including frontier orbitals (HOMO-LUMO) were obtained by using time-dependent DFT (TD-DFT)
method by Gaussian’03 Rev. B.0.3 suite12 of programs using 6-31++G(d) basis set.
ACKNOWLEDGEMENTS
The authors thank Analytical Center of Chiba University for her assistance of characterization of the
compounds. This research project was financially supported by Grants-in-Aid for Scientific Research (No.
20550056) from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT).
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