Facile synthesis of 2-substituted 4H-1,3-thiazines and 3-substituted 1,2-isothiazoles VIA benzyne intermediates

Article abstract of DOI:10.3987/COM-05-10414

Substituted 2-dialkylamino-4H-1,3-benzothiazines were Synthesizedby the reaction of (phenyl)[o-(trimethylsilyl)aryl]iodonium triflates and dialkyl-aminothiazadienes in the presence of 1.5 equivalent of Bu₄NF. However, when these reactions were carried out in the presence of 4 equivalents of Bu₄NF, 3-substituted 1,2-benzisothiazoles were obtained. Additionally, the reaction of phenyl[(3-trimethylsilyl)-2-naphthyl]iodonium triflate with dialkylaminothia-zadienes in the presence of Bu₄NF gave 3-substituted 1,2-naphthisothiazoles. A possible mechanism for the latter reaction involving the trapping of a benzyne intermediate with a nitrile sulfide generated in situ by the reaction of dialkylaminothiazadiene, fluoride ion and trimethylsilyl fluoride is proposed.

Full text of DOI:10.3987/COM-05-10414

HETEROCYCLES, Vol. 65, No. 7, 2005
1615
HETEROCYCLES, Vol. 65, No. 7, 2005, pp. 1615 - 1627
Received, 31st March, 2005, Accepted, 27th April, 2005, Published online, 28th April, 2005
FACILE SYNTHESIS OF 2-SUBSTITUTED 4H-
1,3-THIAZINES AND 3-SUBSTITUTED 1,2-ISO-
THIAZOLES VIA BENZYNE INTERMEDIATES
a
a
b
Ramadas Sathunuru, Hongming Zhang, Charles W. Rees, and
*
a
Edward Biehl
a
Department of Chemistry, Southern Methodist University, Dallas, TX
7
5275, U.S.A. ebiehl@smu.edu.
b
Department of Chemistry, Imperial College London, SW7 2AZ, UK
Communicating author: ebiehl@smu.edu
*
ꢀ
Abstract – Substituted 2-dialkylamino-4H-1,3-benzothiazines were
Synthesizedby the reaction of (phenyl)[o-(trimethylsilyl)aryl]iodonium
triflates and dialkyl-aminothiazadienes in the presence of 1.5 equivalent
ꢀ
of Bu NF. However, when these reactions were carried out in the presence
4
of 4equivalents of Bu NF, 3-substituted 1,2-benzisothiazoles were obtained.
4
Additionally, the reaction of phenyl[(3-trimethylsilyl)-2-naphthyl]iodo-
nium triflate with dialkylaminothia-zadienes in the presence of Bu NF gave
4
3-substituted 1,2-naphthisothiazoles. A!possible mechaism for the
latter reaction involving the trapping of a benzyne intermediate with a
nitrile sulfide generated in situ by the reaction of dialkylaminothiazadiene,
fluoride ion and trimethylsilyl fluoride is proposed.
INTRODUCTION
Although 1,3-thiazines and isothiazoles show a wide range of biological activity, the synthetic and
1
–7
8–10
1
1–14
biological chemistry of 1,3-benzothiazine and benzisothiazole nuclei are relatively unexplored.
Thus,
there is much interest in developing efficient methods for their synthesis. In this regard, we recently

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HETEROCYCLES, Vol. 65, No. 7, 2005
reported the preparation of a series of 4H-naphtho[2,3-e]-1,3-selenazines by the reaction of benzynes
1
5
with selenoazadienes. We also substituted the selenium atom in certain selenazines with sulfur and
found that the resulting dialkylaminothiazadienes reacted with 2,3-naphthalyne to give 1,3-
1
5
naphthothiazines. We have expanded this synthesis to the preparation of 4H-1,3-benzothiazines and
report the results here. In addition, we report a novel synthesis of benzo- and naphthoisothiazoles,
unexpectedly discovered during this work, and suggest a possible explanation for their formation.
RESULTS AND DISCUSSION
Synthesis of 2-Amino-4H-1,3-benzothiazines (4a-i). The required (phenyl)[o-trimethylsilyl-
1
6
aryl]iodonium triflates (1a-d) were prepared from substituted dichlorobenzenes
while the
aminothiazadienes (3a-f) were on hand from a previous study. The generation of benzynes (2a-d) were
initially carried out by adding Bu NF (1.5 equivalents) to a solution of the precursors (1a-d) at 0 °C in
1
5
4
the presence of the dialkylaminothiazadienes. As shown in Scheme 1, the aminothiazadienes (3a–f)
reacted with 2a–d to give 2-amino-4H-1,3-benzothiazenes (4a-i) in 80-95% yields, which are shown in
Table 1.
R1
R5
R1
R1
R5
R2
R3
S
N
R2
R3
SiMe3
Bu NF (1.5 equiv.)
R6
R2
R3
S
4
N
+
R6
N
•
N
CH Cl , 0 C, 1 h
2
2
R4
a–d
OTf
I-Ph
R4
a–d
NMe2
a–f
R4
2
4a–i
3
1
1
2
3
4
1
2
3
4
5
6
a) R = R = R = H, R = OMe
a) R =R = R = H, R = OMe, R + R = CH CH CH CH
2
2
2
2
1
2
3
4
1
2
3
4
5
6
b) R = R = R = R = H
b) R = R = R = R = H, R + R = CH CH CH CH
2 2 2 2
1
4
2
3
1
2
3
4
5
6
c) R = R = H, R = R = OMe
c) R = R = R = R = H, R = R = i-Pr
1
4
2
3
1
2
3
4
5
6
d) R = R = H, R = R = OMe
d) R = R = R = R = H, R + R = CH CH OCH CH
2 2 2 2
1
2
3
4
5
6
e) R = R = R = R = H, R = R = Et
1
2
3
4
5
6
f) R = R = R = R = H, R = R = Me
2
3
1
4
5
6
g) R = R = H, R = R = OMe, R = R = Me
2
3
1
4
5
6
h) R =R = H, R = R = OMe, R +R = CH CH CH CH
2
2
2
2
1
4
2
3
5
6
i) R = R = H, R = R = OMe, R + R = M
Scheme 1
1
13
Compounds (4a–i) were identified on the basis of H NMR and C NMR spectroscopy. The structure of
2
-(pyrrolidin-1-yl)-5-methoxy-4H-benzo[e][1,3]thiazine (4a) (entry 1) was also confirmed by X-Ray

HETEROCYCLES, Vol. 65, No. 7, 2005
1617
crystallographic analysis; an ORTEP drawing for 4a is shown in Figure 1. This unexpected product
suggests that the aminothiazadiene (3a) added regioselectively to ultimately give 4a as shown in Figure
Table 1. Preparation of 4a-i
1
2
3
4
5
6
entry
1
4
a
R
R
R
R
R
R
Yield, %
94
H
H
H
OMe
CH CH CH CH
2 2 2
2
2
3
4
5
6
7
8
9
b
c
d
e
f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH CH CH CH
91
83
89
94
80
95
91
89
2
2
2
2
i-Pr
i-Pr
H
H
CH CH OCH CH
2
2
2
2
H
H
Et
Et
H
H
Me
Me
Me
Me
g
h
i
OMe
OMe
H
OMe
OMe
H
CH CH CH CH
2
2
2
2
OMe OMe
Me
Me
Figure 1 ORTEP of Compound (4a)
1
2
suggests that the aminothiazadiene (3a) added regioselectively to ultimately give 4a as shown in Figure
. None of the 8-methoxy regioisomer was detected. The preferred addition of the sulfur atom in 3a to
1
7
the 3-position of 1a is in accord with the strong meta directing effect of methoxy in aryne reactions. It

1618
HETEROCYCLES, Vol. 65, No. 7, 2005
also indicates (as shown in Figure 2) that the formation of the powerfully nucleophilic sulfur atom of the
thiocarbonyl group in 3a occurs! ahead of that of the carbon of the C=N resulting in some charge
d-
S
N
d-
OMe
N
NMe2
d+
Figure 2 A possible transition state for the cycloaddition of 2a and aminothiazadiene (3a)
build up and indicating that the [4+2] process is probably not completely concerted. A possible
explanation for the preparation of 4a is shown in Scheme 2. Accordingly, the initial hetero-Diels-Alder
reaction would give the adduct (5) which could afford the adduct (6) by a retro-ene reaction. A final 1,3-
H shift would then give the more stable thiazine (4a). We are investigating the mechanism of these
intriguing reactions.
S
N
S
N
S
H
N
H
_
N
H
4a
N
N
CH2
OMe
H
N
NMe2
MeO
MeO
Me
6
5
Scheme 2
Synthesis of Benzisothiazoles.
During this investigation, we made another remarkable and unexpected discovery. When 4 equivalents
of Bu NF was added to the reaction mixture of 1b and 3 rather than the previous 1.5 equivalents, under
4
the same very mild conditions (DCM, 0 °C, 1 h), the reaction took an entirely different course. As shown
in Scheme 3, instead of producing the benzothiazines (4) , it gave the benzisothiazoles (7a–f) in high
yields, which are shown in Table 2.
R
S
SiMe3
S
N
N
Bu NF (4 equiv.)
4
N
+
R1
N
o
CH Cl , 0 C, 1 h
2
2
I+
Ph OTf
NMe2
3a-f
R1
R
1b
7a-f
Scheme 3

HETEROCYCLES, Vol. 65, No. 7, 2005
1619
Table 2. Preparation of Compounds (7a–f)
7
a
b
c
Benzisothiazoles
Yield, %
1
R + R = CH CH CH CH
90
86
94
2
2
2
2
1
R = R = i-Pr
1
R + R = CH CH OCH CH
2
2
2
2
1
d
e
f
R = R = Et
93
91
85
1
R = R = Me
1
R + R = CH CH CH CH CH
2
2
2
2
2
Similarly, phenyl[3-trimethylsilyl-2-naphthyl]iodonium triflate (1e) reacted with 3a–f to give
naphthisothiazoles (8a–f) in 81-96% yields (see Scheme 4). The results are given in Table 3.
NRR1
R
SiMe3
S
N
Bu NF (4 equiv.)
4
N
+
R1
N
o
S
CH Cl , 0 C, 1 h
2
2
I Ph OTf
NMe2
8a-f
3
a-f
Scheme 4
Table 3. Preparation of Compounds (8a–f)
8
a
b
c
d
e
f
Naphthisothiazoles
Yield, %
1
R + R = CH CH CH CH
82
92
94
88
81
96
2
2
2
2
1
R = R = i-Pr
1
R + R = CH CH OCH CH
2
2
2
2
1
R = R = Et
1
R = R = Me
1
R + R =CH CH CH CH CH
2
2
2
2
2
1
13
The structures of 7 and 8 were determined by H NMR and C NMR spectroscopy and in the case of 8f
by X-Ray crystallography; an ORTEP of 8f is shown in Figure 3.
Our immediate thought was that the excess of Bu NF might be converting the 1,3-benzothiazines (4) into
4
the benzisothiazoles (7). However, isothiazole (7a) was not detected after treating thiazine (4b) with 4
equivalents of Bu NF under the same conditions. Furthermore, Bu NF does not react with the
4
4

1620
HETEROCYCLES, Vol. 65, No. 7, 2005
aminothiazadienes (3a) even after stirring at 45 °C overnight.
Figure 3 ORTEP of Compound (8f)
An explanation of the striking effect of Bu NF concentration on the reaction pathway could be as follows.
4
As shown in Scheme 5, with the higher concentration of fluoride ion, and the resulting generation of
SiMe3
Bu NF (4 equiv.)
4
-
- PhI
- OTf
I+
Ph OTf
I+ Ph OTf
-
Me SiF
3
2b
9
10
1
b
Me3
Si
S
F / Me SiF
S
3
F
R N
N
NMe2
2
R N
2
NMe2
H
N
3
1
1
F
S
Me Si
3
R N
+
Me
3
SiF + Me
2
N-CH
2
Me N
H
2
N
1
2
1
3
+
Me N=CH
2
N S
O
O
14
D
R N
2
R N-C
N
S
2
1
7
1
5
2
b
NR2
N
S
7
Scheme 5

HETEROCYCLES, Vol. 65, No. 7, 2005
1621
Me SiF (9) from 1b occurring more rapidly, there is a possibility of reaction between the dialkyl-
3
aminothiazadienes (3) with fluoride ion and Me SiF (9) to form an adduct (11) . This could result in the
3
cleavage of 3 generating fluoro(dimethylamino)(trimethylsilyl)methane (13) and the thiazirine (12),
which rapidly rearranges to nitrile sulfide (15) and subsequently traps benzyne (2b) as it is formed from
the arene anion (10). With the lower concentration of Bu NF the rate of reaction of 3 with fluoride ion
4
and 9 will be reduced and the benzyne generated will be intercepted by the highly nucleophilic reactant
(
3) acting as a Diels-Alder diene, as shown previously in Scheme 2.
Interestingly, substituted thiazirines like 12 have been proposed before, particularly as intermediates in
the extrusion of N , CO , etc. from 5-membered heterocyclic rings (e.g., 17 shown in Scheme 5), on their
2
2
1
8
way to nitrile sulfides. Furthermore, dimethylaminonitrile sulfide (15, R = Me) itself has been generated
by thermolysis of 5-dimethylamino-1,3,4-oxathiazol-2-one (17, R = Me) and trapped by cycloaddition to
1
9
an electron-deficient cyanide.
In summary, a novel approach to substituted 2-amino-4H-1,3-benzothiazines and 3-aminobenzoiso-
thiazoles was successfully achieved by a direct one-pot reaction of (phenyl)[o-trimethylsilylaryl]-
iodonium triflates with aminothiazadienes. The 1,3-benzothiazines were obtained in high yields when 1.5
equivalents of Bu NF was used. However, the isothiazoles were obtained in excellent yields when the
4
reactions were carried out with 4 equivalents of Bu NF; if our mechanism is correct, this is, to the best of
4
our knowledge, the first reported cycloaddition of a nitrile sulfide to a benzyne.
EXPERIMENTAL
General Data. Melting points were taken on a Mel-Temp capillary apparatus and are uncorrected with
1
13
respect to stem exposure. H NMR and C NMR spectra were recorded on a 400 MHz Bruker AVANCE
DRX-400 Multi-nuclear NMR spectrometer. Chemical shifts are reported in reference to TMS as internal
standard. Elemental analyses were carried out in the SMU Analytical Laboratory. The glassware was
°
heated overnight in an oven at 125 C prior to use. All the reactions were done under an atmosphere of
dry O –free Ar via balloon. Column chromatography refers to flash chromatography performed on Merck
2
silica gel 60, 230–400 mesh.
General Procedure for the Synthesis of 2-Substituted 4H-Benzo[1,3]thiazines (4a–f). A solution of
Bu NF in THF (0.84 mL of a 1 M solution) was added to a solution containing the aryne precursor (1a-d)
4
(
0.56 mmol), and the aminothiazadiene (3a–f) (0.84 mmol) in CH Cl (15 mL) at 0 °C and stirred at this
2 2
temperature for 1 h. The reaction mixture was then quenched with H O and the resulting mixture was
2
extracted with 3 X 20 mL portions of CH Cl . The combined extracts were dried (Na SO ) and evaporated
2
2
2
4
under reduced pressure. The crude product was then purified by column chromatography using
hexanes–ethyl acetate mixtures (9:1 to 5:5, respectively) as eluents. The physical and spectral properties

1622
HETEROCYCLES, Vol. 65, No. 7, 2005
of 4a–f are shown below.
2
-(Pyrrolidin-1-yl)-5-methoxy-4H-benzo[e][1,3]thiazine (4a) was obtained as a colorless solid, mp
°
1
1
42 C (CHCl /hexanes) in 94% yield (132 mg). H NMR (400 MHz, CDCl ) d 1.76 (4H, m, 2xCH ), 3.54
3 3 2
(
4H, m, CH NCH ), 3.84 (3H, s, 5-OCH ), 4.51 (2H, s, 4-CH ), 6.41 (1 H, d, J =8 Hz, 6-H), 6.92 (1H, d J
2
2
3
2
1
3
=
7 Hz, 7-H), 7.17–7.20 (1H, m, 8-H). C NMR (100 MHz, CDCl ) d 25.3 (2 x CH ), 49.5 (CH NCH ),
3
2
2
2
5
1
2
3.8 (CH C ), 56.1 (5-OCH ), 125.1 (C ), 126.3 (C ), 128.7 (C ), 131.3 (C ), 134.2 (C ), 155.6 (C ),
2 4 3 4a 5 6 7 8 8a
56.8 (C ). Anal. Calcd for C H N OS: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.84; H, 6.42; N, 11.23.
2
13 16
2
°
-(Pyrrolidin-1-yl)-4H-benzo[e][1,3]thiazine (4b) was obtained as a colorless solid, mp 120 C
1
(
CHCl /hexanes), in 91% yield (124 mg). H NMR (400 MHz, CDCl ) d 1.93 (4H, m, 2 x CH ),
3
3
2
3
.52–3.56 (4H, m, CH NCH ), 4.55 (2H, s, 4-CH ), 7.41 (2H, m, 5-H, 8-H), 7.86–7.89 (2H, m, 6-H, 7-H).
2 2 2
1
3
C NMR (100 MHz, CDCl ) d 25.7 (2 x CH ), 46.3 (-NCH ), 48.8 (-NCH ), 52.4 (CH C ), 109.5 (C ),
3
2
2
2
2
4
4a
1
6
2
19.7 (C ), 123.6 (C ), 127.8 (C ), 133.2 (C ), 154.8 (C ), 156.4 (C ). Anal. Calcd for C H N S: C,
5 6 7 8 8a 2 12 14 2
6.02; H, 6.46; N, 12.83. Found: C, 66.15; H, 6.51; N, 12.87.
°
-Diisopropylamino-4H-benzo[e][1,3]thiazine (4c) was obtained as a light brown solid, mp 134 C
1
(
CHCl /hexanes), in 83% yield (145 mg). H NMR (400 MHz, CDCl ) d 1.33 (12H, t, J = 5 Hz, 4 x CH ),
3
3
3
1
3
4
.05 (2 H, m, 2 x NCH), 4.21 (2H, s, 4-CH ), 7.45–7.48 (2H, m, 5-H, 8-H), 7.85 (2 H, m, 6-H, 7-H). C
2
NMR (100 MHz, CDCl ) d 21.5 (2 x CH ), 22.7 (2 x CH ), 48.4 (NCH), 51.2 (NCH), 53.5 (CH C ),
3
3
3
2
4
1
21.5 (C ), 122.3 (C ), 124.7 (C ), 125.3 (C ), 133.21 (C ), 154.1 (C ), 159.3 (C ). Anal. Calcd for
4a 5 6 7 8 8a 2
C H N S: C, 67.70; H, 8.12; N, 11.28. Found: C, 67.66; H, 8.05; N, 11.19.
1
4
20
2
°
2
-(Morpholin-4-yl)-4H-benzo[e][1,3]thiazine (4d) was obtained as a colorless solid, mp 128 C
1
(
CHCl /hexanes), in 89% yield (250 mg). H NMR (400 MHz, CDCl ) d 3.56–3.60 (4H, m, CH OCH ),
3
3
2
2
1
3
3
.71 (4H, m, CH NCH ), 4.15 (2H, s, 4-CH ), 7.50 (2H, m, 5-H, 8-H), 7.85 (2H, m, 6-H, 7-H). C NMR
2 2 2
(
100 MHz, CDCl ) d 47.2 (CH OCH ), 52.7 (CH NCH ), 66.8 (CH C ), 122.5 (C ), 125.0 (C ), 125.6
3 2 2 2 2 2 4 4a 5
(
C ), 127.9 (C ), 128.4 (C ), 151.7 (C ), 163.3 (C ). Anal. Calcd for C H N OS: C, 61.51; H, 6.02; N,
6 7 8 8a 2 12 14 2
1
1.96. Found: C, 61.57; H, 6.09; N, 11.91.
-Diethylamino-4H-benzo[e][1,3]thiazine (4e) was obtained as a colorless liquid in 94% yield (135 mg).
2
1
H NMR (400 MHz, CDCl ) d 1.28 (6 H, t, J = 6 Hz, 2 x CH ), 3.57 (4H, q, J = 6.0 Hz, CH NCH ), 4.31
3
3
2
2
1
3
(
2H, s, 4-CH ), 7.25 (2H, m, 5-H, 8-H), 7.45–7.49 (2H, m, 6-H, 7-H); C NMR (100 MHz, CDCl ) d
2 3
1
3.91 (2 x CH ), 43.3 (CH NCH ), 56.6 (CH C ), 125.4 (C ), 125.4 (C ), 126.9 (C ), 127.7 (C ), 132.1
3 2 2 2 4 4a 5 6 7
(
C ), 135.4 (C ), 158.2 (C ). Anal. Calcd for C H N S: C, 65.41; H, 7.32; N, 12.71. Found: C, 65.38; H,
8 8a 2 12 16 2
7
2
.36; N, 12.69.
o
-Dimethylamino-4H-benzo[e][1,3]thiazine (4f) was obtained as a brown solid, mp 74–76 C
1
(
CHCl /hexanes), in 80% yield (118 mg). H NMR (400 MHz, CDCl ) d 3.18 (6H, s, CH NCH ), 4.23
3
3
3
3

HETEROCYCLES, Vol. 65, No. 7, 2005
1623
1
3
(
2H, s, 4-CH ), 7.39 (2H, dd J = 6.3 Hz, 3.1 Hz, 5-H, 8-H), 7.85–7.89 (2H, m, 6-H, 7-H); C NMR (100
2
MHz, CDCl ) d 41.2 (CH NCH ), 57.2 (CH C ), 122.6 (C ), 125.1 (C ), 125.9 (C ), 127.5 (C ), 128.2
3
3
3
2
4
4a
5
6
7
(
C ), 138.3 (C ), 159.4 (C ). Anal. Calcd for C H N S: C, 62.46; H, 6.29; N, 14.57. Found: C, 62.47; H,
8 8a 2 10 12 2
6
2
9
.32; N, 14.59.
-Dimethylamino-5, 8-dimethoxy-4H-benzo[e][1,3]thiazine (4g) was obtained as a light red liquid in
1
5% yield (126 mg). H NMR (400 MHz, CDCl ) d 3.28 (6H, s, CH NCH ), 3.77 (3H, s, 5-OCH ), 3.45
3
3
3
3
1
3
(
3H, s, 8-OCH ), 4.50 (2H, s, 4-CH ), 6.69 (1H, d, J = 8.0 Hz, 6-H), 6.82 (1H, d, J = 8.0 Hz, 7-H). C
3 2
NMR (100 MHz, CDCl ) d 41.3 (CH NCH ), 54.2 (5-OCH ), 55.5 (8-OCH ), 62.2 (CH C ), 109.4 (C ),
3
3
3
3
3
2
4
4a
1
5
2
1
10.1 (C ), 118.8 (C ), 123.6 (C ), 148.8 (C ), 150.3 (C ), 155.2 (C ). Anal. Calcd for C H N O S: C,
5 6 7 8 8a 2 12 16 2 2
7.12; H, 6.39;N, 11.10. Found: C, 57.09; H, 6.33; N, 11.07.
-(Pyrrolidin-1-yl)-5,8-dimethoxy-4H-benzo[e][1,3]thiazine (4h) was obtained as a colorless solid, mp
°
1
26–127 C (CHCl /hexanes), in 91% yield (106 mg). H NMR (400 MHz, CDCl ) d 1.94 (4 H, m, 2 x
3
3
CH ), 3.48–3.51 (4 H, m, CH NCH ), 3.79 (3 H, s, 5-OCH ), 3.83 (3H, s, 8-OCH ), 4.47 (2 H, s, 4-CH ),
2
2
2
3
3
2
1
3
6
4
.73 (1 H, d, J = 8Hz, 6-H), 6.81 (1 H, d, J = 8Hz, 7-H). C NMR (100 MHz, CDCl ) d 25.1 (2 x CH ),
3
2
8.5 (-NCH ), 48.9 (NCH ), 57.1 (5-OCH ), 57.2 (8-OCH ), 64.8 (CH C ), 109.4 (C ), 110.2 (C ), 118.4
2
2
3
3
2
4
4a
5
(
C ), 125.6 (C ), 149.7 (C ), 152.2 (C ), 154.8 (C ). Anal. Calcd for C H N O S: C, 60.41; H, 6.52; N,
6 7 8 8a 2 14 18 2 2
1
6
1
3
0.06. Found: C, 60.45; H, 6.47; N, 10.11.
, 7-Dimethoxy-2-dimethylamino-4H-benzo[e][1,3]thiazine (4i) was obtained as colorless solid, mp
°
1
35 C (CHCl /hexanes), in 89% yield (129 mg). H NMR (400 MHz, CDCl ) d 1.58 (6H, s, CH NCH ),
3
3
3
3
1
3
.67 (3H, s, 6-OCH ), 3.72 (3H, s, 7-OCH ), 4.53 (2H, s, 4-CH ), 7.22 (1H, s, 5-H), 7.34 (1H, s, 8-H); C
3
3
2
NMR (100 MHz, CDCl ) d 40.6 (CH NCH ), 54.8 (6-OCH ), 55.4 (7-OCH ), 61.7 (CH C ), 110.1 (C ),
3
3
3
3
3
2
4
4a
1
5
11.4 (C ), 119.7 (C ), 124.9 (C ), 147.9 (C ), 151.3 (C ), 156.2 (C ). Anal. Calcd for C H N O S: C,
5 6 7 8 8a 2 12 16 2 2
7.12; H, 6.39; N, 11.10. Found: C, 57.09; H, 6.37; N, 11.06.
General Procedure for the Preparation of 3-Substituted 1,2-Benzisothiazoles (7a-f). To a solution of
(0.59 mmol) and 3 (0.84 mmol) in CH Cl (15 mL) was added a THF solution of Bu NF (1M, 2.39 mL)
1
2
2
4
0
°
at 0 C. After 1 h of stirring at 0 C, 40 mL of water was added and the resulting medium was allowed to
warm to rt. After extraction with CH Cl and washing with water, the combined organic phases were
2
2
dried (Na SO ) and evaporated under reduced pressure. The crude product was then purified by column
2
4
chromatography on silica gel using hexane–ethyl acetate (9:1 to 5:5, respectively) mixtures as eluents.
The physical and spectral properties of 7a-f are shown below.
°
3
-(Pyrrolidin-1-yl)-1,2-benzisothiazole (7a) was obtained as a colorless solid, mp 50 C(CHCl /hexanes),
3
2
0
°
1
(
lit., mp 49-50 C) in 90% yield (111 mg). H NMR (400 MHz, CDCl ). d 1.86 (4 H, m, 2 x CH ), 3.61
3 2

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HETEROCYCLES, Vol. 65, No. 7, 2005
(
4 H, m, CH NCH ), 7.31 (1 H, d, J = 7.0 Hz, H-5), 7.42 (1 H, d, J =7.0 Hz, H-6), 7.75 (1 H, t, J = 6.8 Hz,
2 2
1
3
H-7), 7.89 (1H, t, J = 6.7 Hz, H-4). C NMR (100 MHz, CDCl ) d 26.5, 49.2, 121.2, 124.5, 125.1, 126.3,
3
1
28.5, 130.4, 164.8.
°
3
-Diisopropylamino-1,2-benzisothiazole (7b) was obtained as a light brown solid, mp 89 C (CHCl /
3
1
hexanes), in 86 % yield (186 mg). H NMR (400 MHz, CDCl ) d 1.34 (12H, t, J = 5.0 Hz, 4 x CH ), 3.99
3
3
(
2H, m, 2 x CH), 7.33 (1H, t, J = 7.4 Hz, H-5), 7.43 (1H, t, J =7.5 Hz, H-6), 7.82 (1H, d, J = 8.0 Hz, H-7),
1
3
7
1
3
.95 (1H, d, J = 8.0 Hz, H-4). C NMR (100 MHz, CDCl ) d 22.4, 50.1, 120.6, 124.0, 124.9, 127.4, 132.1,
3
52.3, 163.4. Anal. Calcd for C H N S: C, 66.62; H, 7.74; N, 11.95. Found: C, 66.58; H, 7.62; N, 11.84.
1
3
18
2
°
-(Morpholin-4-yl)-1,2-benzisothiazole (7c) was obtained as colorless solid, mp 53 C (CHCl /hexanes)
3
2
1
°
1
(
lit., mp 52-53 C), in 94% yield (146 mg). H NMR (400 MHz, CDCl ) d 3.56 (4H, t, J = 4.7 Hz, CH -
3 2
NCH ), 3.95 (4H, t, J = 4.6Hz, CH -O-CH ), 7.38 (1H, t, J = 7.3 Hz, H-5), 7.50 (1H, t, J = 7.3 Hz, H-6),
2
2
2
1
3
7
1
3
.85 (1H, d, J = 8.1 Hz, H-7), 7.92 (1H, d, J = 8.1 Hz, H-4); C NMR (100 MHz, CDCl ) d 51.0, 67.1,
3
21.0, 124.1, 124.3, 128.0, 128.2, 153.3, 164.2.
2
2
-Diethylamino-1,2-benzisothiazole (7d) was obtained as a colorless viscous oil (reported as a solid
1
with mp 95-115 °C) in 93% yield (152 mg). H NMR (400 MHz, CDCl ) d 1.31 (6H, t, J = 7.0 Hz, 2 x
3
CH ), 3.64 (4H, q, J = 7.0 Hz, 2 x CH ), 7.34 (1H, t, J = 7.8 Hz, H-5), 7.45 (1H, t, J = 7.6 Hz, H-6), 7.79
3
2
1
3
(
1H, d, J = 8.0 Hz, H-7), 7.96 (1H, d, J = 8.1 Hz, H-4); C NMR (100 MHz, CDCl ) d 13.8, 45.6, 120.8,
3
1
24.0, 124.6, 127.5, 128.3, 153.3, 162.5. Anal. Calcd for C H N S: C, 64.04; H, 6.84; N, 13.58. Found:
11 14 2
C, 64.10; H, 6.75; N, 13.41.
0
3
-Dimethylamino-1,2-benzisothiazole (7e) was obtained as a colorless solid, mp 94 C ( CHCl /
3
1
hexanes), in 91% yield (185 mg). H NMR (400 MHz, CDCl ) d 3.23 (6H, br s, CH NCH ), 7.35 (1H, t, J
3
3
3
=
7.7 Hz, H-5), 7.46 (1H, t, J = 7.3 Hz, H-6), 7.80 (1H, d, J = 8.0 Hz, H-7), 8.05 (1H, d, J = 8.1 Hz, H-4);
1
3
C NMR (100 MHz, CDCl ) d 42.2, 120.8, 124.0, 124.8, 127.7, 128.2, 153.4, 164.4. Anal. Calcd for
3
C H N S: C, 60.64; H, 5.65; N, 15.72. Found: C, 60.73; H, 5.72; N, 15.83.
9
10
2
3
-(Piperidin-1-yl)-1,2-benzisothiazole (7f) was obtained as a colorless liquid, in 85% yield (128 mg).
1
H NMR (400 MHz, CDCl ) d 1.82 (6H, br s, 3 x CH ), 3.49 (4H, br s, CH NCH ), 7.36 (1H, d, J = 7.1
3
2
2
2
1
3
Hz, H-5), 7.45 (1H, d, J = 7.0 Hz, H-6), 7.81 (1H, t, J = 6.7 Hz, H-7), 7.92 (1H, t, J = 6.5Hz, H-4); C
NMR (100 MHz, CDCl ) d 25.0, 26.3, 51.8, 120.8, 124.1, 124.4, 127.7, 128.7, 129.2, 152.4, 165.3. Anal.
3
Calcd for C H N S: C, 66.02; H, 6.46; N, 12.03. Found: C, 66.14; H, 6.35; N, 12.12.
1
2
14
2
General Procedure for the Synthesis of 3-Pyrrolidin-2-yl-1,2-naphthoisothiazoles (8a–f). These
compounds were similarly prepared as described for the synthesis of 7a-f with the exception that phenyl-

HETEROCYCLES, Vol. 65, No. 7, 2005
1625
3
-trimethylsilyl-2-naphthyliodonium triflate (1e) (300 mg, 0.54 mmol), 3 (0.82 mmol), and
tetrabutylammonium fluoride (1M, 2.17 mL) were used. The physical and spectral properties of 8a–f are
shown below.
°
3
-(Pyrrolidin-1-yl)-1,2-naphthisothiazole (8a) was obtained as a colorless solid, mp 135 C (CHCl /
3
1
hexanes), in 82% yield (195 mg). H NMR (400 MHz, CDCl ) d 1.92 (4H, m, 2 x CH ), 3.59 (4H, m,
3
2
CH NCH ), 7.53 (1H, t, J = 7.0 Hz, H-7), 7.59 (1H, t, J = 7.0 Hz, H-6), 7.95 (1H, d, J = 8.4 Hz, H-8),
2
2
1
3
8
4
.03 (1H, d, J = 8.3 Hz, H-5), 8.21 (1H, s, H-9), 8.37 (1H, s, H-4); C NMR (100 MHz, CDCl ) d 26.1,
3
9.4, 120.2, 123.5, 124.1, 126.4, 127.5, 128.7, 129.6, 130.1, 131.8, 149.0, 163.7. Anal. Calcd for
C H N S: C, 70.83; H, 5.55; N, 11.01. Found: C, 70.76; H, 5.47; N, 11.09.
1
5
14
2
°
3
-Diisopropylamino-1,2-naphthoisothiazole (8b) was obtained as a light brown solid, mp 78 C
1
(
CHCl /hexanes), in 92 % yield (150 mg). H NMR (400 MHz, CDCl ) d 1.41 (12H, t, J = 5.1 Hz, 4 x
3
3
CH ), 4.12 (2H, m, 2 x CH), 7.49 (1H, t, J = 7.3 Hz, H-7), 7.56 (1H, t, J =7.4 Hz, H-6), 7.92 (1H, d, J =
3
1
3
8
.0 Hz, H-8), 8.01 (1H, d, J = 8.0 Hz, H-5), 8.25 (1H, s, H-9), 8.49 (1H, s, H-4); C NMR (100 MHz,
CDCl ) d 22.5, 50.1, 118.0, 124.3, 125.4, 127.5, 129.8, 130.2, 130.6, 131.8, 132.8, 147.5, 162.9. Anal.
3
Calcd for C H N S: C, 71.79; H, 7.09; N, 9.85. Found: C, 71.84; H, 7.15; N, 9.76.
1
7
20
2
3
-(Morpholin-4-yl)-1,2-naphthoisothiazole (8c) was obtained as colorless crystals, mp 120 °C
1
(
CHCl /hexanes), in 94 % yield (148 mg). H NMR (400 MHz, CDCl ) d 3.66 (4H, t, J = 4.8 Hz, CH N-
3
3
2
CH ), 4.02 (4H, t, J = 4.7 Hz, CH -O-CH ), 7.52 (1H, t, J = 7.8 Hz, H-7), 7.59 (1H, t, J = 7.9 Hz, H-6),
2
2
2
1
3
7
.94 (1H, d, J = 8.1 Hz, H-8), 8.03 (1H, d, J = 8.2 Hz, H-5), 8.28 (1H, s, H-9), 8.46 (1H, s, H-4); C
NMR (100 MHz, CDCl ) d 51.0, 67.2, 118.6, 123.7, 125.9, 127.7, 127.9, 127.9, 129.5, 130.6, 133.0,
3
1
1
48.1, 163.8. Anal. Calcd for C H N OS: C, 66.64; H, 5.22; N, 10.36. Found: C, 66.72; H, 5.29; N,
15 14 2
0.43.
-Diethylamino-1,2-naphthoisothiazole (8d) was obtained as a colorless liquid in 88% yield (95 mg).
3
1
H NMR (400 MHz, CDCl ) d 1.38 (6H, t, J = 7.0 Hz, 2 x CH ), 3.74 (4H, q, J = 7.0 Hz, CH N-CH ),
3
3
2
2
7
8
1
6
3
.49 (1H, t, J = 7.9 Hz, H-7), 7.57 (1H, t, J = 7.8 Hz, H-6), 7.91 (1H, d, J = 8.3 Hz, H-8), 8.01 (1H, d, J =
1
3
.2 Hz, H-5), 8.23 (1H, s, H-9), 8.51 (1H, s, H-4); C NMR (100 MHz, CDCl ) d 13.8, 45.7, 118.1, 124.2,
3
25.5, 127.5, 127.7, 128.4, 129.8, 130.5, 132.7, 148.4, 162.1. Anal. Calcd for C H N S: C, 70.27; H,
1
5
16
2
.29; N, 10.93. Found: C, 70.16; H, 6.18; N, 10.86.
°
-Dimethylamino-1,2-naphthoisothiazole (8e) was obtained as a colorless solid, mp 94 C (CHCl /
3
1
hexanes), in 81% yield (185 mg). H NMR (400 MHz, CDCl ) d 3.34 (6H, s, CH NCH ), 7.51 (1H, t, J =
3
3
3
7
8
1
.7 Hz, H-7), 7.58 (1H, t, J = 7.6 Hz, H-6), 7.92 (1H, d, J = 8.3 Hz, H-8), 8.02 (1H, d, J = 8.1 Hz, H-5),
1
3
.23 (1H, s, H-9), 8.61 (1H, s, H-4); C NMR (100 MHz, CDCl ) d 42.4, 118.3, 124.8, 125.7, 126.4,
3
27.5, 128.0, 128.9, 129.2, 130.2, 151.2, 166.7. Anal. Calcd for C H N S: C, 68.39; H, 5.30; N, 12.27.
1
3
12
2

1626
HETEROCYCLES, Vol. 65, No. 7, 2005
°
3
-(Piperdin-1-yl)-1,2-naphthoisothiazole (8f) was obtained as colorless crystals, mp 121 C (CHCl /
3
1
hexanes), in yield of 96% (174 mg). H NMR (400 MHz, CDCl ) d 1.58 (6H, br s, 3 x CH ), 3.60 (4H, br
3
2
s, CH NCH ), 7.51 (1H, t, J = 7.0 Hz, H-7), 7.58 (1H, t, J = 7.0 Hz, H-6), 7.93 (1H, d, J = 8.3 Hz, H-8),
2
2
1
3
8
2
.03 (1H, d, J = 8.2 Hz, H-5), 8.25 (1H, s, H-9), 8.46 (1H, s, H-4); C NMR (100 MHz, CDCl ) d 25.1,
3
6.3, 51.9, 118.3, 124.0, 125.6, 127.6, 127.7, 128.4, 129.6, 130.5, 132.9, 148.0, 164.9. Anal. Calcd for
C H N S: C, 71.61; H, 6.01; N, 10.44. Found: C, 71.54; H, 5.87; N, 10.36.
1
6
16
2
ACKNOWLEDGEMENTS
We thank the Welch Foundation, Houston, TX for partial financial support for this work.
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