Synthesis of N,N′-linked bisazaheterocycles with sulfonamide structure via oxidation of S,N-heteroaromatic cations

Article abstract of DOI:10.1055/s-2008-1066984

N-Phthalimidyl- and N-quinazolinyl-substituted 3-hydroperoxy-, 3-hydroxy- and 3-oxoisothiazole 1,1-dioxides have been synthesized by the sequence of oxidation reactions from N,N′-linked isothiazolium perchlorates with hydrogen peroxide, MMPP, and pyridini

Full text of DOI:10.1055/s-2008-1066984

PAPER
1133
Synthesis of N,N¢-Linked Bisazaheterocycles with Sulfonamide Structure via
Oxidation of S,N-Heteroaromatic Cations
O
xidation of S,N-H
a
e
teroarom
l
a
tic Ca
e
tions to
N
,N
r
¢
-Linke
i
dBisa
z
j
ahetero
a
cycles M. Zakharova,a Camino M. González Tanarro,b Michael Gütschow,b Lothar Hennig,a Joachim Sieler,c
Bärbel Schulze*a
a
Institut für Organische Chemie, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany
E-mail: bschulze@chemie.uni-leipzig.de
Pharmazeutisches Institut, Pharmazeutische Chemie I, Universität Bonn, An der Immenburg 4, 53121 Bonn, Germany
Institut für Anorganische Chemie, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany
b
c
Received 7 December 2007
R3
N
Abstract: N-Phthalimidyl- and N-quinazolinyl-substituted 3-hy-
O
X
droperoxy-, 3-hydroxy- and 3-oxoisothiazole 1,1-dioxides have
been synthesized by the sequence of oxidation reactions from N,N¢-
linked isothiazolium perchlorates with hydrogen peroxide, MMPP,
and pyridinium dichromate. Isothiazolium salts without acceptor
substituents did not give N-substituted sultams. Novel N,N¢-bisaza-
heterocycles were investigated as inhibitors of acetylcholinesterase
(AChE) and human leukocyte elastase (HLE). Two 2,3-dihydro-3-
hydroperoxy-2-(phthalimid-1-yl)isothiazole 1,1-dioxides were
found to inhibit AChE.
O
N
N
N
N
N
R2
N
COR
O
S
1
2
R1 = Me, R2 = 4-ClC6H4
R3 = 4-MeC6H4, 4-ClC6H4,
4-BrC6H4
X = H, Hal, NC, Alk, Ar
R = H, OH, Alk, Ar
Key words: b-thiocyanatovinyl aldehydes, N-aminoheterocycles,
isothiazolium salts, N,N¢-linked bisazaheterocycles, sultams
O
O
S
N
N
R1 = Me, Et
2 = Ph, 2-ClC6H4,
4-NMe2C6H4, 2-furyl
During the last years N,N¢-linked bisazaheterocycles have
gained significant importance in view of their pharmaco-
logical activities as potential anticonvulsant,1 antidepres-
sant,2 antiinflammatory,3 antimicrobial,4 and antifilarial
agents,5 reductase inhibitors,6 and anti-Parkinson agents.7
They are also excellent precursors of nitrogen centered
free radicals, which play an important role in the physio-
logical processes of living organisms and in understand-
ing the mode of action of many toxins.8
R2
R
R1
N
3
O
O
N
R
N
R
S
S
O
O
O
O
5
R = triazolo,
4
The structure of bisazaheterocycles described in the liter-
ature differs both in symmetry (identical or different
rings) and in the size and nature of the heterocycles in-
cluded.8a The compounds bearing a phthalimide or
quinazolinone unit often possess biological activities. For
example, 2-(pyrrol-1-yl)phthalimides 1 can be used as a
glycine partial agonists.9 3-Triazinyl-4(3H)-quinazoli-
none derivatives 2 showed anticonvulsant activity,1
whereas compounds 3 were studied for their anti-Parkin-
son activity7 (Figure 1).
OCOMe, O-styroyl, SO2R1,
OCO-2,6-Cl2-C6H3,
O-heterocyclyl
R = H, Ar
Figure 1 Some biologically active N,N¢-linked bisazaheterocycles
and N-substituted sultams
activities, for example, N-arylbenzisothiazol-3-one 1,1-
dioxides 4 (R = Ar) and 2-methylene derivatives 5 are po-
tent, mechanism-based inhibitors of serine proteases.10 In
view of these observations we became interested in N,N¢-
linked bisazaheterocycles, containing an isothiazole frag-
ment in their structure.11
However, to the best of our knowledge, there is no litera-
ture report on N,N¢-linked bisazaheterocycles containing
a fragment of saccharin (4, R = H) or its analogues. Sac-
charin-based compounds show a broad range of biological
Recently, the synthesis of a series of monocyclic and bi-
cyclic 2-arylsultams with hydroperoxy, hydroxy, alkoxy
or oxo groups in C-3 position was developed by the reac-
tion of b-thiocyanatovinyl aldehydes with the correspond-
ing amino compounds, followed by oxidation of the
formed iminium salts.12 Some of the 3-oxo derivatives
were found to inhibit human leukocyte elastase (HLE) in
a time-dependent manner.10b,13 Moreover, 3-hydroperoxy-
sultams can be used as renewable chemoselective electro-
philic oxidants for a wide range of substrates in
SYNTHESIS 2008, No. 7, pp 1133–1141
x
x
.
x
x
.2
0
0
8
Advanced online publication: 06.03.2008
DOI: 10.1055/s-2008-1066984; Art ID: Z28207SS
© Georg Thieme Verlag Stuttgart · New York

1134
V. M. Zakharova et al.
PAPER
O
Table 1 Isothiazolium Salts 10–12 Prepared
R1
R2
CHO
SCN
Product
10a
R1
R2
R3/X
–
Yield (%)
93
H2N
N
Me
Me
O
7
6
10b
11a
(CH2)4
Me
–
89
R1 = R2 = Me,
R1R2 = (CH2)4
Me
Me
H
86
O
11b
11c
Me
Me
H
84
H2N
N
H2N
N
X
(CH2)4
(CH2)4
Me
84
R3
N
11d
12a
Me
NMe
CH2
O
97
8
9
3 = H, Me
X = CH2, O, NMe
Me
9816
5416
7716
9316
R
12b
12c
(CH2)4
(CH2)4
(CH2)4
Figure 2 Starting b-thiocyanatovinyl aldehydes 6 and N-amino-
heterocycles 7–9
O
O
R1
R1
12d
NMe
N+
R3
N
N+
N
S
S
R2
Table 2 Sultams 13–15 Prepared
R2
N+
H
O
–
–
ClO4
2ClO4
Product
13a
R1
R2
Isolated yield (%)
10a,b
11a–d
Me
Me
51
44
R1
N+
N
X
13b
(CH2)4
Me
S
R2
14a
Me
Me
98 (from 13a), 41 (from 10a)
93 (from 13b), 36 (from 10b)
38 (from 10a), 79 (from 14a)
41 (from 10b), 82 (from 14b)
–
ClO4
12a–d
14b
(CH2)4
Me
Figure 3 Isothiazolium salts, prepared by cyclocondensation reac-
tion of b-thiocyanatovinyl aldehydes with N-amino compounds
15a
15b
(CH2)4
nonaqueous media, for example, with nitrogen, sulfur,
and phosphorus heteroatoms.14
HMQC experiments and were found at d = 174.8–178.2,
159.9–161.1, and 132.1–133.1 ppm, respectively. The di-
agnostic signal of the H-3 atom in the 1H NMR spectra ap-
peared in the region d = 9.31–9.48 ppm as usual for
isothiazolium salts.
Herein we report on a study of the reaction of b-thiocy-
anatovinyl aldehydes with N-aminoheterocycles and an
approach to N,N¢-linked bisazaheterocycles via intramo-
lecular cyclocondensation and oxidation reactions. The
two b-thiocyanatovinyl aldehydes 6 [R1 = R2 = Me;
R1R2 = -(CH2)4-] used in this study were synthesized by a
known method from the corresponding ketones.15 Con-
versions were carried out with N-aminophthalimide (7),
N-amino-4(3H)-quinazolinones 8, and heterocycles of
type 9 (Figure 2).
The oxidation reactions of the iminium salts 10, 11 pre-
pared were studied using the standard system H2O2–
AcOH and with magnesium monoperoxyphthalate
(MMPP) under different reaction conditions, such as sol-
vent, temperature, and reaction time.
The oxidation of phthalimidyl isothiazolium perchlorates
10a,b was carried out at first with hydrogen peroxide in
glacial acetic acid at room temperature during 1–2 days.
The oxidation occurred at both C-3 carbon and sulfur at-
oms of the isothiazole ring to give stable hydroperoxysul-
tams 13a,b as colorless crystals in moderate yields
(Scheme 1, Table 2).
Thiocyanates 6 reacted with the N-aminoheterocycles 7–
9 in glacial acetic acid in the presence of perchloric acid
for the salt formation.12 The first stage of the reaction
leads to hydrazonium salts, which then undergo intramo-
lecular cyclocondensation giving rise to N,N¢-linked
isothiazolium salts 10–12 (Figure 3, Table 1). Com-
pounds 11a–d were obtained as hygroscopic bisperchlor-
ate salts.
In accordance to a previous investigation using an HPLC
methodology,17 the supposed mechanism for this reaction
includes an oxidation cascade with the initial nucleophilic
attack of H2O2 at C-3 of the salts 10 with the formation of
3-hydroperoxyisothiazoles (Scheme 1). The second at-
tack of the hydrogen peroxide molecule occurs at the S-
atom giving rise to S-oxides, which undergo further oxi-
dation to the 3-hydroperoxysultams 13.
The IR spectra of the isothiazolium perchlorates 10, 11
showed absorption bands of perchlorate anion at 1079–
1090 cm–1. NMR spectra of the salts 10, 11 are compatible
with the structure of isothiazolium salts. The characteris-
tic signals in the 13C NMR spectra for C-5 (C-7a), C-3,
and C-4 (C-3a) were elucidated by additional HMBC and
Synthesis 2008, No. 7, 1133–1141 © Thieme Stuttgart · New York

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Oxidation of S,N-Heteroaromatic Cations to N,N¢-Linked Bisazaheterocycles
1135
ultrasound conditions at 50 °C. The 3-hydroxyisothiazole
1,1-dioxides 14a,b, in every respect identical to the corre-
sponding sultams prepared using H2O2–DMSO, were ob-
tained by this pathway in moderate yields (Table 2).
Obviously, the mechanism of MMPP oxidation reaction
in this case is similar to that described for 2-arylisothia-
zolium salts, where the oxidation sequence was opposite
compared to the H2O2–AcOH system (Scheme 1).12e
O
R1
R2
N+
N
S
–
ClO4
O
10
MMPP, MeCN,
ultrasound, 50 °C
H2O2
AcOH,
r.t. or 80 °C
To develop an alternative approach to N,N¢-linked isothi-
azol-3(2H)-one 1,1-dioxides, the oxidation of 3-hydroxy-
sultams 14 with pyridinium dichromate in CH2Cl2 was
applied. It resulted in the preparation of 3-oxosultams 15,
already obtained by H2O2 oxidation, in good yields
(Table 2).
O
O
H
OOH
R1
R1
R2
N+
N
N
N
S
S
R2
O
O
O
The structures of the compounds 13–15 were established
by NMR spectroscopy and confirmed by IR spectroscopy,
mass spectrometry, and elemental analysis. In the IR spec-
tra of sultams 13–15, two absorption bands for the SO2
groups, known to be characteristic for the 1,1-dioxides,
were observed at 1299–1323 and 1161–1180 cm–1 for the
antisymmetric and symmetric vibrations, respectively.
Phthalimide carbonyl bands together with isothiazole-
3(2H)-one carbonyl signals for isothiazol-3(2H)-ones 15
could be found in the region of 1736–1754 cm–1.
O
O
H
OOH
O
OH
H
R1
R1
DMSO
N
O
N
N
O
N
R2
S
R2
S
O
O
O
13
14
80 °C
– H2O
R1
(pyH)2Cr2O7, CH2Cl2, r.t.
1
The H NMR spectra of sultams 13 and 14 showed the
O
O
typical absorption of the H-3 atom at d = 5.73–6.04 ppm,
while the OOH groups of 3-hydroperoxysultams 13 and
the OH of 3-hydroxy derivatives 14 resonated at
d = 11.46–11.68 (OOH) and 6.16–7.21 (OH) ppm. In the
13C NMR spectra, the diagnostic C-3 signals of isothia-
zole 1,1-dioxides 13–15 differed significantly and were
located at d = 94.1–95.0, 83.3–83.7 and 157.8–158.7
ppm, respectively.
N
N
R2
S
O
O
O
15
Scheme 1
From the structure of hydroperoxides 13 one may expect
that the peroxide oxygen atom is electron-deficient due to
the strong electron-withdrawing effect of the sulfonamide
function adjacent to the hydroperoxy group. Therefore,
hydroperoxysultams 13 are potential oxidants, especially
since the related 2-aryl-3-hydroperoxysultams were al-
ready found to be suitable and mild reagents for hetero-
atom oxidations.14 The hydroperoxides 13 were reduced
using DMSO to give 3-hydroxyisothiazole 1,1-dioxides
14 (Scheme 1). After stirring for two hours and removal
of DMSO in vacuo, 3-hydroxysultams 14a,b were isolat-
ed in almost quantitative yields (Table 2).
The oxidation reactions of quinazolinyl isothiazolium
salts 11 were investigated with the same oxidants, H2O2
and MMPP, as in the case of compounds 10. However, the
reaction of salts 11a,c,d with H2O2 at room temperature or
at 80 °C failed to give positive results and either initial
salts 11 or decomposition products were obtained after
workup.
Nevertheless, oxidation of the isothiazolium salt 11b by
H2O2 at room temperature after 48 hours furnished 3-hy-
droperoxysultam 16b (Scheme 2). Unexpectedly, increas-
ing the temperature to 80 °C had a destructive effect on
the quinazolinone part of the molecule, which was trans-
formed during the oxidation process to the nitro com-
pound 17, prepared before by H2O2 oxidation of 4,5-
dimethyl-2-[N-(2-nitro)benzamidyl]isothiazolium per-
chlorate.18 Like its analogues 13, 3-hydroperoxy sultam
16b could be quantitatively converted into the 3-hydroxy
derivative 18b in the presence of DMSO (Scheme 2,
Table 3).
It has been reported that 2-aryl-3-hydroperoxysultams
could be transformed into 3-oxo derivatives by heating in
ethanol followed by the addition of concentrated HCl.12a
Hydroperoxides 13a,b were found to be more stable under
such dehydration conditions and were regenerated from
the reaction mixture after refluxing for two hours. Howev-
er, increasing the temperature to 80 °C in the reaction of
salts 10a,b with H2O2 and reflux during 17 hours gave di-
rectly 3-oxosultams 15a,b as the final products of the ox-
idation cascade (Scheme 1, Table 2).
The oxidation reactions of isothiazolium salts 11a–d with
MMPP were carried out in acetonitrile–water system at
room temperature during 12 hours. However, after the
usual workup procedure the quinazolinyl substituted 3-
hydroxysultams 18 were obtained in only low yields as
The oxidation reaction of isothiazolium salts 10 using
MMPP in water–acetonitrile system was carried out under
Synthesis 2008, No. 7, 1133–1141 © Thieme Stuttgart · New York

1136
V. M. Zakharova et al.
PAPER
O
O
N
R1
R2
H
O
MMPP,
MeCN
r.t., 12 h
OH
N
O
N
Me
R1
R2
N+
N
N+
N+
N+
–
S
S
2ClO4
Me
–
S
N
2ClO4
H
H
R3
Me
11b
O
R3
11a–d
H2O2, AcOH
18a–d
(pyH)2Cr2O7
CH2Cl2
r.t., 24 h
80 °C, 8 h
O
O
O
N
R1
R2
OOH
N
O
H
O
O
N
O
Me
Me
Me
Me
S
N
N
S
N
H
N
O
R3
N
S
O2N
O
O
O
CH3
19a,b,d
16b
17
DMSO
Scheme 3
OH
O
H
Me
N
O
N
N
S
Me
O
Me
18b
Scheme 2
Table 3 Sultams 16–19 Prepared
Figure 4 Molecular structure of 4,5-dimethyl-2-(phthalimid-1-
yl)isothiazol-3(2H)-one 1,1-dioxide (15a)
Product
16b
17
R1
R2
R3
Isolated yield (%)
Me
Me Me 31
Me Me 28
Me
18a
18b
18c
Me
Me
Me Me 95 (from 16b), 18 (from 11b)
16 (from 11c)
Me 16 (from 11d)
88
H
33 (from 11a)
Me
(CH2)4
(CH2)4
Me
H
18d
19a
19b
19d
Me
H
Figure 5 Molecular structure of 2,3,4,5,6,7-hexahydro-3-hydroxy-
2-[2-methyl-4-oxo-3(4H)-quinazolinyl]-1,2-benzisothiazole 1,1-di-
oxide (18d)
Me
Me Me 71
Me 73
(CH2)4
bands for the SO2 group at 1167–1180 and 1308–1347
cm–1. In the 13C NMR spectra of 3-hydroxyisothiazole
1,1-dioxides 18 the chemical shift corresponding to the C-
3 atom occurred at d = 82.9–84.7 ppm, while for sultams
19 the signal for the new carbonyl group appeared instead
at d = 156.5–157.9 ppm. Characteristic chemical shifts of
3-H and OH groups of compounds 18 were found at
d = 5.84–6.07 and 6.48–7.40 ppm, respectively.
colorless crystals (Scheme 3, Table 3). Unfortunately, in
contrast to the increase in the yields described for N-aryl-
sultams,12d,e the use of an ultrasound bath in this case was
not helpful.
3-Oxosultams, containing a quinazolinyl substituent were
not available by oxidation of isothiazolium salts 11 with
hydrogen peroxide. Therefore, the oxidation of 3-hydroxy
derivatives 18 was carried out with pyridinium dichro-
mate. Using this procedure, the 3-oxosultams 19a,b,d
were obtained in good yields in agreement with previous
results for the preparation of sultams 15.
Structures of the novel N,N¢-linked isothiazole 1,1-diox-
ides 15a, 18d, and 19b were confirmed by X-ray crystal
structure analyses (Figures 4–6).19–21 Sultams 15a, 18d,
and 19b are sterically demanding compounds. The analy-
sis of dihedral angles between two heterocyclic rings
showed values of 84–88° and thus the planes of two cycles
are almost perpendicularly orientated.
The IR spectra of the new compounds 18, 19 exhibited
signals for the carbonyl group of the quinazolinone ring at
1674–1715 cm–1, absorption bands for C=N bonds at
1605–1614 cm–1 and symmetrical and antisymmetrical
Unlike isothiazolium salts 10 and 11, their analogues 12
failed to undergo oxidation to N-substituted sultams. Un-
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Oxidation of S,N-Heteroaromatic Cations to N,N¢-Linked Bisazaheterocycles
1137
Mass spectra (70 eV) were determined on Quadrupol-MS VG 12-
250.
Isothiazolium Perchlorates 10, 11; General Procedure
To a magnetically stirred solution of b-thiocyanatovinyl aldehyde
6a,b (1 mmol) in glacial AcOH (2 mL) under argon was added the
N-amino compound 7, 8 (1 mmol). The mixture was stirred for 15
min and HClO4 (0.4 mL) was added. After stirring for 50 min, the
mixture was diluted with Et2O (20 mL). The precipitate was collect-
ed by filtration, washed with Et2O (3 ×) and air dried (for 10a,b) or
dried in vacuo (for 11a–d). The salts 11a–d are hygoscopic and
therefore the mps were not measured.
Figure 6 Molecular structure of 4,5-dimethyl-2-[2-methyl-4-oxo-
3(4H)-quinazolinyl]isothiazol-3(2H)-one 1,1-dioxide (19b)
4,5-Dimethyl-2-(phthalimid-1-yl)isothiazolium Perchlorate
(10a)
Yield: 333 mg (93%); white solid; mp 240–242 °C.
IR (KBr): 1753 (C=O), 1079 (ClO4) cm–1.
der different reaction conditions either initial salts or de-
composition products were isolated.
1H NMR (300 MHz, DMSO-d6): d = 2.35 (s, 3 H, CH3), 2.84 (s, 3
H, CH3), 8.04 (d, J = 7.8 Hz, 2 Harom), 8.13 (d, J = 7.8 Hz, 2 Harom),
9.31 (s, 1 H, CH).
13C NMR (75 MHz, DMSO-d6): d = 11.4 (CH3), 15.0 (CH3), 125.4
(2 CHarom), 130.0 (2 Carom), 132.1 (C-4), 136.7 (2 CHarom), 160.4 (C-
3), 162.9 (2 C=O), 174.8 (C-5).
Compared to the 13C NMR data of 12,16 the main diagnos-
tic signals of the salts 10a,b, 11a,c were shifted to lower
field. This can serve as further evidence for the difference
in electrophilicity of the salts 12 and their acceptor substi-
tuted analogues 10, 11, and explain the reduced reactivity
of 12 with nucleophilic reagents H2O2 and MMPP. The
formation of decomposition products during the attempts
to oxidize 12 might result from undesired N-oxidation re-
actions known for tertiary amines.14,22
MS (ESI): m/z = 259 [M – ClO4]+.
Anal. Calcd for C13H11ClN2O6S: C, 43.51; H, 3.07; N, 7.81; S, 8.93.
Found: C, 43.64; H, 3.26; N, 7.81; S, 9.31.
4,5,6,7-Tetrahydro-2-(phthalimid-1-yl)-1,2-benzisothiazolium
Perchlorate (10b)
Yield: 342 mg (89%); white solid; mp 247–249 °C.
IR (KBr): 1753 (C=O), 1090 (ClO4) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.90 (m, 4 H, 2 CH2), 2.90 (m,
2 H, CH2), 3.28 (m, 2 H, CH2), 8.08–8.21 (m, 4 Harom), 9.36 (s, 1 H,
CH).
13C NMR (75 MHz, DMSO-d6): d = 21.0, 21.7, 22.9, 27.2 (C-
4,5,6,7), 125.4 (2 CHarom), 130.1 (2 Carom), 132.9 (C-3a), 136.7 (2
CHarom), 159.9 (C-3), 162.9 (2 C=O), 175.2 (C-7a).
The newly synthesized N,N¢-linked bisazaheterocycles
13a,b, 14a,b, 15a, 17, 18b,d, and 19a,d were evaluated as
inhibitors of acetylcholinesterase (AChE) from Electro-
phorus electricus and human leukocyte elastase (HLE).
The hydroperoxides 13a and 13b showed inhibitory activ-
ity towards acetylcholinesterase with IC50 values of 14.7
2.4 mM, and 15.7 0.6 mM, respectively. However, no
HLE inhibition was found for the investigated sultams.
In conclusion, a series of N,N¢-connected 3-hydroperoxy-,
3-hydroxy-, and 3-oxosultams have been prepared by the
oxidation of N,N¢-linked isothiazolium perchlorates.
These new isothiazolium salts were found to be less reac-
tive in oxidation reactions with hydrogen peroxide and
MMPP than their N-arylsubstituted analogues, described
in the literature. Thus, the oxidation process in this case
was found to depend on the nature of the cyclic substituent
at the isothiazole N-atom. The presence of acceptor
substituents, such as carbonyl groups in phthalimidyl or
4-oxoquinazolin-3-yl rings, assisted the oxidation reac-
tion. The new N,N¢-linked sultams were evaluated for
their inhibitory activity toward HLE and AChE. Two 2,3-
dihydro-3-hydroperoxy-2-(phthalimid-1-yl)isothiazole
1,1-dioxides were found to inhibit AChE.
MS (ESI): m/z = 285 [M – ClO4]+.
Anal. Calcd. for C15H13ClN2O6S: C, 46.82; H, 3.41; N, 7.28; S,
8.33. Found: C, 46.50; H, 3.55; N, 6.84; S, 7.87.
4,5-Dimethyl-2-[4-oxo-3(4H)-quinazolinyl]isothiazolium Per-
chlorate (11a)
Yield: 394 mg (86%); yellow solid.
IR (KBr): 1713 (C=O), 1086 (ClO4) cm–1.
1H NMR (300 MHz, acetone-d6): d = 2.55 (s, 3 H, CH3 at C-4), 3.08
(s, 3 H, CH3 at C-5), 8.00 (m, 1 H, H-6¢), 8.08 (d, J = 8.9 Hz, 1 H,
H-8¢), 8.25 (m, 1 H, H-7¢), 8.47 (d, J = 9.3 Hz, 1 H, H-5¢), 9.48 (s, 1
H, H-3), 9.79 (s, 1 H, NH), 10.12 (s, 1 H, H-2¢).
13C NMR (75 MHz, acetone-d6): d = 10.5 (CH3 at C-5), 13.8 (CH3
at C-4), 120.3 (C-4a¢), 120.7 (C-8¢), 128.9 (C-5¢), 131.8 (C-6¢),
133.1 (C-4), 138.5 (C-7¢), 152.1 (C-2¢), 154.5 (C-8a¢), 155.8 (C=O),
160.5 (C-3), 176.5 (C-5).
MS (ESI): m/z = 258 [M – 2 ClO4 – H]+.
Melting points were determined on Boetius micro-melting-point
apparatus and are corrected. 1H and 13C NMR spectra were recorded
at 300 or 400 MHz (1H) and 75 or 100 MHz (13C) with Varian Mer-
cury Plus 300 or 400 NMR spectrometers in DMSO-d6 or acetone-
d6 solution using TMS as internal standard. IR spectra were record-
ed on a spectrophotometer Genesis FTIR Unicam Analytical Sys-
tem (ATI Mattson) with KBr pellets; values in cm–1. Elemental
analyses were performed on a Heraeus CHNO Rapid Analyzer.
4,5-Dimethyl-2-[2-methyl-4-oxo-3(4H)-quinazolinyl]isothiazo-
lium Perchlorate (11b)
Yield: 397 mg (84%); yellow solid.
1H NMR (300 MHz, acetone-d6): d = 1.87 (s, 3 H, CH3 at C-2¢), 2.32
(s, 3 H, CH3 at C-4), 2.83 (s, 3 H, CH3 at C-5) 7.60–8.70 (m, 5 H, 4
Harom + NH), 9.42 (s, 1 H, H-3).
Synthesis 2008, No. 7, 1133–1141 © Thieme Stuttgart · New York

1138
V. M. Zakharova et al.
PAPER
MS (ESI): m/z = 272 [M – 2 ClO4 – H]+.
3-Hydroxysultams 14 from 3-Hydroperoxysultams 13; General
Procedure
4,5,6,7-Tetrahydro-2-[4-oxo-3(4H)-quinazolinyl]-1,2-benz-
isothiazolium Perchlorate (11c)
Yield: 407 mg (84%); yellow solid.
DMSO (2 mL) was added to 13 (0.2 mmol). After 2 h, DMSO was
evaporated in vacuum, the residue was washed with H2O (2 mL),
and air dried.
IR (KBr): 1731 (C=O), 1100 (ClO4) cm–1.
3-Hydroxysultams 14 by MMPP Oxidation of Isothiazolium
Salts 10; General Procedure
1H NMR (300 MHz, acetone-d6): d = 2.00 (m, 4 H, 2 CH2), 3.03 (m,
2 H, CH2), 3.47 (m, 2 H, CH2), 8.00 (m, 1 H, H-6¢), 8.10 (d, J = 9.0
Hz, 1 H, H-8¢), 8.23 (m, 1 H, H-7¢), 8.47 (d, J = 9.3 Hz, 1 H, H-5¢),
9.47 (s, 1 H, H-3), 9.80 (s, 1 H, NH), 10.09 (s, 1 H, H-2¢).
13C NMR (75 MHz, acetone-d6): d = 21.9, 22.5, 23.8, 27.4 (C-
4,5,6,7), 121.4 (C-4a¢), 122.0 (C-8¢), 129.7 (C-5¢), 132.3 (C-6¢),
133.0 (C-3a), 139.1 (C-7¢), 151.8 (C-2¢), 153.3 (C-8a¢), 155.8
(C=O), 161.1 (C-3), 178.2 (C-7a).
A stirred solution of appropriate isothiazolium salt 10 (0.6 mmol) in
MeCN (13 mL) was treated in portions with MMPP (890 mg, 1.8
mmol) and the mixture was left in the ultrasound bath at 50 °C for
3 h. Then, sat. aq NaHCO3 (5 mL) was added, the mixture extracted
with Et2O (3 × 25 mL) and the combined organic layers were dried
(MgSO4). The solvent was evaporated and the respective product 14
was purified by recrystallization from EtOH–H2O.
MS (ESI): m/z = 284 [M – 2 ClO4 – H]+.
2,3-Dihydro-3-hydroxy-4,5-dimethyl-2-(phthalimid-1-yl)isothi-
azole 1,1-Dioxide (14a)
Yield: 60 mg (98%) (from 13a); 54 mg (41%) (from 10a); white sol-
id; mp 198–200 °C.
4,5,6,7-Tetrahydro-2-[2-methyl-4-oxo-3(4H)-quinazolinyl]-1,2-
benzisothiazolium Perchlorate (11d)
Yield: 483 mg (97%); yellow solid.
1H NMR (200 MHz, DMSO-d6: d = 1.86 (m, 4 H, 2 CH2), 2.39 (s,
3 H, CH3 at C-2¢), 2.84 (m, CH2, CH2), 3.25 (m, CH2, CH2), 7.60–
8.18 (m, 5 H, 4 Harom + NH), 9.4 (s, 1 H, H-3).
IR (KBr): 1752 (C=O), 1307 (SO2), 1180 (SO2) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.94 (s, 3 H, CH3), 2.04 (s, 3
H, CH3), 5.73 (s, 1 H, 3-H), 7.21 (s, 1 H, OH), 7.95–8.01 (m, 4
Harom).
13C NMR (75 MHz, DMSO-d6): d = 7.4 (CH3), 12.0 (CH3), 83.7 (C-
3), 123.9 (2 CHarom), 129.0 (Carom), 129.2 (Carom), 129.6 (C-5), 135.6
(2 CHarom), 141.8 (C-4), 164.6 (C=O), 164.8 (C=O).
MS (ESI): m/z = 298 [M – 2 ClO4 – H]+.
2,3-Dihydro-3-hydroperoxy-2-(phthalimid-1-yl)isothiazole 1,1-
Dioxides 13; General Procedure
H2O2 (2.8 mL, 30%) was added at r.t. to a stirred suspension of 10
(0.7 mmol) in AcOH (4.2 mL). After 24–48 h, the solution was di-
luted with cold H2O (3–5 mL), and the colorless crystals of 13 were
collected by filtration, and recrystallized from EtOH–H2O.
MS (ESI): m/z = 331 [M + Na]+.
Anal. Calcd for C13H12N2O5S: C, 50.64; H, 3.92; N, 9.09; S, 10.40.
Found: C, 50.35; H, 3.98; N, 9.00; S, 10.47.
2,3,4,5,6,7-Hexahydro-3-hydroxy-2-(phthalimid-1-yl)-1,2-
benzisothiazole 1,1-Dioxide (14b)
Yield: 62 mg (93%) (from 13b); 72 mg (36%) (from 10b); white
solid; mp 185–187 °C.
2,3-Dihydro-3-hydroperoxy-4,5-dimethyl-2-(phthalimid-1-
yl)isothiazole 1,1-Dioxide (13a)
Yield: 115 mg (51%); white solid; mp 215–217 °C.
IR (KBr): 1180 (SO2), 1323 (SO2), 1736 (C=O) cm–1.
1H NMR (400 MHz, acetone-d6): d = 2.07 (s, 3 H, CH3), 2.13 (s, 3
H, CH3), 5.99 (s, 1 H, H-3), 7.99 (m, 4 Harom), 11.68 (s, 1 H, OOH).
13C NMR (100 MHz, acetone-d6): d = 7.4 (CH3), 11.8 (CH3), 94.1
(C-3), 124.0 (CHarom), 124.2 (arom. CH), 129.0 (Carom), 130.0
(Carom), 133.6 (C-4), 135.7 (2 CHarom), 137.9 (C-5), 164.8 (C=O),
165.4 (C=O).
IR (KBr): 1747 (C=O), 1283 (SO2), 1139 (SO2) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.82 (m, 4 H, 2 CH2), 2.04 (m,
2 H, CH2), 2.42 (m, 2 H, CH2), 5.89 (s, 1 H, CH), 6.16 (s, 1 H, OH),
7.84 (m, 2 Harom), 7.95 (m, 2 Harom).
13C NMR (75 MHz, DMSO-d6): d = 20.1 (CH2), 22.3 (2 CH2), 24.3
(CH2), 85.8 (C-3), 124.4 (2 CHarom, 3¢, 6¢), 131.3 (C-7a), 135.7 (2
CHarom, 4¢, 5¢), 136.7 (2 Carom, 2a¢,6a¢), 145.6 (C-3a), 160.3 (2 C=O).
MS (EI): m/z = 324 [M]+.
MS (ESI): m/z = 357 [M + Na]+.
Anal. Calcd for C13H12N2O6S: C, 48.15; H, 3.73; N, 8.64; S, 9.89.
Found: C, 48.10; H, 3.85; N, 8.60; S, 9.89.
Anal. Calcd for C15H14N2O5S: C, 53.89; H, 4.22; N, 8.38; S, 9.59.
Found: C, 53.70; H, 4.16; N, 8.61; S, 9.68.
2,3,4,5,6,7-Hexahydro-3-hydroperoxy-2-(phthalimid-1-yl)-1,2-
benzisothiazole 1,1-Dioxide (13b)
Yield: 108 mg (44%); white solid; mp 184–187 °C.
IR (KBr): 1173 (SO2), 1323 (SO2), 1741 (C=O) cm–1.
1H NMR (400 MHz, acetone-d6): d = 1.85 (m, 4 H, 2 CH2), 2.47 (m,
4 H, 2 CH2), 6.04 (s, 1 H, H-3), 7.98 (m, 4 Harom), 11.46 (s, 1 H,
OOH).
13C NMR (100 MHz, acetone-d6): d = 20.3 (CH2), 22.2 (2 CH2),
24.6 (CH2), 95.0 (C-3), 125.3 (CHarom), 125.5 (CHarom), 131.1
(Carom), 131.3 (Carom), 137.0 (2 CHarom), 137.6 (C-3a), 142.5 (C-7a),
166.2 (C=O), 166.9 (C=O).
3-Oxosultams 15 from Isothiazolium Salts 10; General Proce-
dure
H2O2 (2.8 mL, 30%) was added at r.t. to a stirred suspension of 10
(0.7 mmol) in AcOH (4.2 mL). The solution was stirred for 18–20
h at 80 °C. After cooling, the product was isolated by filtration. In
case when no precipitate was formed, H2O and AcOH were re-
moved in vacuum, cold H2O (3 mL) was added to the mixture and
the solid was isolated and recrystallized from EtOH–H2O.
3-Oxosultams 15 from 3-Hydroxysultams 14; General Proce-
dure
To a stirred solution of 3-hydroxysultam 14 (0.25 mmol) in CH2Cl2
(2 mL) was added (pyH)2Cr2O7 (0.63 mmol) at r.t. The mixture was
stirred 8 h and the product purified by column chromatography us-
ing EtOAc as eluent to give 15 as colorless crystals.
MS (EI): m/z = 350 [M]+.
Anal. Calcd for C15H14N2O6S: C, 51.42; H, 4.03; N, 8.00; S, 9.15.
Found: C, 51.27; H, 3.69; N, 7.88; S, 9.33.
Synthesis 2008, No. 7, 1133–1141 © Thieme Stuttgart · New York

PAPER
Oxidation of S,N-Heteroaromatic Cations to N,N¢-Linked Bisazaheterocycles
1139
4,5-Dimethyl-2-(phthalimid-1-yl)isothiazol-3(2H)-one 1,1-Diox-
ide (15a)
Yield: 81 mg (38%) (from 10a), 61 mg (79%) (from 14a); white sol-
id; mp 267–269 °C.
13C NMR (75 MHz, acetone-d6): d = 7.7 (CH3), 8.6 (CH3), 129.4
(Carom), 129.8 (CHarom), 129.9 (CHarom), 132.4 (CHarom), 133.1 (C-4),
134.1 (CHarom), 143.3 (CNO2), 147.7 (C-5), 159.3 (C-3), 164.5
(C=O).
IR (KBr): 1754 (C=O), 1299 (SO2), 1161 (SO2) cm–1.
MS (EI): m/z = 325 [M]+.
1H NMR (400 MHz, DMSO-d6): d = 2.18 (s, 3 H, CH3), 2.41 (s, 3
H, CH3), 7.85 (m, 2 Harom), 8.06 (m, 2 Harom).
Anal. Calcd for C12H11N3O6S: C, 44.31; H, 3.41; N, 12.92; S, 9.86.
Found: C, 43.89; H, 3.56; N, 12.81; S, 10.04.
13C NMR (100 MHz, DMSO-d6): d = 8.4 (CH3 at C-5), 9.3 (CH3 at
C-4), 124.8 (2 CHarom), 128.8 (2 Carom), 133.3 (C-4), 136.3 (2
CHarom), 144.6 (C-5), 158.7 (C=O), 162.7 (2 C=O).
2,3-Dihydro-3-hydroxy-4,5-dimethyl-2-[2-methyl-4-oxo-3(4H)-
quinazolinyl]isothiazole 1,1-Dioxide (18b) from 3-Hydroper-
oxysultam (16b)
DMSO (2 mL) was added at r.t. to 16b (0.2 mmol). After 2 h,
DMSO was evaporated in vacuo, the residue was washed with H2O
(2 mL) and air dried.
MS (EI): m/z = 306 [M]+.
Anal. Calcd for C13H10N2O5S: C, 50.98; H, 3.29; N, 9.15; S, 10.47.
Found: C, 50.45; H, 3.39; N, 9.10; S, 10.61.
3-Hydroxy-2-[4-oxo-3(4H)-quinazolinyl]sultams 18 from
Isothiazolium Salts 11; General Procedure
4,5,6,7-Tetrahydro-2-(phthalimid-1-yl)-1,2-benzisothiazol-
3(2H)-one 1,1-Dioxide (15b)
A stirred solution of isothiazolium salts 11 (0.9 mmol) in MeCN (15
mL) was treated portionwise with MMPP (1.336 g, 2.7 mmol) and
the mixture was stirred during 16 h at r.t. Then, sat. aq NaHCO3 (5
mL) was added to the mixture and it was extracted with Et2O (3 ×
25 mL). The combined organic layers were dried (MgSO4). The sol-
vent was evaporated and the products 18 were purified by recrystal-
lization from EtOH–H2O.
Yield: 95 mg (41%) (from 10b), 68 mg (82%) (from 14b); white
solid; mp 185–187 °C.
IR (KBr): 1751 (C=O), 1307 (SO2), 1177 (SO2) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.91 (m, 2 H, CH2), 1.98 (m, 2
H, CH2), 2.58 (m, 2 H, CH2), 2.71 (m, 2 H, CH2), 7.88 (m, 2 Harom),
8.07 (m, 2 Harom).
13C NMR (75 MHz, DMSO-d6): d = 18.9 (CH2), 19.7 (CH2), 20.2 (2
CH2), 124.7 (2 CHarom), 128.8 (2 Carom), 134.8 (C-4), 136.22 (2
CHarom), 147.4 (C-5), 157.8 (C=O), 162.8 (2 C=O).
2,3-Dihydro-3-hydroxy-4,5-dimethyl-2-[4-oxo-3(4H)-quinazoli-
nyl]isothiazole 1,1-Dioxide (18a)
Yield: 91 mg (33%) (from 11a); white solid; mp 220–223 °C.
IR (KBr): 1714 (C=O), 1613 (C=N), 1325 (SO2), 1178 (SO2) cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.98 (s, 3 H, CH3 at C-4), 2.07
(s, 3 H, CH3 at C-5), 5.84 (s, 1 H, H-3), 7.40 (s, 1 H, OH), 7.64 (m,
1 Harom, H-6¢), 7.76 (m, 1 Harom, H-8¢), 7.92 (m, 1 Harom, H-7¢), 8.17
(m, 1 Harom, H-5¢), 8.19 (s, 1 H, H-2¢).
13C NMR (100 MHz, DMSO-d6): d = 7.3 (CH3 at C-5), 12.2 (CH3
at C-4), 83.2 (C-3), 122.2 (C-4a¢), 126.6 (C-5¢), 127.7 (C-8¢), 128.1
(C-6¢), 129.4 (C-5), 135.5 (C-7¢), 141.5 (C-4), 146.5 (C-8a¢), 149.3
(C-2¢), 158.6 (C=O).
MS (EI): m/z = 332 [M]+.
Anal. Calcd for C15H12N2O5S: C, 54.21; H, 3.64; N, 8.43; S, 9.65.
Found: C, 54.29; H, 3.58; N, 8.47; S, 9.64.
2,3-Dihydro-3-hydroperoxy-4,5-dimethyl-2-[2-methyl-4-oxo-
3(4H)-quinazolinyl]isothiazole 1,1-Dioxide (16b)
H2O2 (2.8 mL, 30%) was added at r.t. to a stirred suspension of 11b
(0.7 mmol) in AcOH (4.2 mL). After 48 h, H2O and AcOH were re-
moved in vacuum and the residue was washed with a mixture of
H2O–EtOH (3 mL, 2:3) to give a white precipitate; yield: 73 mg
(31%); white solid; mp 108–111 °C.
1H NMR (300 MHz, DMSO-d6): d = 2.15 (s, 3 H, CH3), 2.72 (s, 3
H, CH3), 2.81 (s, 3 H, CH3), 6.12 (s, 1 H, H-3), 7.52 (m, 1 Harom, H-
6¢), 7.63 (d, J = 8.6 Hz, 1 Harom, H-8¢), 7.87 (m, 1 Harom, H-7¢), 8.13
(d, J = 8.8 Hz, 1 Harom, H-5¢), 11.74 (s, 1 H, OOH).
13C NMR (75 MHz, DMSO-d6): d = 7.4 (CH3), 11.9 (CH3), 22.0
(CH3 at C-2¢), 93.9 (C-3), 121.8 (C-4a¢), 126.8 (C-5¢), 127.1 (C-8¢),
127.5 (C-6¢), 133.5 (C-4), 135.3 (C-7¢), 137.5 (C-5), 146.1 (C-8a¢),
157.8 (C-2¢), 159.5 (C=O).
MS (EI): m/z = 307 [M]+.
Anal. Calcd for C13H13N3O4S: C, 50.81; H, 4.26; N, 13.67; S, 10.43.
Found: C, 50.69; H, 4.35; N, 13.65; S, 10.47.
2,3-Dihydro-3-hydroxy-4,5-dimethyl-2-[2-methyl-4-oxo-3(4H)-
quinazolinyl]isothiazole 1,1-Dioxide (18b)
Yield: 61 mg (95%) (from 16b); 52 mg (18%) (from 11b); white
solid; mp 238–240 °C.
IR (KBr): 1709 (C=O), 1608 (C=N), 1315 (SO2), 1173 (SO2) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.05 (s, 3 H, CH3 at C-4), 2.05
(s, 3 H, CH3 at C-5), 2.64 (s, 3 H, CH3 at C-2¢), 5.87 (d, J = 4.8 Hz,
1 H, H-3), 7.30 (d, J = 6.6 Hz, 1 H, OH), 7.54 (m, 1 Harom, H-6¢),
7.66 (m, 1 Harom, H-8¢), 7.87 (m, 1 Harom, H-7¢), 8.08 (m, 1 Harom, H-
5¢).
13C NMR (75 MHz, DMSO-d6): d = 7.4 (CH3 at C-5), 12.2 (CH3 at
C-4), 22.0 (CH3 at C-2¢), 83.7 (C-3), 121.1 (C-4a¢), 126.5 (C-5¢),
127.1 (C-8¢), 127.2 (C-6¢), 129.6 (C-5), 135.5 (C-7¢), 141.5 (C-4),
146.1 (C-8a¢), 157.7 (C-2¢), 159.0 (C=O).
MS (EI): m/z = 337 [M]+.
Anal. Calcd for C14H15N3O5S: C, 49.85; H, 4.48; N, 12.46; S, 9.50.
Found: C, 49.11; H, 4.23; N, 12.61; S, 9.08.
4,5-Dimethyl-2-[N-(2-nitro)benzamidyl]isothiazol-3(2H)-one
1,1-Dioxide (17)
H2O2 (2.8 mL, 30%) was added at r.t. to a stirred suspension of 11b
(0.7 mmol) in AcOH (4.2 mL). The solution was stirred for 18–20
h at 80 °C. After cooling, H2O and AcOH were removed in vacuum.
Cold H2O (3 mL) was added to the residue and the precipitated solid
was isolated and recrystallized from EtOH–H2O; yield: 64 mg
(28%); white solid; mp 242–244 °C.
MS (EI): m/z = 321 [M]+.
Anal. Calcd for C14H15N3O4S: C, 52.33; H, 4.70; N, 13.08; S, 9.98.
Found: C, 52.21; H, 4.77; N, 13.15; S, 9.84.
IR (KBr): 1758 (C=O), 1690 (C=O), 1533 (NO2), 1351 (NO2), 1329
(SO2), 1186 (SO2) cm–1.
1H NMR (300 MHz, acetone-d6): d = 2.12 (s, 3 H, CH3), 2.33 (s, 3
H, CH3), 7.85–7.82 (m, 2 Harom), 7.91 (d, J = 8 Hz, 1 Harom), 8.16 (d,
J = 8 Hz, 1 Harom), 10.40 (s, 1 H, NH).
2,3,4,5,6,7-Hexahydro-3-hydroxy-2-[4-oxo-3(4H)-quinazoli-
nyl]-1,2-benzisothiazole 1,1-Dioxide (18c)
Yield: 48 mg (16%) (from 11c); white solid; mp 217–220 °C.
Synthesis 2008, No. 7, 1133–1141 © Thieme Stuttgart · New York

1140
V. M. Zakharova et al.
PAPER
IR (KBr): 1674 (C=O), 1609 (C=N), 1308 (SO2), 1182 (SO2) cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.75 (m, 4 H, 2 CH2), 2.38 (m,
2 H, CH2), 2.48 (m, 2 H, CH2), 5.89 (d, J = 6.8 Hz, 1 H, H-3), 7.39
1H NMR (300 MHz, acetone-d6): d = 2.43 (s, 3 H, CH3 at C-4), 2.61
(s, 3 H, CH3 at C-5), 2.87 (s, 3 H, CH3 at C-2¢), 7.57 (d, J = 8 Hz, 1
H
arom), 7.70 (m, 1 Harom), 7.92 (m, 1 Harom), 8.16 (d, J = 8 Hz, 1
Harom).
(d, J = 7.2 Hz, 1 H, OH), 7.61 (m, 1 Harom, H-6¢), 7.72 (m, 1 Harom
,
H-8¢), 7.91 (m, 1 Harom, H-7¢), 8.16 (m, 1 Harom, H-5¢), 8.22 (s, 1 H,
13C NMR (75 MHz, acetone-d6): d = 8.6 (CH3 at C-5), 9.5 (CH3 at
C-4), 21.7 (CH3 at C-2¢), 121.5 (C-4a¢), 127.8 (C-5¢), 128.4 (C-8¢),
128.6 (C-6¢), 134.6 (C-4), 136.6 (C-7¢), 145.2 (C-8a¢), 147.4 (C-5),
156.1 (C-2a¢), 157.8 (C=O), 160.4 (C=O).
H-2¢).
13C NMR (100 MHz, DMSO-d6): d = 18.17, 21.5, 20.6, 22.7 (4
CH2), 82.9 (C-3), 122.0 (C-4a¢), 126.4 (C-5¢), 127.7 (C-8¢), 128.1
(C-6¢), 132.2 (C-7a), 135.0 (C-7¢), 144.6 (C-3a), 147.2 (C-8a¢),
150.0 (C-2¢), 158.5 (C=O).
MS (EI): m/z = 319.1 [M]+.
Anal. Calcd for C14H13N3O4S: C, 52.66; H, 4.10; N, 13.16; S, 10.04.
Found: C, 52.28; H, 4.11; N, 13.31; S, 10.20.
MS (EI): m/z = 333 [M]+.
Anal. Calcd for C15H15N3O4S: C, 54.04; H, 4.54; N, 12.60; S, 9.62.
Found: C, 54.18; H, 4.52; N, 12.67; S, 9.68.
4,5,6,7-Tetrahydro-2-[2-methyl-4-oxo-3(4H)-quinazolinyl]-1,2-
benzisothiazol-3(2H)-one 1,1-Dioxide 19d
Yield: 63 mg (73%); white solid; mp 135–137 °C.
2,3,4,5,6,7-Hexahydro-3-hydroxy-2-[2-methyl-4-oxo-3(4H)-
quinazolinyl]-1,2-benzisothiazole 1,1-Dioxide (18d)
Yield: 50 mg (16%) (from 11d); white solid; mp 233–235 °C.
IR (KBr): 1765 (C=O), 1702 (C=O), 1612 (C=N), 1238 (SO2), 1173
(SO2) cm–1.
IR (KBr): 1691 (C=O), 1609 (C=N), 1314 (SO2), 1173 (SO2) cm–1.
1H NMR (400 MHz, acetone-d6): d = 1.9 (m, 2 H, CH2), 1.98 (m, 2
H, CH2), 2.58 (m, 2 H, CH2), 2.61 (s, 3 H, CH3 at C-2¢), 2.72 (m, 2
H, CH2), 7.58 (d, J = 8 Hz, 1 Harom), 7.70 (m, 1 Harom), 7.91 (m, 1
Harom), 8.16 (d, J = 8 Hz, 1 Harom).
13C NMR (100 MHz, acetone-d6): d = 19.9 (CH2), 20.9 (CH2), 21.2
(CH2), 21.3 (CH3 at C-2¢), 21.7 (CH2), 121.5 (C-4a¢), 127.8 (C-5¢),
128.4 (C-8¢), 128.6 (C-6¢), 136.6 (C-7¢), 137.4 (C-3a), 147.4 (C-
8a¢), 148.2 (C-7a), 156.2 (C-2a¢), 157.9 (C=O), 159.7 (C=O).
1H NMR (300 MHz, acetone-d6): d = 1.83 (m, 2 H, CH2), 2.36 (m,
2 H, CH2), 2.70 (s, 3 H, CH3 at C-2¢), 2.90 (m, 4 H, 2 CH2), 6.07 (d,
J = 7.5 Hz, 1 H, H-3), 6.48 (d, J = 8.1 Hz, 1 H, OH), 7.51 (m, 1
Harom, H-6¢), 7.64 (d, J = 8.33 Hz, 1 Harom, H-8¢), 7.87 (m, 1 Harom
H-7¢), 8.13 (d, J = 9.0 Hz, 1 Harom, H-5¢).
,
13C NMR (75 MHz, acetone-d6): d = 19.4 (CH2), 21.7 (CH3), 21.9
(3 CH2), 22.7, 23.7, 84.7 (C-3), 122.6 (C-4a¢), 127.4 (C-5¢), 127.7
(C-8¢), 128.2 (C-6¢), 134.2 (C-7a), 135.9 (C-7¢), 144.8 (C-3a), 147.6
(C-8a¢), 158.8 (C-2¢), 160.3 (C=O).
MS (EI): m/z = 345.1 [M]+.
Anal. Calcd for C16H15N3O4S: C, 55.64; H, 4.38; N, 12.17; S, 9.28.
Found: C, 55.37; H, 4.51; N, 12.01; S, 9.33.
MS (EI): m/z = 347 [M]+.
Anal. Calcd for C16H17N3O4S: C, 55.32; H, 4.93; N, 12.10; S, 9.23.
Found: C, 55.61; H, 4.79; N, 12.16; S, 9.20.
X-ray Crystal Structure Analysis
Crystals of compounds 15a, 18b, 19d were obtained from acetone-
d6. The intensities were measured on an IPDS1 diffractometer
(STOE). The structures were solved by direct methods, and refine-
ment was performed with SHELX-97.23,24
2-[4-Oxo-3(4H)-quinazolinyl]isothiazol-3(2H)-one 1,1-Dioxides
19; General Procedure
To a stirred solution of 3-hydroxysultam 18 (0.25 mmol) in CH2Cl2
(2 mL) was added (pyH)2Cr2O7 (0.63 mmol) at r.t. The mixture was
stirred 8 h and purified by column chromatography using EtOAc as
eluent. After removal of the solvent, the colorless crystals were
washed with EtOH (2 mL) and collected by filtration.
Enzyme Inhibition
Acetyl cholinesterase from Electrophorus electricus was assayed
spectrophotometrically at 412 nm at 25 °C in duplicate experi-
ments.25,26 Assay buffer was 100 mM Na3PO4 in 100 mM NaCl, pH
7.3. Acetyl thiocholine (ATCh) (10 mM) and 5,5¢-dithiobis(2-ni-
trobenzoic acid) (DTNB) (7 mM) were dissolved in the assay buff-
er. Stock solutions of the inhibitors were prepared in MeCN. Into a
cuvette containing 825 mL of assay buffer were added 50 mL of the
DTNB solution, 55 mL MeCN, 10 mL of an inhibitor solution, and
10 mL of an enzyme solution (~3 U/mL), and the contents were thor-
oughly mixed. After incubation for 15 min at 25 °C, the reaction
was initiated by adding 50 mL of the ATCh solution and was fol-
lowed over 5 min. IC50 values were calculated from the linear
steady-state turnover of the substrate using the four-parametric lo-
gistic equation. Compounds 13a and 13b were measured at six dif-
ferent concentrations between 5 and 30 mM.
4,5-Dimethyl-2-[4-oxo-3(4H)-quinazolinyl]isothiazol-3(2H)-one
1,1-Dioxide (19a)
Yield: 67 mg (88%); white solid; mp 188–190 °C.
IR (KBr): 1756 (C=O), 1712 (C=O), 1605 (C=N), 1347 (SO2), 1180
(SO2) cm–1.
1H NMR (300 MHz, acetone-d6): d = 2.13 (s, 3 H, CH3 at C-4), 2.40
(s, 3 H, CH3 at C-5), 7.69 (m, 1 Harom), 7.84 (d, J = 8 Hz, 1 Harom),
7.99 (m, 1 Harom), 8.20 (d, J = 8 Hz, 1 Harom), 8.49 (s, 1 H, H-2¢)
13C NMR (75 MHz, acetone-d6): d = 8.3 (CH3 at C-5), 9.3 (CH3 at
C-4), 121.4 (C-4a¢), 126.9 (C-5¢), 128.1 (C-8¢), 128.7 (C-6¢), 133.6
(C-4), 136.2 (C-7¢), 143.6 (C-8a¢), 146.4 (C-5), 147.1 (C-2a¢), 156.5
(C=O), 158.7 (C=O).
Human leukocyte elastase (HLE) was assayed spectrophotometri-
cally at 405 nm at 25 °C in duplicate experiments.13 Assay buffer
was 50 mM sodium phosphate buffer in 500 mM NaCl, pH 7.8. In-
hibitor stock solutions were prepared in DMSO. A stock solution of
the chromogenic substrate MeOSuc-Ala-Ala-Pro-ValpNA was pre-
pared in DMSO and diluted with assay buffer. Final concentration
of the chromogenic substrate MeOSuc-Ala-Ala-Pro-ValpNA was
100 mM, final concentration of DMSO was 1.5%. Assays were per-
formed with a final HLE concentration of 50 ng/mL. Into a cuvette
containing 890 mL of assay buffer were added 10 mL of an inhibitor
solution, 50 mL of the substrate solution, and the contents were thor-
oughly mixed. The reaction was initiated by adding 50 mL of the
HLE solution and was followed over 10 min.
MS (EI): m/z = 305.1 [M]+.
Anal. Calcd for C13H11N3O4S: C, 51.14; H, 3.63; N, 13.76; S 10.50.
Found: C, 50.85; H, 3.51; N, 13.49; S, 10.36.
4,5-Dimethyl-2-[2-methyl-4-oxo-3(4H)-quinazolinyl]isothiazol-
3(2H)-one 1,1-Dioxide 19b
Yield: 57 mg (71%); white solid; mp 205–208 °C.
IR (KBr): 1758 (C=O), 1708 (C=O), 1608 (C=N), 1342 (SO2), 1176
(SO2) cm–1.
Synthesis 2008, No. 7, 1133–1141 © Thieme Stuttgart · New York

PAPER
Oxidation of S,N-Heteroaromatic Cations to N,N¢-Linked Bisazaheterocycles
1141
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Acknowledgment
The work was supported by the Deutsche Forschungsgemeinschaft,
the Graduiertenkolleg 378 ‘Mechanistische und Anwendungs-
aspekte nichtkonventioneller Oxidationsreaktionen’, and the Gra-
duiertenkolleg 677 ‘Struktur und molekulare Interaktion als Basis
der Arzneimittelwirkung’.
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Triclinic; space group P–1; Unit cell dimensions a = 8.030
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D
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(20) Crystal data for 18d: C16H17N3O4S·H2O; M = 365.4; T = 213
(2) K; l = 0.71073 Å; Colorless prism; 0.2 × 0.2 × 0.2 mm3;
Triclinic; Space group P–1; Unit cell dimensions a = 8.163
(2) Å, b = 8.906 (2) Å, c = 11.862 (4) Å, a = 83.76 (2)°,
b = 87.82 (2)°, g = 81.28 (2)°, V = 847.1 (4) Å3, Z = 2,
D
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(21) Crystal data for 19b: C14H13N3O4S; M = 319.3; T = 213 (2)
K; l = 0.71073 Å; Colorless prism; 0.3 × 0.2 × 0.2 mm3;
Orthorhombic; Space group Pna21; Unit cell dimensions
a = 10.811 (1) Å, b = 12.632 (1) Å, c = 10.654 (1) Å,
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R1 = 0.0281, wR2 = 0.0681; Largest diff. Peak/hole 0.183/
–0.136 e Å–3.
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the data can be obtained, free of charge, from CCDC, 12
Union Road, Cambridge, CB2 1EZ UK (fax: +44 1233
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Synthesis 2008, No. 7, 1133–1141 © Thieme Stuttgart · New York