Synthesis of diazaheterocyclic ring-fused 1,2,4-benzothiadiazine 1,1-dioxides by a sequential aza-Wittig/NH-addition cyclization/nucleophilic ring-closure methodology with N-alkenyl-2-carbodiimidobenzenesulfonamides as key intermediates

Article abstract of DOI:10.1002/ejoc.200701131

Treatment of N-alkenyl-2-azidobenzenesulfonamides with triphenylphosphane and subsequent subjection of the resulting iminophosphoranes to aza-Wittig reactions with isocyanates generated functionalized carbodiimides, which spontaneously underwent cyclization to form 2-alkenyl-3-(R²- substituted amino)-2H-1,2,4-benzothiadiazine 1,1-dioxides by internal nucleophilic addition. Subsequent (tandem) cyclizations through iodoamination or hydroamination with Hg^II/NaBH₄ produced a variety of diazaheterocyclic ring-fused benzothiadiazine dioxides. In one case a methanobridged benzothiatriazabicyclotridecanone was obtained. The scope and limitations of these cyclizations are reported. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200701131

FULL PAPER
DOI: 10.1002/ejoc.200701131
Synthesis of Diazaheterocyclic Ring-Fused 1,2,4-Benzothiadiazine 1,1-Dioxides
by a Sequential Aza-Wittig/NH-Addition Cyclization/Nucleophilic
Ring-Closure Methodology with N-Alkenyl-2-carbodiimidobenzenesulfonamides
as Key Intermediates
Shinsuke Hirota,[a] Ryo Kato,[a] Madoka Suzuki,[a] Yuji Soneta,[a] Takashi Otani,*[a] and
Takao Saito*[a]
Keywords: Tandem reactions / Carbodiimides / Nitrogen heterocycles / Fused-ring systems / 1,2,4-Benzothiadiazine
1,1-dioxides
Treatment of N-alkenyl-2-azidobenzenesulfonamides with
cyclizations through iodoamination or hydroamination with
triphenylphosphane and subsequent subjection of the re- HgII/NaBH4 produced a variety of diazaheterocyclic ring-
sulting iminophosphoranes to aza-Wittig reactions with iso-
cyanates generated functionalized carbodiimides, which
spontaneously underwent cyclization to form 2-alkenyl-3-
(R2-substituted amino)-2H-1,2,4-benzothiadiazine 1,1-diox-
ides by internal nucleophilic addition. Subsequent (tandem)
fused benzothiadiazine dioxides. In one case a methano-
bridged benzothiatriazabicyclotridecanone was obtained.
The scope and limitations of these cyclizations are reported.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
Cyclic guanidine moieties are found in a variety of biolo-
gically active natural compounds, such as marine alka-
loids.[1] One of the most convenient synthetic methods for
cyclic guanidines would be nucleophilic addition of a nitro-
gen species to a functionalized carbodiimide. Many groups
(Molina,[2] Wamhoff,[3] Ding,[4] Quintela,[5] Eguchi,[6] Nog-
uchi,[7] Nitta,[8] and Abe[9]), also including our own,[10] have
independently developed various (tandem) processes involv-
ing aza-Wittig reactions between iminophosphoranes and
isocyanates to give functionalized carbodiimides, followed
by various types of ring-forming reaction (Scheme 1).[11]
These variously functionalized carbodiimides undergo
initial cyclizations onto the cumulene functionality, in the
forms of: a) intramolecular addition of a nitrogen nucleo-
phile,[6b,9c,10b] b) electrocyclization,[5a] c) intermolecular
[4+2] cycloaddition,[8a,8b] or d) intermolecular nucleophilic
addition of an amine and various subsequent types of ring-
forming reactions between the acyclic guanidine nitrogen
and the available inner functional group, to give monocyclic
guanidines A.[3c,4e,6a,7b–d,10a,12] The second cyclization of the
monocyclic guanidines A, in which the R group is a func-
Scheme 1. a) Intramolecular nucleophilic addition, b) electrocycl-
ization, c) [4 + 2] cycloaddition, or d) intermolecular nucleophilic
addition, followed by various types of ring-forming reaction.
tional group reacting with the internal amino group, leads
to the formation of the bicyclic guanidines B [step (e)]. In-
deed, various types of second cyclization reactions with the
resulting guanidine nitrogen – including nucleophilic substi-
tution,[6b] nucleophilic addition,[2h,4e,12] Michael ad-
dition,[10c] and iodoamination[6,7b–7d] – have been success-
fully applied. Ring-closing metathesis of A was also re-
ported when R and RЈ were terminal alkenyl groups.[3d]
[a] Department of Chemistry, Faculty of Science, Tokyo University
of Science,
Kagurazaka, Shinjuku, Tokyo, 162-8601, Japan
Fax: +81-3-5261-4631
E-mail: totani@rs.kagu.tus.ac.jp
tsaito@rs.kagu.tus.ac.jp
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 2075–2083
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. Hirota, R. Kato, M. Suzuki, Y. Soneta, T. Otani, T. Saito
FULL PAPER
Thus, synthetic methods for a variety of bicyclic guanidines Table 1. Preparation of iminophosphoranes 4.
have been developed by the sequential cyclization method-
ology with the combined use of a wide range of bond-form-
ing transformations. The utility of this methodology has
been shown by the fact that appropriate routes have been
applied as key steps in syntheses of mono- and bicyclic gua-
nidine natural products such as the monocyclic guanidines
leucettamine B,[2c] isonaanime A,[2d] doriimiazole A,[2d] pre-
clathridine A,[2d] and variolin B,[2e] as well as the bicyclic
guanidines (+)-batzelladine A and (–)-batzelladine D.[13]
3-Amino-1,2,4-benzothiadiazine 1,1-dioxides are known
to possess diverse biological activities, including potas-
sium[14] and calcium[15] channel modulation and adrenergic
antagonism effects.[16,17a] Moreover, various azaheterocycle-
fused 1,2,4-benzothiadiazine 1,1-dioxide derivatives are
expected to display a variety of concomitant bioactivi-
ties,[16,17a] so the development of simple synthetic methods
to prepare such heterocycles is of value. A survey of the
literature showed us that multistep sequences seemed to be
necessary in order to gain access to these heterocyclic ring-
fused benzothiazine derivatives.[16,17] We therefore started
our own study on the synthesis of a variety of diazahetero-
cyclic ring-fused 1,2,4-benzothiadiazine 1,1-dioxides by a
tandem cyclization methodology using 2-(N-alkenylsulfa-
moyl)phenylcarbodiimides as the key intermediates.[18] For
the tandem cyclization protocol to produce bicyclic guani-
dines, we employed iodocyclization[19] and hydroamin-
ation[20] with HgII/NaBH4 (aminomercuration/demercura-
tion) as the second ring-closing reaction between alkenyl
and amine groups after the initial cyclization by internal
nucleophilic sulfonamide/NH addition onto the cumulene
carbon. Although each cyclization is a well documented re-
action, it is rare for the cyclizations to be used combinatori-
ally in a tandem methodology for heterocumulene-mediated
synthesis of fused heterocycles bearing multicyclic guani-
dine moieties.[6,7] We report here the novel synthesis of five-
to seven-membered aza-heterocyclic ring-fused 1,2,4-benzo-
thiadiazine 1,1-dioxides by this tandem methodology.[18]
Entry
2
R1
4
% Yield[a]
1
2
3
4
5
6
2A
2B
2C
2D
2E
2F
CH2CH=CH2
4A
94
87
87
96
92
87
(CH2)2CH=CH2 4B
(CH2)3CH=CH2 4C
(CH2)4CH=CH2 4D
nPr
Ph
4E
4F
[a] Conversion from 1.
Table 2. Preparation of guanidines 7.
Entry
4
5
Conditions
7
% Yield
1
2
3
4
5
6
7
8
4A
4A
4A
4A
4A
4B
4B
4B
4B
4B
4C
4C
4C
4C
4C
4D
4D
4D
4D
4D
4E
4F
5a
5b
5c
5d
5e
5a
5b
5c
5d
5e
5a
5b
5c
5d
5e
5a
5b
5c
5d
5e
5e
5e
PhMe, 110 °C, 13 h
PhMe, 110 °C, 2 h
PhMe, 110 °C, 2 h
7Aa
7Ab
7Ac
99
90
90
99
92
99
89
94
97
91
99
97
94
98
90
99
95
93
99
85
94
99
CH2Cl2, room temp., 0.5 h 7Ad
PhMe, 110 °C, 5 h
PhMe, 110 °C, 6 h
PhMe, 110 °C, 3 h
PhMe, 110 °C, 3 h
7Ae
7Ba
7Bb
7Bc
9
CH2Cl2, room temp., 0.2 h 7Bd
10
11
12
13
14
15
16
17
18
19
20
21
22
PhMe, 110 °C, 6 h
PhMe, 110 °C, 4 h
PhMe, 110 °C, 3 h
PhMe, 110 °C, 3 h
7Be
7Ca
7Cb
7Cc
Results and Discussion
CH2Cl2, room temp., 0.2 h 7Cd
PhMe, 110 °C, 5 h
PhMe, 110 °C, 5 h
PhMe, 110 °C, 3 h
PhMe, 110 °C, 3 h
7Ce
7Da
7Db
7Dc
The prerequisite iminophosphoranes 4 were prepared by
treatment of o-azidobenzenesulfonyl chloride (1) with
amines 2 in the presence of triethylamine, followed by
Staudinger reactions of the resultant azides 3 with tri-
phenylphosphane (Table 1). The reactions between 4 and
various isocyanates 5 proceeded smoothly under the condi-
tions described in Table 2 to produce 3-aminobenzo-1,2,4-
thiadiazine 1,1-dioxides 7[21] in good to excellent yields. The
CH2Cl2, room temp., 0.2 h 7Dd
PhMe, 110 °C, 4 h
PhMe, 110 °C, 5 h
PhMe, 110 °C, 3 h
7De
7Ee
7Fe
carbodiimides 6 would be the most probable intermediate and N-homoallylbenzothiadiazines 7Aa–7Ad (n = 1) and
formed by the initial aza-Wittig reaction.[22] Subsequent in- 7Ba–7Bd (n = 2) underwent iodocyclization smoothly in the
tramolecular nucleophilic addition of NH to the cumulene presence of threefold molar excesses of molecular iodine
carbon of 6 would provide 7 as the final product.[22]
and K2CO3 at room temperature in CH2Cl2 to produce im-
The benzothiadiazine 1,1-dioxides 7, bearing substitu- idazo and pyrimido ring-fused benzothiadiazines 8a–d and
ents with carbon chain lengths of n = 1, 2, 3, were subjected 9a–d, respectively, in good to high yields and with excellent
to iodocyclization (Method A) and aminomercuration/de- selectivity for the exo-trig mode (Table 3, Entries 1–8).[23]
mercuration (Method B) cyclizations (Scheme 2). N-Allyl Similarly, benzothiadiazines 7Ca–7Cd with a chain length
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Diazaheterocyclic Ring-Fused 1,2,4-Benzothiadiazine 1,1-Dioxides
Scheme 2. Syntheses of diazaheterocyclic ring-fused benzothiadiazine 1,1-dioxides 8–13 by iodoamination (Method A) or hydroamination
(Method B) of 7 and by the one-pot method from 4.
of n = 3 gave diazepine-fused benzothiadiazines 10b–d in Table 4. Syntheses of diazaheterocyclic ring-fused benzothiadiazine
1,1-dioxides 11–13 by hydroamination of 7 (Method B) and by the
high yields (Entries 10–12), except in one case of a 41%
one-pot method from 4.
yield (Entry 9, 10a). It is noteworthy that the one-pot
R2
Time [h]
Product
% Yield
from 7 from 4
method in tandem[24] through three steps starting from imi-
nophosphoranes 4 was efficiently applied to these iodoam-
ination cyclizations to provide the target compounds 8–10
in fair to high yields.
Entry
n
1
2
3
4
5
6
7
8
1
1
1
1
2
2
2
2
3
3
3
3
nPr
Ph
pTol
Ts
nPr
Ph
pTol
Ts
nPr
Ph
pTol
Ts
0.1
0.5
0.5
6
5
2
11a
11b
11c
11d
12a
12b
12c
12d
13a
13b
13c
13d
85
91
93
66
86
70
66
57
61
56
64
47
80
88
88
50
72
72
70
66
47
47
57
37
Table 3. Syntheses of diazaheterocyclic ring-fused benzothiadiazine
1,1-dioxides 8–10 by iodoamination of 7 (Method A) and by the
one-pot method from 4.
2
Entry
n
R2
Time [h]
% Yield
48
12
3
2
48
Product
from 7
from 4
9
10
11
12
1
2
3
4
5
6
7
8
1
1
1
1
2
2
2
2
3
3
3
3
nPr
Ph
pTol
Ts
nPr
Ph
pTol
Ts
nPr
Ph
pTol
Ts
1
2
2
15
1
0.5
0.5
1
8a
8b
92
99
97
92
88
89
94
96
41
99
95
99
97
90
90
99
55
81
81
90
35
92
93
96
8c
8d
9a
9b
We next examined the regioselectivities of the two cycli-
zations – iodoamination (Method A) and hydroamination
(Method B) – of 1,2,4-benzothiadiazine 1,1-dioxides 7Ae–
7Ce bearing two alkenyl groups, one at the endocyclic N at
the 2-position (R1) and the other at the exocyclic N at the
3-position. If the alkenyl group at the 2-position (R1) were
involved in cyclizations by either Method A or B, products
9c
9d
9
26
0.5
3
10a
10b
10c
10d
10
11
12
8
Hydroamination of alkenylbenzothiadiazines 7 with 16 and 17 would be formed in the same manner as de-
HgII–NaBH4 (aminomercuration/demercuration, Method scribed in Tables 3 and 4, respectively. Alternatively, if the
B) also proceeded smoothly to afford the corresponding cyclizations were to take place on the N-allyl group at the
exo-mode cyclization products 11–13 (Table 4). Thus, treat- 3-position, then the corresponding products would be com-
ment of 7 with Hg(OAc)2 in CH2Cl2, followed by treatment pounds 14 and 15. In fact, compounds 14A (Method A)
with aqueous NaOH and NaBH4, yielded five- to seven- and 15A (Method B) were obtained in 92% and 86% yields,
membered ring-fused products 11–13, with no endo-mode- respectively, from 7Ae (Table 5, Entries 1 and 6). Similarly,
cyclized products being formed. The one-pot procedure for the 2-(but-3-enyl)- and 2-(pent-4-enyl)-1,2,4-benzothiadiaz-
this tandem cyclization starting from iminophosphoranes 4 ine 1,1-dioxides 7Be and 7Ce reacted regioselectively to pro-
was also found to be effective, the results comparing favor- duce the cyclized products 14B and 14C (Entries 2 and 3)
ably with those of the stepwise methods.
and 15C (Entry 7) in moderate to good yields. As expected,
Eur. J. Org. Chem. 2008, 2075–2083
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S. Hirota, R. Kato, M. Suzuki, Y. Soneta, T. Otani, T. Saito
FULL PAPER
7Ee and 7Fe also gave 14E and 14F (Entries 4 and 5) and = Ph) and 7Dc (R2 = pTol) were carried out at 80 °C in 1,2-
15F (Entry 8) in good yields. It was of interest that the ni- dichloroethane, compounds 19b and 19c, and not 18b and
trogen at the 4-position rather than the exocyclic allylamino 18c, were obtained in 15% and 18% yields, respectively,
nitrogen of 7 was a predominant participant as an active along with the starting materials (7Db: 61%, 7Dc: 61%).
nucleophile in both cyclizations to form the [2,1-c]-fused The reaction yielding 18b and 18c would be a useful novel
imidazoline ring system exclusively.
synthetic method for novel 12-membered bicyclic thiatriaza
heterocycles.
Table 5. Stepwise iodoamination (Method A) and hydroamination
(Method B) method for 7Ae–7Fe.
Scheme 3. Iodocyclization of 7Db and 7Dc.
Entry
7
n
Method
Time Product % Yield
1
2
3
4
5
6
7
8
7Ae
7Be
7Ce
7Ee
7Fe
7Ae
7Ce
7Fe
1
2
3
–
–
1
3
–
A[a]
A[a]
A[a]
A[a]
A[a]
B[b]
B[b]
B[b]
3
22
0.5
0.2
4
6
6
14A
14B
14C
14E
14F
15A
15C
15F
92
44
42
96
82
86
60
83
5
[a] Method A: I2 (3.0 equiv.), CH2Cl2, room temp., time stated.
[b] Method B: 1) Hg(OAc)2 (1.0 equiv.), CH2Cl2, room temp., time
stated. 2) NaBH4, NaOH aq. room temp., 1 h.
Figure 1. Crystal structure of 18b.
Further efforts were made to obtain eight-membered
These results can be explained as shown in Scheme 4.
ring-fused benzothiadiazines from 7, bearing a hex-5-enyl The reaction is initiated by an 8-exo-trig mode iodocycli-
group at the 2-position (R1).[25] Disappointingly, neither the zation to form the anticipated intermediate A, and subse-
iodoamination nor the aminomercuration of 7Da (R2
=
quent intramolecular nucleophilic attack by the proximal
nPr) and 7Dd (R2 = Ts) proceeded under the above reaction nitrogen then leads to the iminium salt B. Hydrolysis of
conditions, resulting in quantitative recovery of the starting salt B by a small amount of contaminating water or during
materials. However, compounds 7Db (R2 = Ph) and 7Dc workup then takes place at room temperature finally to give
(R2 = pTol) did react under the iodocyclization conditions 18b and 18c via the hemiaminal intermediate C, whereas
to give the unexpected products 18b and 18c, albeit in low upon heating, nucleophilic attack by an iodide anion in B
yields (18b: 16%, 18c: 17%) with recovery of 7Db (62%) occurs to give 19b and 19c. This is probably because the
and 7Dc (72%) (Scheme 3). The product structures were de- salt B has both the more nucleophilic iodide anion and the
duced by various NMR spectroscopy techniques and were iminium-sulfonamide group with good leaving ability in a
unambiguously determined by X-ray structural analysis of strained bridging structure. The formation of the initial
18b (Figure 1). Interestingly, when the reactions of 7Db (R2 iodocyclization intermediate A is supported by the fact that
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Diazaheterocyclic Ring-Fused 1,2,4-Benzothiadiazine 1,1-Dioxides
and 13C NMR spectroscopic data were obtained with a JEOL
JNM-EX 500, a JEOL JNM-EX 300, or a Bruker AV 600 instru-
ment. Chemical shifts (δ) are quoted in ppm relative to tetramethyl-
silane (δ = 0) for 1H NMR and CDCl3 (δ = 77.0) for 13C NMR
spectroscopy. Mass spectra were measured on a Bruker Daltonics
microTOF or a Hitachi double-focusing M-80B spectrometer. Ele-
mental analyses were performed with a Yanaco CHN-CODER
MT-6 model. Column chromatography was conducted on silica gel
60 (Kanto Chemical Co.).
upon heating 10b and 10c (isolated in the case of chain
length n = 3, Table 3, Entries 10 and 11) at 115 °C in chlo-
robenzene, the analogous transformation of 10b and 10c to
20b and 20c (b: 68%, c: 72% yield) was observed
(Scheme 5).
Typical Procedure for Preparation of Iminophosphoranes 4: Allyl-
amine (0.38 mL, 5.1 mmol) and triethylamine (1.42 mL, 10.2 mmol)
were added at 0 °C with stirring to a solution of 1[19,26] (1.01 g,
4.64 mmol) in CH2Cl2 (10 mL). After the system had been stirred
for 15 min, triphenylphosphane (1.22 g, 4.64 mmol) in CH2Cl2
(5 mL) was added. The mixture was stirred for 8 h at room tem-
perature and then concentrated under reduced pressure. The resi-
due was purified by column chromatography on silica gel with
CH2Cl2 as the eluent to yield 4a as a colorless solid (2.07 g, 94%).
N-(Prop-2-enyl)-2-[(triphenylphosphoranylidene)amino]benzenesulf-
onamide (4A): M.p. 171–172 °C (hexane/CH2Cl2). 1H NMR
(500 MHz, CDCl3): δ = 3.41 (dddd, J = 1.5, 1.5, 6.0, 6.0 Hz, 2 H,
NCH2), 4.85 [ddt, J = 1.5, 10.2, 1.5 Hz, 1 H, CH=CH2(cis)], 4.91
[ddt, J = 1.5, 17.1, 1.5 Hz, 1 H, CH=CH2(trans)], 5.64 (ddt, J =
10.2, 17.1, 5.8 Hz, 1 H, CH=CH2), 6.45 (dd, J = 1.1, 8.1 Hz, 1 H,
Ar), 6.69 (ddd, J = 1.1, 7.5, 7.7 Hz, 1 H, Ar), 6.86 (t, J = 6.4 Hz,
1 H, NH), 7.01 (ddd, J = 1.7, 7.5, 8.1 Hz, 1 H, Ar), 7.47–7.51 (m,
6 H, PPh3), 7.55–7.59 (m, 3 H, PPh3), 7.74–7.79 (m, 6 H, PPh3),
7.84–7.87 (m, 1 H, Ar) ppm. 13C NMR (125 MHz, CDCl3): δ =
46.2 (CH2), 116.1 (CH2), 116.5 (CH), 121.9 (d, 3JP,C = 11 Hz, CH),
129.0 (d, 3JP,C = 12 Hz, 6 CH), 129.2 (d, 1JP,C = 100 Hz, 3 C), 129.5
Scheme 4. Probable pathways for the formation of 18 and 19.
4
2
4
(d, JP,C = 3 Hz, CH), 130.2 (d, JP,C = 24 Hz, 1 C), 132.3 (d, JP,C
2
= 2 Hz, 3 CH), 132.4 (d, JP,C = 10 Hz, 6 CH), 132.7 (CH), 133.8
(CH), 148.9 (C) ppm. IR (KBr): ν = 1155, 1335, 1464, 1585, 3055,
˜
3174 cm–1. HRMS (ESI): calcd. C27H26N2O2PS [M + H]+:
473.1447; found 473.1444. C27H25N2O2PS (472.54): calcd. C 68.63,
H 5.33, N 5.93; found C 69.03, H 5.61, N 5.66.
Scheme 5. Thermal rearrangement of 10b and 10c.
Typical Procedure for Preparation of Benzo-1,2,4-thiadiazine 1,1-
Dioxides 7 by Aza-Wittig Reactions of Iminophosphoranes 4 and
Subsequent Cyclization: Phenyl isocyanate (49 µL, 0.45 mmol) was
added to a stirred solution of 4B (200 mg, 0.41 mmol) in toluene
(4 mL). The mixture was heated at reflux for 3 h, cooled to room
temperature, and quenched with water (2 mL). The organic layer
was separated, and the aqueous layer was extracted with CH2Cl2
(5 mL). The combined organic extracts were washed with water
Conclusions
In conclusion, we have developed practical syntheses for
a variety of diazaheterocyclic ring-fused 1,2,4-benzothiadi-
azine 1,1-dioxides by a tandem aza-Wittig reaction/intramo-
lecular nucleophilic reaction/iodoamination or hydroamin- (5 mL) and brine (5 mL), dried with MgSO4, and concentrated un-
der reduced pressure. The residue was purified by silica gel column
chromatography with AcOEt/Hex (1:4) as the eluent to yield 7Bb
as a colorless solid (119 mg, 89%).
ation methodology from iminophosphoranes 4. Its advan-
tages, such as convenient tandem synthesis and one-pot
procedures, good to high yields with highly predictable
selectivity, and availability of a broad range of unsaturated
alkenylamines, make this protocol attractive. Particularly
noticeable is the unexpected formation of the methano-
2-(But-3-enyl)-3-phenylamino-2H-1,2,4-benzothiadiazine 1,1-Di-
oxide (7Bb): M.p. 133.6–134.3 °C (hexane/CH2Cl2). 1H NMR
(300 MHz, CDCl3): δ = 2.22 (dt, J = 6.7, 6.7 Hz, 2 H, CH2), 3.79
bridged benzothiatriazabicyclo[8.2.1]tridecanones 18b and (t, J = 6.6 Hz, 2 H, NCH2), 4.80 [d, J = 17.2 Hz, 1 H, CH=CH2
(trans)], 4.84 [d, J = 10.1 Hz, 1 H, CH=CH2 (cis)], 5.59 (ddt, J =
10.1, 17.2, 6.6 Hz, 1 H, CH=CH2), 6.79–7.12 (m, 2 H, Ar, NH),
7.23–7.44 (m, 6 H, Ar), 7.55 (dd, J = 7.7, 7.7 Hz, 1 H, Ar), 7.76
(d, J = 7.8 Hz, 1 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ =
33.7 (CH2), 46.9 (CH2), 118.7 (CH2), 120.4 (2 CH), 121.2 (CH),
124.1 (CH), 124.2 (CH), 125.7 (CH), 127.6 (C), 129.3 (2 CH),
133.35 (CH), 133.41 (CH), 138.6 (C), 143.3 (C), 147.4 (C) ppm. IR
18c with unique structures. Further applications are cur-
rently under investigation in our laboratory.
Experimental Section
General Remarks: All melting points were determined on a Yanaco
MP apparatus and are uncorrected. Infrared spectra were recorded
on a Hitachi 270–30 or a Horiba FT-710 spectrophotometer. 1H
(KBr): ν = 1173, 1335, 1574, 1613, 3363 cm–1. HRMS (ESI): calcd.
˜
C17H17N3NaO2S [M + Na]+ : 350.0934; found 350.0935.
Eur. J. Org. Chem. 2008, 2075–2083
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2079

S. Hirota, R. Kato, M. Suzuki, Y. Soneta, T. Otani, T. Saito
FULL PAPER
C17H17N3O2S (327.40): calcd. C 62.36, H 5.23, N 12.83; found C
62.01, H 5.38, N 13.19.
CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 1.85–2.12 (m, 3 H,
CH2), 2.37 (s, 3 H, CH3), 2.33–2.46 (m, 1 H, CH2), 3.28 (dd, J =
12.4, 12.4 Hz, 1 H, NCH2), 3.73–3.80 (m, 2 H, CH2I), 4.26–4.38
(m, 2 H, NCH, NCH2), 7.11 (dd, J = 0.6, 8.1 Hz, 1 H, Ar), 7.16–
7.22 (m, 5 H, Ar), 7.43 (ddd, J = 1.5, 7.4, 8.2 Hz, 1 H, Ar), 7.71
(dd, J = 1.4, 7.9 Hz, 1 H, Ar) ppm. 13C NMR (150 MHz, CDCl3):
δ = 3.8 (CH2), 21.0 (CH3), 23.1 (CH2), 28.4 (CH2), 47.8 (CH2),
65.1 (CH), 121.0 (CH), 123.8 (CH), 126.0 (2 CH), 126.6 (CH),
126.9 (C), 129.8 (2 CH), 133.0 (CH), 136.3 (C), 142.2 (C), 143.8
Typical Procedure for the Iodocyclization of 7 to Produce 8–10 and
14: K2CO3 (136 mg, 0.98 mmol) and I2 (250 mg, 0.98 mmol) were
added to a stirred solution of benzothiadiazine dioxide 7Bb
(108 mg, 0.33 mmol) in CH2Cl2 (3 mL). After being stirred for
30 min, the reaction mixture was quenched with saturated aqueous
Na2SO3 (2 mL). The organic layer was separated, and the aqueous
layer was extracted with AcOEt (5 mL). The combined organic ex-
tracts were washed with water (5 mL) and brine (5 mL), dried with
MgSO4, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography with AcOEt/Hex
(1:4) as the eluent to yield 9b as a colorless solid (133 mg, 89%).
(C), 151.1 (C) ppm. IR (KBr): ν = 577, 1180, 1344, 1562 cm–1
.
˜
LRMS-EI: m/z (%) = 481 (88) [M]+, 354 (46), 340 (100), 207 (29),
91 (42), 28 (43). HRMS (ESI): calcd. C19H20IN3O2S [M]+:
481.0321; found 481.0314. C19H20IN3O2S (481.35): calcd. C 47.41,
H 4.19, N 8.73; found C 47.81, H 4.34, N 8.91.
Typical Procedure for One-Pot Iodoamination from Iminophos-
phorane 4 to Produce 8–10 and 14: Phenyl isocyanate (37 µL,
0.34 mmol) was added at room temperature to a stirred solution of
4B (150 mg, 0.31 mmol) in (CH2Cl)2 (3 mL). The mixture was
heated at reflux for 3 h and cooled to room temperature, and then
K2CO3 (128 mg, 0.92 mmol) and I2 (234 mg, 0.92 mmol) were
added. After being stirred for 30 min, the reaction mixture was
quenched with saturated aqueous Na2SO3 (2 mL). The organic
layer was separated, and the aqueous layer was extracted with Ac-
OEt (5 mL). The combined organic extracts were washed with
water (5 mL) and brine (5 mL), dried with MgSO4, and concen-
trated under reduced pressure. The residue was purified by silica
gel column chromatography with AcOEt/Hex (1:4) as the eluent to
yield 9b as a colorless solid (113 mg, 81%).
1-Iodomethyl-4-(prop-2-enyl)-2,4-dihydro-1H-imidazo[2,1-c][1,2,4]-
benzothiadiazine 5,5-Dioxide (14A): Colorless solid. Yield 211 mg
(92 %) from 7Ae (158 mg). M.p. 90–91 °C (hexane/CH2Cl2). 1H
NMR (600 MHz, CDCl3): δ = 3.31 (dd, J = 9.7, 9.7 Hz, 1 H,
CH2I), 3.41 (dd, J = 2.7, 10.4 Hz, 1 H, CH2I), 3.80 (dd, J = 4.8,
14.4 Hz, 1 H, CH2), 4.17 (dd, J = 9.9, 14.3 Hz, 1 H, CH2), 4.45–
4.54 (m, 2 H, CH2), 4.65–4.70 (m, 1 H, CH), 5.25 [dd, J = 0.6,
10.3 Hz, 1 H, CH=CH2(cis)], 5.37 [dd, J = 0.6, 16.8 Hz, 1 H,
CH=CH2(trans)], 6.01 (ddt, J = 10.6, 16.8, 5.8 Hz, 1 H, CH=CH2),
6.94 (d, J = 8.3 Hz, 1 H, Ar), 7.16 (dd, J = 7.7, 7.7 Hz, 1 H, Ar),
7.59 (ddd, J = 1.0, 8.4, 8.4 Hz, 1 H, Ar), 7.80 (dd, J = 1.0, 7.8 Hz,
1 H, Ar) ppm. 13C NMR (150 MHz, CDCl3): δ = 6.5 (CH2), 45.9
(CH2), 58.1 (CH2), 58.7 (CH), 112.4 (CH), 118.8 (CH2), 121.7
(CH), 123.5 (CH), 124.1 (C), 131.8 (CH), 134.6 (CH), 134.8 (C),
2-Iodomethyl-1-phenyl-1,2,3,4-tetrahydropyrimido[1,2-b][1,2,4]ben-
zothiadiazine 6,6-Dioxide (9b): M.p. 203–205 °C (hexane/CH2Cl2).
1H NMR (300 MHz, CDCl3): δ = 2.43–2.57 (m, 1 H, CH2), 2.70
(dddd, J = 4.3, 4.4, 4.4, 14.1 Hz, 1 H, CH2), 3.23 (ddd, J = 0.6,
10.4, 10.4 Hz, 1 H, CH2I), 3.43 (ddd, J = 1.0, 3.4, 10.4 Hz, 1 H,
CH2I), 3.97–4.12 (m, 3 H, NCH, NCH2), 7.01 (ddd, J = 0.4, 1.0,
8.3 Hz, 1 H, Ar), 7.13 (ddd, J = 1.1, 7.3, 7.9 Hz, 1 H, Ar), 7.30–
7.50 (m, 6 H, Ar), 7.73 (ddd, J = 0.4, 1.1, 7.9 Hz, 1 H, Ar) ppm.
13C NMR (75 MHz, CDCl3): δ = 5.6 (CH2), 27.2 (CH2), 36.1
(CH2), 58.7 (CH), 121.0 (CH), 122.7 (CH), 123.8 (C), 126.2 (CH),
127.6 (CH), 128.2 (2 CH), 129.4 (2 CH), 133.5 (CH), 141.5 (C),
150.1 (C) ppm. IR (KBr): ν = 581, 752, 1173, 1182, 1342, 1645,
˜
2939 cm–1. LRMS-EI: m/z = 403 (38) [M]+, 338 (39), 212 (100),
171 (48), 170 (53), 41 (27). HRMS (EI): calcd. C13H14IN3O2S
[M]+: 402.9851; found 402.9844. C13H14IN3O2S (403.24): calcd. C
38.72, H 3.50, N 10.42; found C 39.09, H 3.54, N 10.45.
Typical Procedure for Aminomercuration/Demercuration of 7 to Pro-
duce 11–13 and 15: Hg(OAc)2 (76.5 mg, 0.24 mmol) was added at
room temperature to a stirred solution of benzothiadiazine dioxide
7Bb (78.6 mg, 0.24 mmol) in CH2Cl2 (3 mL). After the system had
been stirred for 2 h, aqueous NaOH (3 , 3 drops) and aqueous
NaBH4 (9 mg, 0.2 mmol, in 1 mL) were added to form Hg0. The
precipitated Hg was removed by passing through a pad of silica
gel, and the filtrate was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography with Ac-
OEt/Hex (1:4) as the eluent to give 12b as a colorless solid (54.6 mg,
70%).
143.8 (C), 146.8 (C) ppm. IR (KBr): ν = 569, 690, 1144, 1182, 1329,
˜
1535 cm–1. C17H16IN3O2S (453.30): calcd. C 45.04, H 3.56, N 9.27;
found C 44.88, H 3.66, N 8.94.
2-Iodomethyl-1-propyl-2,3-dihydro-1H-imidazo[1,2-b][1,2,4]benzo-
thiadiazine 5,5-Dioxide (8a): Colorless solid. Yield 87 mg (92%)
from 7Aa (65 mg). M.p. 147–149 °C (hexane/CH2Cl2). 1H NMR
(500 MHz, CDCl3): δ = 0.96 (t, J = 7.4 Hz, 3 H, Me), 1.56–1.76
(m, 2 H, CH2Me), 3.15 (ddd, J = 5.3, 9.2, 14.3 Hz, 1 H, NCH2),
3.17 (dd, J = 8.8, 10.6 Hz, 1 H, CH2I), 3.43 (dd, J = 2.8, 10.6 Hz,
1 H, CH2I), 3.70 (ddd, J = 6.9, 9.3, 14.3 Hz, 1 H, NCH2), 3.88 (dd,
J = 5.3, 9.7 Hz, 1 H, NCH2), 3.94–4.00 (m, 1 H, NCH), 4.18 (dd,
J = 8.5, 9.7 Hz, 1 H, NCH2), 7.16 (ddd, J = 1.0, 7.4, 7.9 Hz, 1 H,
Ar), 7.27 (dd, J = 1.0, 8.3 Hz, 1 H, Ar), 7.51 (ddd, J = 1.5, 7.4,
8.3 Hz, 1 H, Ar), 7.81 (dd, J = 1.5, 7.9 Hz, 1 H, Ar) ppm. 13C
NMR (125 MHz, CDCl3): δ = 5.5 (CH2), 11.2 (CH3), 20.5 (CH2),
44.1 (CH2), 45.3 (CH2), 55.5 (CH), 122.0 (CH), 122.7 (CH), 123.3
(C), 125.9 (CH), 134.0 (CH), 145.3 (C), 151.6 (C) ppm. IR (KBr):
Typical Procedure for One-Pot Aminomercuration/Demercuration
from Iminophosphorane 4 to Produce 11–13 and 15: Phenyl isocyan-
ate (30 µL, 0.28 mmol) was added to a stirred solution of 4B
(122 mg, 0.25 mmol) in (ClCH2)2 (3 mL). The mixture was heated
at reflux for 3 h and cooled to room temperature, and Hg(OAc)2
(80 mg, 0.25 mmol) was added. After the system had been stirred
for 2 h, aqueous NaOH (3 , 3 drops) and aqueous NaBH4 (9 mg,
0.2 mmol, in 1 mL) were added to form Hg. Hg particles were re-
moved by passing through a pad of silica gel, and the filtrate was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography with AcOEt/Hex (1:4) as the elu-
ent to yield 12b as a colorless solid (58.8 mg, 72%).
ν = 579, 1180, 1304, 1581, 1635 cm–1. HRMS (ESI): calcd.
˜
C13H16IN3NaO2S [M + Na]+: 427.9900; found 427.9918.
C13H16IN3O2S (405.25): calcd. C 38.53, H 3.98, N 10.37; found C
38.31, H 4.11, N 9.98.
2-Methyl-1-phenyl-1,2,3,4-tetrahydropyrimido[1,2-b][1,2,4]benzothia-
diazine 6,6-Dioxide (12b): M.p. 141–142 °C (hexane/CH2Cl2). 1H
NMR (300 MHz, CDCl3): δ = 1.25 (dd, J = 0.6, 6.6 Hz, 3 H, Me),
2.05–2.15 (m, 1 H, CH2), 2.34–2.47 (m, 1 H, CH2), 3.94–4.14 (m,
3 H, NCH, NCH2), 6.97 (ddd, J = 0.5, 1.1, 8.3 Hz, 1 H, Ar), 7.06
(ddd, J = 1.1, 7.3, 8.0 Hz, 1 H, Ar), 7.24–7.45 (m, 6 H, Ar), 7.70
2-Iodomethyl-1-(4-methylphenyl)-2,3,4,5-tetrahydro[1,3]diazepino-
[1,2-b][1,2,4]benzothiadiazine 7,7-Dioxide (10c): Colorless solid.
Yield 103 mg (95%) from 7Cc (80.1 mg). M.p. 153–154 °C (hexane/
2080
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2075–2083

Diazaheterocyclic Ring-Fused 1,2,4-Benzothiadiazine 1,1-Dioxides
(ddd, J = 0.5, 1.5, 8.0 Hz, 1 H, Ar) ppm. 13C NMR (75 MHz, trated under reduced pressure. The residue was purified by silica
CDCl3): δ = 19.8 (CH3), 29.6 (CH2), 36.5 (CH2), 53.9 (CH), 120.9
gel column chromatography with AcOEt/Hex (1:1) as the eluent to
(CH), 121.9 (CH), 123.6 (C), 125.9 (CH), 126.9 (CH), 128.2 (2 yield 18b as a colorless solid (14.9 mg, 16%).
CH), 129.1 (2 CH), 133.3 (CH), 142.2 (C), 144.2 (C), 147.6
8,8-Dioxo-15-phenyl-8λ6-thia-1,9,15-triazatricyclo[12.2.1.02,7]hepta-
deca-2,4,6-trien-16-one (18b): M.p. 222–224 °C (hexane/CH2Cl2).
1H NMR (600 MHz, CDCl3): δ = 1.46–1.52 (m, 1 H, CH2), 1.64–
1.75 (m, 3 H, CH2), 1.77–1.85 (m, 1 H, CH2), 2.11–2.18 (m, 1 H,
CH2), 3.21–3.27 (m, 1 H, NCH2), 3.61–3.67 (m, 1 H, NCH2), 3.96
(dd, J = 9.1, 9.1 Hz, 1 H, NCH2), 4.21 (dd, J = 1.0, 9.2 Hz, 1 H,
NCH2), 4.65–4.69 (m, 1 H, NCH), 4.71 (dd, J = 5.7, 5.7 Hz, 1 H,
NH), 7.11 (dd, J = 7.4, 7.4 Hz, 1 H, Ar), 7.37 (dd, J = 7.5, 8.5 Hz,
2 H, Ar), 7.42–7.47 (m, 2 H, Ar), 7.61 (d, J = 7.9 Hz, 2 H, Ar),
7.64 (ddd, J = 1.5, 7.8, 7.8 Hz, 1 H, Ar), 8.23 (dd, J = 1.3, 8.0 Hz,
1 H, Ar) ppm. 13C NMR (150 MHz, CDCl3): δ = 17.7 (CH2), 28.8
(CH2), 29.0 (CH2), 41.1 (CH2), 50.4 (CH2), 53.3 (CH), 120.2 (2
CH), 123.7 (CH), 127.8 (CH), 129.1 (2 CH), 129.9 (CH), 131.2
(CH), 134.3 (CH), 137.3 (C), 138.1 (C), 138.5 (C), 157.4 (C) ppm.
(C) ppm. IR (KBr): ν = 567, 760, 1151, 1331, 1531 cm–1
.
˜
C17H17N3O2S (327.40): calcd. C 62.36, H 5.23, N 12.83; found C
62.08, H 5.44, N 12.67.
2-Methyl-1-phenyl-2,3-dihydro-1H-imidazo[1,2-b][1,2,4]benzothiadi-
azine 5,5-Dioxide (11b): Colorless solid. Yield 91 mg (91%) from
7Ab (100 mg). M.p. 158–160 °C (hexane/CH2Cl2). 1H NMR
(300 MHz, CDCl3): δ = 1.38 (d, J = 6.6 Hz, 3 H, Me), 3.82 (dd, J
= 6.6, 9.0 Hz, 1 H, NCH2), 4.30 (dd, J = 8.6, 9.0 Hz, 1 H, NCH2),
4.49 (ddq, J = 6.6, 8.6, 6.6 Hz, 1 H, NCH), 7.19 (ddd, J = 1.2, 7.3,
8.0 Hz, 1 H, Ar), 7.25 (dd, J = 8.2, 8.9 Hz, 1 H, Ar), 7.26–7.31 (m,
1 H, Ar), 7.42–7.53 (m, 5 H, Ar), 8.54 (dd, J = 1.6, 7.9 Hz, 1 H,
Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 18.5 (CH3), 45.5 (CH2),
52.8 (CH), 121.8 (CH), 123.1 (CH), 123.4 (C), 124.7 (2 CH), 126.2
(CH), 126.3 (CH), 129.1 (2 CH), 133.9 (CH), 136.8 (C), 145.1 (C),
IR (KBr): ν = 602, 1149, 1288, 1404, 1705, 3271 cm–1. HRMS
˜
(ESI): calcd. C19H21N3NaO3S [M + Na]+: 394.1196; found
394.1202.
150.4 (C) ppm. IR (KBr): ν = 1180, 1304, 1581, 1628 cm–1
.
˜
C16H15N3O2S (313.37): calcd. C 61.32, H 4.82, N 13.41; found C
61.39, H 5.01, N 13.45.
Iodoamination of 7db at 80 °C to Produce 19b: I2 (183 mg,
0.72 mmol) was added to a stirred solution of benzothiadiazine di-
oxide 7Db (85 mg, 0.24 mmol) in (ClCH2)2 (3 mL). The mixture
was heated at reflux for 12 h and then cooled to room temperature,
and the reaction mixture was quenched with saturated aqueous
Na2SO3 (2 mL). The organic layer was separated, and the aqueous
layer was extracted with CH2Cl2 (5 mL). The combined organic
extracts were washed with water (5 mL) and brine (5 mL), dried
with MgSO4, and concentrated under reduced pressure. The resi-
due was purified by silica gel column chromatography with AcOEt/
Hex (1:2) as the eluent to yield 19b as a colorless solid (18 mg,
15%).
2-Methyl-1-phenyl-2,3,4,5-tetrahydro[1,3]diazepino[1,2-b][1,2,4]ben-
zothiadiazine 7,7-Dioxide (13b): Colorless solid. Yield 71.6 mg
1
(61%) from 7Cb (117 mg). M.p. 234–236 °C (hexane/CH2Cl2). H
NMR (500 MHz, CDCl3): δ = 1.56 (d, J = 6.9 Hz, 3 H, CH3),
1.80–1.87 (m, 1 H, CH2), 1.89–1.98 (m, 2 H, CH2), 2.09–2.20 (m,
1 H, CH2), 3.42–3.54 (m, 1 H, NCH2), 4.18–4.30 (m, 1 H, NCH2),
4.30–4.38 (m, 1 H, NCH), 7.08 (dd, J = 1.0, 8.3 Hz, 1 H, Ar), 7.19
(ddd, J = 1.1, 7.3, 7.9 Hz, 1 H, Ar), 7.23–7.29 (m, 3 H, Ar), 7.38–
7.42 (m, 2 H, Ar), 7.43 (ddd, J = 1.5, 7.3, 8.2 Hz, 1 H, Ar), 7.73
(dd, J = 1.4, 7.9 Hz, 1 H, Ar) ppm. 13C NMR (125 MHz, CDCl3):
δ = 18.6 (CH3), 23.9 (CH2), 32.1 (CH2), 48.0 (CH2), 59.1 (CH),
121.0 (CH), 123.5 (CH), 126.2 (CH), 126.6 (CH), 126.7 (2 CH),
127.0 (C), 129.1 (2 CH), 132.9 (CH), 144.2 (C), 145.1 (C), 152.3
2-(4-Iodobutyl)-3-phenyl-2,3-dihydro-1H-imidazo[2,1-c][1,2,4]benzo-
thiadiazine 5,5-Dioxide (19b): M.p. 172–174 °C (hexane/CH2Cl2).
1H NMR (500 MHz, CDCl3): δ = 1.35–1.47 (m, 2 H, CH2), 1.48–
1.58 (m, 1 H, CH2), 1.68–1.80 (m, 3 H, CH2), 3.07–3.14 (m, 2 H,
CH2I), 3.81 (dd, J = 6.4, 9.4 Hz, 1 H, NCH2), 4.22 (dd, J = 9.4,
9.4 Hz, 1 H, NCH2), 4.48–4.56 (m, 1 H, NCH), 6.92 (d, J = 8.3 Hz,
1 H, Ar), 7.25–7.32 (m, 2 H, Ar), 7.37–7.44 (m, 4 H, Ar), 7.50 (dd,
J = 7.6, 7.6 Hz, 1 H, Ar), 7.94 (d, J = 7.6 Hz, 1 H, Ar) ppm. 13C
NMR (125 MHz, CDCl3): δ = 6.0 (CH2), 24.9 (CH2), 31.1 (CH2),
32.4 (CH2), 48.0 (CH2), 56.7 (CH), 113.3 (CH), 122.7 (C), 124.3
(CH), 124.7 (CH), 124.9 (2 CH), 127.0 (CH), 129.3 (2 CH), 132.7
(C) ppm. IR (KBr): ν = 1180, 1335, 1558 cm–1. HRMS (ESI):
˜
calcd. C18H20N3O2S [M + H]+: 342.1271; found 342.1276.
C18H19N3O2S (341.43): calcd. C 63.32, H 5.61, N 12.31; found C
63.39, H 5.76, N 12.30.
1-Methyl-4-(prop-2-enyl)-2,4-dihydro-1H-imidazo[2,1-c][1,2,4]ben-
zothiadiazine 5,5-Dioxide (15A): Colorless oil. Yield 191 mg (86%)
1
from 7Ae (166 mg). H NMR (300 MHz, CDCl3): δ = 1.43 (d, J =
6.2 Hz, 3 H, CH3), 3.60 (dd, J = 5.6, 13.8 Hz, 1 H, CH2), 4.15 (dd,
J = 10.0, 13.8 Hz, 1 H, CH2), 4.51 (dd, J = 1.2, 5.7 Hz, 2 H, CH2),
4.50–4.64 (m, 1 H, CH), 5.24 [dd, J = 0.8, 10.3 Hz, 1 H,
CH=CH2(cis)], 5.36 [dd, J = 1.1, 17.1 Hz, 1 H, CH=CH2(trans)],
6.03 (ddt, J = 10.3, 17.1, 5.5 Hz, 1 H, CH=CH2), 6.96 (d, J =
8.4 Hz, 1 H, Ar), 7.10 (dd, J = 7.7, 7.7 Hz, 1 H, Ar), 7.56 (ddd, J
= 1.3, 7.7, 8.1 Hz, 1 H, Ar), 7.76 (dd, J = 1.4, 7.8 Hz, 1 H, Ar) ppm.
13C NMR (75 MHz, CDCl3): δ = 19.1 (CH3), 45.4 (CH2), 54.5
(CH), 58.6 (CH2), 112.7 (CH), 118.2 (CH2), 120.7 (CH), 122.8
(CH), 123.3 (C), 131.8 (CH), 134.1 (CH), 135.3 (C), 149.8 (C) ppm.
(CH), 135.0 (C), 135.4 (C), 151.0 (C) ppm. IR (KBr): ν = 1119,
˜
1288 cm–1. HRMS (ESI): calcd. C19H20IN3NaO2S [M + Na]+
504.0213; found 504.0189.
Synthesis of Imidazo[2,1-c][1,2,4]benzothiadiazine 20b: A solution
of diazepine-fused benzothiadiazine dioxide 10b (65.0 mg,
0.14 mmol) in chlorobenzene (2 mL) was heated at 115 °C for 12 h.
The mixture was cooled to room temperature and then concen-
trated under reduced pressure. The residue was purified by silica
gel column chromatography with AcOEt/Hex (1:2) as the eluent to
yield 20b as a colorless solid (43.9 mg, 68%).
IR (NaCl, neat): ν = 756, 1180, 1342, 1597, 1643, 2970 cm–1
.
˜
HRMS (ESI): calcd. C13H16N3O2S [M + H]+: 278.0958; found
278.0951.
2-(3-Iodopropyl)-3-phenyl-2,3-dihydro-1H-imidazo[2,1-c][1,2,4]ben-
zothiadiazine 5,5-Dioxide (20b): M.p. 138–139 °C (hexane/CH2Cl2).
1H NMR (500 MHz, CDCl3): δ = 1.71–1.94 (m, 4 H, CH2), 3.10
(t, J = 6.4 Hz, 2 H, CH2I), 3.91 (dd, J = 6.2, 9.4 Hz, 1 H, NCH2),
4.28 (dd, J = 9.4, 9.4 Hz, 1 H, NCH2), 4.44–4.50 (m, 1 H, NCH),
7.19 (dd, J = 0.9, 8.4 Hz, 1 H, Ar), 7.25 (d, J = 8.2 Hz, 1 H, Ar),
7.29 (dd, J = 7.4, 7.4 Hz, 1 H, Ar), 7.46 (dd, J = 8.4, 8.4 Hz, 2 H,
Ar), 7.50 (ddd, J = 1.5, 7.4, 8.2 Hz, 1 H, Ar), 7.52 (dd, J = 0.9,
8.4 Hz, 2 H, Ar), 7.85 (dd, J = 1.5, 7.4 Hz, 1 H, Ar) ppm. 13C
Iodoamination of 7Db to Produce the 11-Membered Ring Compound
18b: I2 (194 mg, 0.76 mmol) was added to a stirred solution of
benzothiadiazine dioxide 7Db (90.4 mg, 0.25 mmol) in CH2Cl2
(3 mL). After being stirred for 24 h, the reaction mixture was
quenched with saturated aqueous Na2SO3 (2 mL). The organic
layer was separated, and the aqueous layer was extracted with
CH2Cl2 (5 mL). The combined organic extracts were washed with
water (5 mL) and brine (5 mL), dried with MgSO4, and concen-
Eur. J. Org. Chem. 2008, 2075–2083
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2081

S. Hirota, R. Kato, M. Suzuki, Y. Soneta, T. Otani, T. Saito
FULL PAPER
[5]
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6081.
NMR (75 MHz, CDCl3): δ = 4.8 (CH2), 27.9 (CH2), 33.0 (CH2),
43.4 (CH2), 55.9 (CH), 121.9 (CH), 123.3 (CH), 123.4 (C), 124.7
(2 CH), 126.4 (CH), 126.5 (CH), 129.3 (2 CH), 134.0 (CH), 136.7
(C), 145.0 (C), 150.2 (C) ppm. IR (KBr): ν = 579, 1173, 1311, 1574,
˜
1628 cm–1. HRMS (ESI): calcd. C18H18IN3NaO2S [M + Na]+
490.0057; found 490.0071.
[6]
[7]
X-ray Crystal Structure Analysis fo Compound 18b: A single crystal
was mounted on a glass capillary, transferred to a Bruker AXS
SMART diffractometer equipped with CCD area detector and Mo-
Kα (λ = 0.71073 Å) radiation, and centered in the beam at 297 K.
The structure was solved and refined with SHELX-97[27] by direct
methods and expanded by Fourier techniques. All non-hydrogen
atoms were refined anisotropically and hydrogens isotropically.
C19H21N3O3S, M = 371.45, a = 11.2721(9) Å, b = 9.8030(8) Å, c =
15.9351(13) Å, β = 93.8970(10)°, V = 1756.8(2) Å3, monoclinic,
space group P21/c, Z = 4, T = 297(2) K, ρcalcd. = 1.404 gcm–3, µ =
[8]
[9]
0.209 mm–1, 10581 reflections measured, 3974 unique (Rint
=
0.0412), GOF (on F2) = 1.035, final R1 (I Ͼ 2σ) = 0.0416, wR2 (I
Ͼ 2σ) = 0.1210, R1 (all data) = 0.0480, wR2 (all data) = 0.1269.
Monocyclic guanidines: a) K. Nagamatsu, H. Fujii, N. Abe, A.
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Serita, J.-H. Zeng, H. Fujii, N. Abe, A. Kakehi, Heterocycles
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CCDC-638254 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via http://www.ccdc.
cam.ac.uk/data_request/cif.
Supporting Information (see also the footnote on the first page of
this article): 1H and 13C NMR spectra for all new compounds and
extended X-ray data of compound 18b.
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2075–2083

Diazaheterocyclic Ring-Fused 1,2,4-Benzothiadiazine 1,1-Dioxides
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Received: November 29, 2007
Published Online: March 3, 2008
Eur. J. Org. Chem. 2008, 2075–2083
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2083