An Efficient Synthesis of 1,3-Benzothiadiazin-4(3 H)-one 2-Oxides: Novel Anthranilic Acid Derivatives

Article abstract of DOI:10.1055/s-0035-1561657

Derivatives of anthranilic acid exhibit a range of useful biological activities. Herein we describe an efficient synthetic route to 1,3-benzothiadiazin-4(3H)-one 2-oxides via copper-catalyzed N-arylation of sulfonimidamides followed by cyclization. Such 1

Full text of DOI:10.1055/s-0035-1561657

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–J
paper
A
I. Sen et al.
Paper
Synthesis
An Efficient Synthesis of 1,3-Benzothiadiazin-4(3H)-one 2-Oxides:
Novel Anthranilic Acid Derivatives
Indira Sena
Swarnendu Sasmala
Roger G. Hallb
O
X
O
N
R1
O
S
R1
O
2 steps
R2
N
OH
N
S
+
R3
R3
NH2
A
A
Sitaram Pal*a
R2
a Syngenta Biosciences Pvt. Ltd., Santa Monica Works,
Corlim, Ilhas, Goa 403110, India
b Syngenta Crop Protection, Muenchwilen AG,
Schaffhauserstrasse, 4332 Stein, Switzerland
sitaram.pal@syngenta.com
16 examples
A = CH, N; R1 = aryl, benzyl, H
R2 = aryl, alkyl
R3 = H, F, Me, OMe, NO2, Cl, Br
Received: 05.04.2016
Accepted after revision: 02.05.2016
Published online: 15.06.2016
sive recent example.11 Constraining the amine and carbox-
ylate functionality within a heterocyclic ring has also been
successful within crop protection with products such as the
fungicide Proquinazid12 and the herbicide Bentazone13 hav-
ing been discovered. As an extension of this theme, we now
report our investigations into the synthesis of 1,3-benzo-
thiadiazin-4(3H)-one 2-oxides, as shown in Figure 1.
DOI: 10.1055/s-0035-1561657; Art ID: ss-2016-t0235-op
Abstract Derivatives of anthranilic acid exhibit a range of useful bio-
logical activities. Herein we describe an efficient synthetic route to 1,3-
benzothiadiazin-4(3H)-one 2-oxides via copper-catalyzed N-arylation of
sulfonimidamides followed by cyclization. Such 1,3-benzothiadiazin-
4(3H)-one 2-oxides can be viewed as novel anthranilic acid derivatives.
H
N
O
N
O
S
Key words 1,3-benzothiadiazin-4(3H)-one 2-oxides, anthranilic acid,
N-arylation, sulfur, cyclization, copper catalysis
O
N
N
I
O
O
proquinazid
bentazone
Sulfonimidamides were first described by Levchenko1
and since their discovery they have continued to attract
much interest from various research groups. Robust meth-
ods have been developed to allow the introduction of struc-
tural diversity,2 and there have been numerous efforts to
use these methods in the search for molecules with inter-
esting biological properties. As agrochemicals, sulfonimid-
amides have been described that exhibited herbicidal3 and
insecticidal4 activity. In the field of medicinal chemistry,
sulfonimidamides have been reported as transition state
analogues,5 enzyme inhibitors,6 or as carboxylic acid bio-
isosteres.7 A recent report8 describes an analysis of the
physical chemical properties of sulfonimidamides, suggest-
ing that such molecules might offer improved oral bioavail-
ability over acidic compounds.
Our interest in sulfonimidamides has focused on devel-
oping methods to constrain the N–S–N linkage in a ring sys-
tem;7,9,10 such compounds can be viewed as restricted con-
formations of open-chain sulfonimidamides, and with the
correct design elements can be expected to offer improved
ligand efficiency and biological activity.
Anthranilic acid derivatives have also been investigated
as bioactive molecules, with the introduction of the anthra-
nilic diamide class of insecticides representing an impres-
R2
N
O
S
O
R3
N
R1
1,3-benzothiadiazin-4(3H)-one 2-oxides
Figure 1 Selected anthranilic acid derivatives
Our synthetic strategy (Scheme 1) focused on the for-
mation of the six-membered ring via an intramolecular
amide bond formation of 7, an approach which we have re-
ported previously.9 We first attempted the synthesis of or-
tho-carboxy-substituted N-arylsulfonimidamides 6. Sul-
fonimidamides are most commonly prepared from sulfin-
amides by performing an oxidative chlorination to generate
a sulfonimidoyl chloride, followed by reaction with an
amine to generate the non-cyclic sulfonimidamide.6,14 In a
first instance, we attempted to use an anthranilic derivative
directly; however, this approach was unsuccessful when we
attempted the reaction of sulfonimidoyl chloride 2a with
ethyl 2-aminobenzoate (3, R3 = H); only the corresponding
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

B
I. Sen et al.
Paper
Synthesis
O
OEt
R2
S
H2N
R1
Pathway A
R3
O
NH
R3
N
O
S
R1
O
S
X
3
R1
R2
N
X
R2
N
OEt
H
R2
S
R1
NH
R2
O
R3
2a: X = Cl
2b: X = F
O
N
1
6
O
OH
S
N
R3
O
N
R1
X
OH
Pathway B
R3
O
O
7
R1
O
S
O
S
R1
O
S
5
8
R1
R2
N
R2
N
R2
N
H
NH2
Cl
1
2a
4
Scheme 1 Synthetic strategy for synthesis of 1,3-benzothiadiazin-4(3H)-one 2-oxides
sulfonamide was obtained. Sulfonimidoyl fluorides are
known to be more stable towards hydrolysis compared to
sulfonimidoyl chlorides.15
the recovery of starting material (Table 2, entry 3). Yields
were inferior when bromo- or chlorobenzoic acids were
used (Table 2, entries 4 and 5). This could also be justified
by the fact that sulfonimidamides are generally moderate to
poor nucleophiles hence aryl iodides gave better yields.
With these optimized conditions in hand (Table 2, entry
2), we then investigated the scope of the N-arylation reac-
tion and the subsequent intramolecular cyclization to af-
ford the 1,3-benzothiadiazin-4(3H)-one 2-oxide ring sys-
tem (Table 3).
However, reaction of sulfonimidoyl fluoride 2b with
ethyl 2-aminobenzoate (3, R3 = H) in DMF at 120 °C for 3–4
hours, led only to the recovery of starting materials. We
concluded that these negative results (Pathway A, Scheme
1) are due to the poor nucleophilicity of ethyl 2-aminoben-
zoate (3, R3 = H). We then attempted to construct the an-
thranilic motif in an intermolecular fashion, via the N-ary-
lation of sulfonimidamides2c–f,16 using substituted aryl ha-
lides. This approach (Pathway B, Scheme 1) ultimately
proved to be successful, and we believe this strategy offers
best scope to allow the efficient variation of substituents R1,
R2, and R3, thus enabling the exploration of such com-
pounds for biological investigations.
The N-arylation reaction gave good yields when R1
=
aryl (Table 3, entries 1–14). However, when R1 = benzyl the
yield dropped to 50% (Table 3, entry 15). Aryl and alkyl sub-
stituents R2 were equally tolerated in the reaction. Substi-
tuted benzoic acids were then investigated; again, yields
were consistently high with all examples studied (Table 3,
The substrates required for the key N-arylation step
were synthesized via the classical oxidative chlorination of
sulfinamides 19 using t-BuOCl followed by passing ammo-
nia gas through the reaction mixture to give compounds 4
in excellent yields as shown in Table 1. Inferior yields were
obtained when the same reaction was performed using liq-
uid ammonia.
Table 1 Synthesis of Sulfonimidamide 4
O
R1
O
S
t-BuOCl, THF
R1
R2
N
S
R2
N
NH3 gas
H
NH2
1
4
In the first instance, we decided to study the reaction of
the diphenylsulfonimidamide 4d with 2-halobenzoic acid
derivatives 5 (R3 = H). The ortho-carboxylate group has
been known to effectively accelerate homogeneous copper-
catalyzed reactions;17 this prompted us to investigate 2-io-
dobenzoic acid (5a) as the coupling partner. Sulfonimid-
amide 4d together with 5a was subjected to CuI (20
mol%)/L-proline (40 mol%)/K2CO3 (2.5 equiv) in DMF at 100
°C, which gave complete conversion within 2 hours to the
desired product 718 (Table 2, entry 1). This reaction was also
performed in the absence of L-proline (Table 2, entry 2) and
we were pleased to find complete conversion into 7 (90%).
Attempting this reaction in the absence of CuI led only to
Entry
R1
R2
Yielda (%) of 4
1
2
3
4
5
6
7
8
Ph
Ph
Et
4a, 95
4b, 90
4c, 90
4d, 90
4e, 85
4f, 80
4g, 75
4h, 80
Bn
Ph
Ph
Et
Bn
Ph
4-MeOC6H4
2-MeC6H4
Et
2,6-Me2C6H3
Et
t-BuO2C
Ph
a Isolated yields.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

C
I. Sen et al.
Paper
Synthesis
Table 2 Optimization of the N-Arylation Reaction between Sulfonimidamide 4d and Aryl Halides 5
H
N
X
O
S
N
CuI (20 mol%), ligand (40 mol%)
base (2.5 equiv), solvent
NH2
O
S
N
OH
+
O
OH
O
4d
5a–c
7
Entry
5
Catalyst
Base
Solvent/ Temp
Time (h)
Yielda (%) of 7
1
2
3
4
5
5a, X = I
5a, X = I
5a, X = I
5b, X = Br
5c, X = Cl
CuI/L-proline
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF/100 °C
DMF/100 °C
DMF/100 °C
DMF/100 °C
DMF/100 °C
2
2
3
3
3
90
90
0
CuI
–
CuI
CuI
70
50
a Isolated yields.
entries 4, 7–10, 12, and 13). The N-arylation reaction also
worked well (70% yield) when 2-chloronicotinic acid was
used (Table 3, entry 14).
For the cyclization step, we employed 1-[3-(dimethyl-
amino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI)
and 1-hydroxybenzotriazole hydrate (HOBt) as acid activat-
ing agents; performing the reaction in the presence of Et3N
Table 3 Scope of the N-Arylation Reaction Followed by Cyclization
OH
O
O
CuI (20 mol%)
6
R1
O
S
5
R1
1
K2CO3 (2.5 equiv)
EDCI, HOBt
Et3N, CH2Cl2
O
OH
R3
N
S
R2
N
R3
R3
+
2
O
R1
NH
A
DMF, 100 °C
N
S
O
NH2
4
A
3
X
A
N
R2
R2
5a
4
7
8
Entry
R1
Ph
R2
Ph
R3
X
A
Yieldb (%) of 7
Yieldb (%) of 8
1
2
H
I
CH
CH
CH
CH
CH
CH
CH
CH
CH
C
7a, 90
7b, 80
7c, 90
7d, 90
7e, 85
7f, 85
7g, 90
7h, 75
7i, 80
7j, 75
7k, 80
7l, 70
7m, 80
7n, 70
7o, 50
8a, 80
8b, 88
8c, 85
8d, 88
8e, 75
8f, 70
8g, 80
8h, 82
8i, 80
8j, 84
8k, 85
8l, 80
8m, 80
8n, 80
8o, 82
Ph
Ph
Ph
Et
H
I
3
Bn
Bn
Et
H
I
4
4-F
H
I
5
2-MeC6H4
I
6
2,6-Me2C6H3
Et
H
I
7
Ph
Bn
Et
5-MeO
5-O2N
6-Me
3-Me
H
I
8
Ph
I
9
Ph
Bn
Et
I
10
11
12
13
14
15
Ph
I
4-MeOC6H4
Et
I
CH
CH
CH
N
Ph
Ph
Ph
Bn
Et
5-Cl
5-Br
H
I
Et
I
Bn
Ph
Cl
I
H
CH
a Numbering is applicable when A = C, CH.
b Isolated yields.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

D
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Paper
Synthesis
O
O
I
EDCI, HOBt
Et3N, CH2Cl2
O
CuI, K2CO3
O
S
N
O
O
+
HN
OH
S
O
S
N
DMF, 100 °C
80%
HCl, H2O
50%
NH
N
NH2
O
O
O
HO
4h
5a
7p
8p
Scheme 2 Synthesis of NH–1,3-benzothiadiazin-4(3H)-one 2-oxide 8p
in dichloromethane at room temperature, good to excellent
yields of the cyclic products 8 were obtained. Increasing the
steric bulk on R1 did not lead to reduced yields (Table 3, en-
tries 5 and 6). Cyclization of compounds 7 could also be
achieved using oxalyl chloride/cat. DMF in dichlorometh-
ane; however yields were inferior. These 1,3-benzothiadi-
azin-4(3H)-one 2-oxides 8 were isolated as solids in high
yields after chromatography.
To prepare the free NH-sulfonimidamide 8p, we carried
out the N-arylation reaction between sulfonimidamide 4h
with a tert-butyloxycarbonyl (Boc) protecting group on one
of the nitrogens, and 2-iodobenzoic acid (5a) to afford 7p in
80% yield.18 After the cyclization reaction the Boc protecting
group was readily removed during workup by treatment
with 2 M HCl to directly afford compound 8p in 50% yield
(Scheme 2). Such an approach offers another opportunity
to introduce further functionality at the nitrogen of 8p.18
The structure of compounds 8 was confirmed by carry-
ing out a Heteronuclear Multiple Bond Correlation (HMBC)
experiment for the compound 8o which clearly showed a 2-
bond correlation between the NCH2 proton (δH = 4.99, 4.82)
and the carbonyl carbon (δC = 162.4) (Figure 2).
All chemical reagents were purchased and used as received, unless
otherwise indicated. Starting materials 1a–g were prepared accord-
ing to the literature;9 1h was also prepared according to the litera-
ture.14c 1H NMR spectra were recorded at 400 MHz and 13C NMR spec-
tra were obtained at 100 MHz using a Bruker Avance II-400 spectrom-
eter in CDCl3 or DMSO-d6. The parameter JCH was adjusted to 8 Hz for
HMBC spectra. HRMS analyses were performed on an Agilent QTOF
6520 mass spectrometer and LCMS on a THERMO MSQ PLUS mass
spectrometer; [M]+ data are given in all cases and calculations are
based on [M + H]+. IR spectra were recorded on Shimadzu DRS Pres-
tige 21. Column chromatographic purifications were performed on a
CombiFlash Rf (Teledyne Isco) with silica gel using the mobile phase
indicated. Melting points were determined with a SRS-OptiMelt digi-
tal melting point apparatus and are uncorrected.
{[Amino(ethyl)oxo-λ6-sulfanylidene]amino}benzene (4a); Typical
Procedure
To a stirred solution of sulfinamide 1a (4.22 g, 25.0 mmol) in anhyd
THF (40 mL) cooled to 0 °C in a 2-necked round-bottomed flask cov-
ered with Al foil was added dropwise t-BuOCl19 (4.05 g, 37.5 mmol) in
THF (5 mL); the mixture was stirred for 1.5 h at 0 °C under N2 atmo-
sphere. The reaction mass was then cooled to –78 °C, and NH3 gas was
purged into the solution for 15 min, the outlet was fitted with a dry
CaCl2 guard tube. The mixture was slowly allowed to come up to r.t.
over 1 h, diluted with water (100 mL), and extracted with EtOAc (3 ×
70 mL). The combined organic layers were dried (Na2SO4), filtered,
and concentrated under reduced pressure. The crude product was pu-
rified by CombiFlash chromatography (silica gel, n-hexane/EtOAc,
7:3) to afford the desired sulfonimidamide 4a as a white solid: yield:
4.37 g (95%); mp 113–115 °C.
N
S
O
N
IR (KBr): 3287, 2983, 1576, 1488, 1263, 1072, 916, 767 cm–1
.
162.4
Ha Hb 4.99, 4.82
O
1H NMR (400 MHz, CDCl3): δ = 1.52 (t, J = 8.0 Hz, 3 H, CH3), 3.36 (dq,
J = 1.0, 7.4 Hz, 2 H, SCH2), 4.14 (br s, 2 H, NH2), 7.10–7.15 (m, 1 H, Ar-
H), 7.24–7.28 (m, 2 H, Ar-H), 7.32–7.38 (m, 2 H, Ar-H).
Figure 2 HMBC correlations observed in 8o
13C NMR (100 MHz, CDCl3): δ = 8.5, 50.0, 122.6, 122.9, 129.2, 141.9.
In summary, we have demonstrated that 2-iodobenzoic
acids can be effectively coupled with sulfonimidamides un-
der copper catalysis. Such ortho-carboxy-substituted N-ar-
ylsulfonimidamides 7 can be effectively cyclized to provide
1,3-benzothiadiazin-4(3H)-one 2-oxides 8, a new heterocy-
clic ring system which may be also be viewed as novel an-
thranilic acid derivatives. We are currently investigating the
chemistry and biological activity of such novel ring sys-
tems.
HRMS (EI): m/z calcd for C8H12N2OS: 184.0670; found: 184.0673.
Compounds 4b–h were prepared similarly following the above proce-
dure.
{[Amino(benzyl)oxo-λ6-sulfanylidene]amino}benzene (4b)14c
White solid; yield: 5.53 g (90%); mp 172–174 °C.
IR (KBr): 3347, 2946, 1586, 1491, 1302, 1207, 1058, 849, 783 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 3.35 (br s, 2 H, NH2), 4.48 (q, J = 13.6
Hz, 2 H, SCH2), 7.01–7.08 (m, 1 H, Ar-H), 7.15 (d, J = 7.8 Hz, 2 H, Ar-H),
7.24–7.30 (m, 2 H, Ar-H), 7.36–7.43 (m, 5 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 60.9, 122.3, 123.0, 128.7, 128.9, 129.1,
129.2, 131.2, 141.6.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

E
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Paper
Synthesis
HRMS (EI): m/z calcd for C13H14N2OS: 246.0827; found: 246.0827.
13C NMR (100 MHz, CDCl3): δ = 9.0, 19.5, 51.5, 123.7, 128.2, 134.0,
138.9.
{[Amino(oxo)phenyl-λ6-sulfanylidene]amino}methylbenzene
HRMS (EI): m/z calcd for C10H16N2OS: 212.0983; found: 212.0981.
(4c)20
tert-Butyl N-[Amino(oxo)phenyl-λ6-sulfanylidene]carbamate
White solid; yield: 5.53 g (90%); mp 92–94 °C.
(4h)14g
IR (KBr): 3321, 1450, 1247, 1065, 751 cm–1
.
Cream solid; yield: 5.12 g (80%); mp 126–128 °C.
IR (KBr): 3315, 2978, 1664, 1444, 1369, 1288, 1163, 954, 786 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 1.20 [s, 9 H, C(CH3)3], 7.52–7.66 (m,
5 H, Ar-H), 7.81–7.89 (m, 2 H, NH2).
13C NMR (100 MHz, CDCl3): δ = 27.9, 80.8, 127.1, 129.0, 133.0, 141.0,
157.0.
1H NMR (400 MHz, CDCl3): δ = 4.07 (d, J = 12.0 Hz, 1 H, NCH2), 4.18 (d,
J = 12.0 Hz, 1 H, NCH2), 7.19–7.24 (m, 2 H, Ar-H), 7.24–7.27 (m, 1 H,
Ar-H), 7.27–7.32 (m, 2 H, Ar-H), 7.48–7.55 (m, 2 H, Ar-H), 7.55–7.61
(m, 1 H, Ar-H), 7.97–8.03 (m, 2 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 47.6, 127.0, 127.2, 127.5, 127.7, 128.5,
128.9, 129.0, 132.1, 136.8, 140.9.
.
HRMS (EI): m/z calcd for C13H14N2OS: 246.0827; found: 246.0829.
HRMS (EI): m/z calcd for C11H16N2O3S: 256.0882; found: 256.0884.
{[Amino(oxo)phenyl-λ6-sulfanylidene]amino}benzene (4d)
2-{[Anilino(oxo)phenyl-λ6-sulfanylidene]amino}benzoic Acid (7a);
White solid; yield: 5.22 g (90%); mp 120–122 °C.
Typical Procedure
IR (KBr): 3280, 2980, 1556, 1469, 1296, 1207, 1051, 883, 771 cm–1
.
A dry sealable vial was charged with sulfonimidamide 4a (368 mg,
2.00 mmol), 2-iodobenzoic acid (494 mg, 2.00 mmol), CuI (76 mg,
0.40 mmol), and K2CO3 (690 mg, 5.00 mmol) in anhyd DMF (5.0 mL).
After heating to 100 °C for 2 h, the heterogeneous mixture was cooled
to r.t. The mixture was diluted with water (10 mL), acidified with 2 M
HCl and extracted with EtOAc (3 × 30 mL). The combined organic lay-
ers were dried (Na2SO4), filtered, and concentrated under reduced
pressure. The crude product was purified by CombiFlash chromatog-
raphy (silica gel, n-hexane/EtOAc, 6:4) to afford the desired product
7a as a cream solid; yield: 633 mg (90%); mp 156–157 °C.
1H NMR (400 MHz, CDCl3): δ = 3.72 (br s, 2 H, NH2), 6.99–7.07 (m, 1 H,
Ar-H), 7.09–7.14 (m, 2 H, Ar-H), 7.18–7.24 (m, 2 H, Ar-H), 7.44–7.50
(m, 2 H, Ar-H), 7.52–7.57 (m, 1 H, Ar-H), 7.98–8.02 (m, 2 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 122.9, 123.4, 127.1, 128.9, 129.0,
132.4, 140.9, 141.3.
HRMS (EI): m/z calcd for C12H12N2OS: 232.0670; found: 232.0673.
1-{[Amino(oxo)phenyl-λ6-sulfanylidene]amino}-4-methoxyben-
zene (4e)
IR (KBr): 3215, 1708, 1597, 1474, 1314, 1279, 1104, 1012, 922, 750
White solid; yield: 4.54 g (85%); mp 95–97 °C.
cm–1
.
IR (KBr): 3300, 3062, 1573, 1504, 1259, 1197, 1074, 839, 744 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.93 (t, J = 7.5 Hz, 1 H, Ar-H), 7.11
(quint, J = 4.3 Hz, 1 H, Ar-H), 7.25 (d, J = 4.3 Hz, 4 H, Ar-H), 7.37–7.46
(m, 1 H, Ar-H), 7.49–7.57 (m, 2 H, Ar-H), 7.59–7.67 (m, 1 H, Ar-H),
7.69–7.76 (m, 1 H, Ar-H), 7.81–7.89 (m, 1 H, Ar-H), 8.16 (d, J = 7.5 Hz,
2 H, Ar-H),
13C NMR (100 MHz, CDCl3): δ = 121.0, 122.2, 122.3, 125.3, 127.4,
129.3, 129.4, 132.3, 133.5, 134.1, 137.3, 138.7, 144.1, 169.7.
1H NMR (400 MHz, CDCl3): δ = 1.42 (t, J = 8.0 Hz, 3 H, CH3), 3.17–3.26
(m, 2 H, SCH2), 3.78 (s, 3 H, OCH3), 3.86 (br s, 2 H, NH2), 6.82 (d, J = 7.7
Hz, 2 H, Ar-H), 7.11 (d, J = 7.7 Hz, 2 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 8.5, 49.2, 55.4, 114.4, 124.4, 134.0,
156.1.
HRMS (EI): m/z calcd for C9H14N2O2S: 214.0776; found: 214.0777.
HRMS (EI): m/z calcd for C19H16N2O3S: 352.0882; found: 352.0884.
1-{[Amino(oxo)phenyl-λ6-sulfanylidene]amino}-2-methylben-
zene (4f)
Compounds 7b–p were prepared similarly following the above proce-
dure.
Brown solid; yield: 3.96 g (80%); mp 95–97 °C.
IR (KBr): 3257, 3062, 1596, 1489, 1290, 1055, 893 cm–1
1H NMR (400 MHz, CDCl3): δ = 1.55 (t, J = 8.0 Hz, 3 H, CH3), 2.36 (s, 3
H, Ar-CH3), 3.34–3.43 (m, 2 H, SCH2), 4.30 (br s, 2 H, NH2), 7.01–7.08
(m, 1 H, Ar-H), 7.16–7.23 (m, 1 H, Ar-H), 7.26 (d, J = 7.5 Hz, 1 H, Ar-H),
7.36–7.43 (m, 1 H, Ar-H).
2-{[Anilino(ethyl)oxo-λ6-sulfanylidene]amino}benzoic Acid (7b)
.
White solid; yield: 486 mg (80%); mp 123–125 °C.
IR (KBr): 3134, 1707, 1598, 1486, 1271, 1045, 1015, 917, 756 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.55 (t, J = 7.4 Hz, 3 H, CH3), 3.43–3.58
(m, 2 H, SCH2), 6.84–6.92 (m, 1 H, Ar-H), 7.18–7.25 (m, 1 H, Ar-H),
7.34–7.41 (m, 3 H, Ar-H), 7.43–7.47 (m, 2 H, Ar-H), 7.64 (d, J = 8.3 Hz,
1 H, Ar-H), 7.85 (dd, J = 1.5, 8.0 Hz, 1 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 8.0, 49.4, 119.5, 120.9, 121.7, 122.1,
125.4, 129.6, 132.1, 134.0, 137.7, 144.2, 169.7.
13C NMR (100 MHz, CDCl3): δ = 8.7, 18.3, 51.0, 122.5, 122.7, 126.3,
130.5, 132.0, 140.9.
HRMS (EI): m/z calcd for C9H14N2OS: 198.0827; found: 198.0824.
2-{[Amino(oxo)phenyl-1λ6-sulfanylidene]amino}-1,3-dimethyl-
HRMS (EI): m/z calcd for C15H16N2O3S: 304.0882; found: 304.0885.
benzene (4g)
2-{[Anilino(benzyl)oxo-λ6-sulfanylidene]amino}benzoic Acid (7c)
Brown solid; yield: 3.97 g (75%); mp 95–97 °C.
White solid; yield: 658 mg (90%); mp 152–154 °C.
IR (KBr,): 3103, 1685, 1594, 1474, 1265, 1023, 926, 754 cm–1
IR (KBr): 3296, 2980, 1556, 1469, 1296, 1051, 883, 771 cm–1
.
.
1H NMR (400 MHz, CDCl3): δ = 1.50 (t, J = 8.0 Hz, 3 H, CH3), 2.34 (s, 6
H, 2 × Ar-CH3), 3.26–3.36 (m, 2 H, SCH2), 3.99 (br s, 2 H, NH2), 6.88–
6.96 (m, 1 H, Ar-H), 7.03 (d, J = 7.5 Hz, 2 H, Ar-H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

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I. Sen et al.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 4.71 (d, J = 16.0 Hz, 1 H, SCH2), 4.83 (d,
J = 16.0 Hz, 1 H, SCH2), 6.91–6.99 (m, 1 H, Ar-H), 7.16–7.23 (m, 1 H,
Ar-H), 7.29–7.40 (m, 8 H, Ar-H), 7.40–7.45 (m, 2 H, Ar-H), 7.55–7.63
(m, 1 H, Ar-H), 7.98 (dd, J = 1.7, 7.9 Hz, 1 H, Ar-H).
HRMS (EI): m/z calcd for C21H20N2O4S: 396.1144; found: 396.1152.
2-{[Anilino(ethyl)oxo-λ6-sulfanylidene]amino}-5-nitrobenzoic
Acid (7h)
13C NMR (100 MHz, CDCl3): δ = 61.1, 119.7, 121.1, 121.7, 122.4, 125.4,
Sticky solid; yield: 523 mg (75%).
126.7, 129.1, 129.6, 131.3, 132.3, 134.1, 137.6, 144.1, 169.5.
IR (film): 3063, 1720, 1604, 1490, 1344, 1283, 1145, 1010, 747 cm–1
.
HRMS (EI): m/z calcd for C20H18N2O3S: 366.1038; found: 366.1044.
1H NMR (400 MHz, CDCl3): δ = 1.57 (t, J = 7.3 Hz, 3 H, CH3), 3.52–3.61
(m, 2 H, SCH2), 7.28–7.33 (m, 1 H, Ar-H), 7.42–7.48 (m, 4 H, Ar-H),
7.76–7.84 (m, 1 H, Ar-H), 8.23 (dd, J = 2.7, 9.2 Hz, 1 H, Ar-H), 8.74 (d,
J = 2.7 Hz, 1 H, Ar-H).
2-{[Anilino(benzyl)oxo-λ6-sulfanylidene]amino}-4-fluorobenzoic
Acid (7d)
Gummy mass; yield: 691 mg (90%).
IR (film): 3119, 1710, 1610, 1483, 1289, 1174, 1033, 946, 772 cm–1
13C NMR (100 MHz, CDCl3): δ = 7.97, 49.6, 119.7, 120.4, 121.5, 122.2,
126.4, 127.9, 128.7, 129.8, 136.3, 141.7, 150.7, 167.8.
.
1H NMR (400 MHz, CDCl3): δ = 4.68 (d, J = 13.8 Hz, 1 H, SCH2), 4.80 (d,
J = 13.8 Hz, 1 H, SCH2), 6.61–6.69 (m, 1 H, Ar-H), 7.17–7.24 (m, 1 H,
Ar-H), 7.29–7.35 (m, 4 H, Ar-H), 7.36–7.41 (m, 6 H, Ar-H), 7.97 (dd, J =
6.8, 8.8 Hz, 1 H, Ar-H).
HRMS (EI): m/z calcd for C15H15N3O5S: 349.0732; found: 349.0736.
2-{[Anilino(benzyl)oxo-λ6-sulfanylidene]amino}-6-methylbenzo-
ic Acid (7i)
13C NMR (100 MHz, CDCl3): δ = 60.9, 107.7, 107.9, 109.6, 109.8, 121.7,
White solid; yield: 608 mg (80%); mp 142–144 °C.
125.4, 126.5, 129.1, 129.5, 131.2, 134.3, 137.5, 146.3, 164.4, 168.7.
IR (KBr): 3142, 1692, 1588, 1491, 1262, 1012, 925, 766 cm–1
.
HRMS (EI): m/z calcd for C20H17FN2O3S: 384.0944; found: 384.0943.
1H NMR (400 MHz, CDCl3): δ = 2.27 (s, 3 H, Ar-CH3), 4.57 (s, 2 H,
SCH2), 6.91–7.00 (m, 4 H, Ar-H), 7.10–7.19 (m, 2 H, Ar-H), 7.24–7.30
(m, 4 H, Ar-H), 7.33–7.39 (m, 2 H, Ar-H), 7.69 (d, J = 7.5 Hz, 1 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 19.9, 60.6, 120.8, 123.5, 124.3, 125.1,
128.5, 128.6, 128.9, 129.2, 129.3, 131.4, 135.7, 136.2, 138.2, 141.3,
170.8.
2-{[Ethyl(2-methylanilino)oxo-λ6-sulfanylidene]amino}benzoic
Acid (7e)
White solid; yield: 540 mg (85%); mp 141–143 °C.
IR (KBr): 3134, 1707, 1598, 1486, 1281, 1045, 917, 756 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.46 (t, J = 7.4 Hz, 3 H, CH3), 2.31 (s, 3
H, Ar-CH3), 3.34–3.44 (m, 2 H, SCH2), 6.90–7.08 (m, 3 H, Ar-H), 7.12
(d, J = 7.5 Hz, 1 H, Ar-H), 7.29 (dd, J = 0.9, 7.9 Hz, 1 H, Ar-H), 7.41 (ddd,
J = 1.6, 7.2, 8.5 Hz, 1 H, Ar-H), 7.72 (d, J = 7.8 Hz, 1 H, Ar-H), 8.05 (dd,
J = 1.8, 8.0 Hz, 1 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 8.1, 18.3, 49.0, 121.8, 123.1, 126.4,
130.5, 132.1, 132.5, 134.0, 143.1, 158.9, 169.5.
HRMS (EI): m/z calcd for C21H20N2O3S: 380.1195; found: 380.1199.
2-{[Anilino(ethyl)oxo-λ6-sulfanylidene]amino}-3-methylbenzoic
Acid (7j)
Gummy mass; yield: 477 mg (75%).
IR (film): 3065, 1703, 1588, 1494, 1283, 1085, 754 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.46 (t, J = 8.0 Hz, 3 H, CH3), 2.30 (s, 3
H, Ar-CH3), 3.40 (q, J = 7.4 Hz, 2 H, SCH2), 6.77 (d, J = 7.5 Hz, 1 H, Ar-H),
7.14 (t, J = 7.9 Hz, 1 H, Ar-H), 7.20–7.29 (m, 5 H, Ar-H), 7.39 (d, J = 8.0
Hz, 1 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 8.1, 23.2, 49.2, 119.9, 121.2, 124.8,
126.2, 129.4, 131.6, 138.1, 140.4, 142.4, 143.2, 170.5.
HRMS (EI): m/z calcd for C16H18N2O3S: 318.1038; found: 318.1036.
2-{[2,6-Dimethylanilino(ethyl)oxo-λ6-sulfanylidene]amino}ben-
zoic Acid (7f)
White solid; yield: 564 mg (85%); mp 137–139 °C.
IR (KBr): 3138, 1712, 1593, 1471, 1255, 1051, 1008, 910, 771 cm–1
.
HRMS (EI): m/z calcd for C16H18N2O3S: 318.1038; found: 318.1044.
1H NMR (400 MHz, CDCl3): δ = 1.60 (t, J = 7.4 Hz, 3 H, CH3), 2.46 (s, 6
H, 2 × Ar-CH3), 3.48–3.72 (m, 2 H, SCH2), 7.00 (m, 1 H, Ar-H), 7.09 (s, 3
H, Ar-H), 7.36–7.43 (m, 1 H, Ar-H), 7.69 (d, J = 8.3 Hz, 1 H, Ar-H), 7.99
(dd, J = 7.9, 1.4 Hz, 1 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 8.5, 19.6, 50.8, 119.5, 121.3, 122.4,
127.2, 129.0, 132.2, 133.3, 134.0, 136.8, 144.2, 169.5.
2-{[Ethyl(4-methoxyanilino)oxo-λ6-sulfanylidene]amino}benzoic
Acid (7k)
White solid; yield: 534 mg (80%); mp 124–126 °C.
IR (KBr): 3093, 1701, 1593, 1469, 1290, 1047, 1014, 925, 756 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.53 (t, J = 7.4 Hz, 3 H, CH3), 3.37–3.53
(m, 2 H, SCH2), 3.81 (s, 3 H, OCH3), 6.86–6.97 (m, 3 H, Ar-H), 7.29–7.35
(m, 2 H, Ar-H), 7.36–7.43 (m, 1 H, Ar-H), 7.63–7.71 (m, 1 H, Ar-H),
7.94 (dd, J = 1.5, 8.0 Hz, 1 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 7.9, 48.8, 55.5, 114.7, 119.8, 120.1,
122.0, 125.0, 129.6, 132.2, 133.9, 144.3, 157.9, 169.3.
HRMS (EI): m/z calcd for C17H20N2O3S: 332.1195; found: 332.1198.
2-{[Anilino(benzyl)oxo-λ6-sulfanylidene]amino}-5-methoxyben-
zoic Acid (7g)
White solid; yield: 712 mg (90%); mp 159–161 °C.
IR (KBr): 3130, 1690, 1593, 1486, 1295, 1192, 1048, 911, 765 cm–1
.
HRMS (EI): m/z calcd for C16H18N2O4S: 334.0987; found: 334.0988.
1H NMR (400 MHz, CDCl3): δ = 3.78 (s, 3 H, OCH3), 4.45–4.53 (m, 2 H,
SCH2), 7.00 (d, J = 8.8 Hz, 1 H, Ar-H), 7.04–7.15 (m, 1 H, Ar-H), 7.27–
7.33 (m, 5 H, Ar-H), 7.35 (d, J = 3.0 Hz, 1 H, Ar-H), 7.44–7.49 (m, 2 H,
Ar-H), 7.52–7.59 (m, 3 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 55.7, 60.5, 110.3, 114.7, 123.9, 124.6,
126.3, 128.7, 129.4, 129.5, 129.8, 130.5, 131.1, 132.1, 139.5, 154.1,
162.7.
2-{[Anilino(ethyl)oxo-λ6-sulfanylidene]amino}-5-chlorobenzoic
Acid (7l)
White solid; yield: 473 mg (70%); mp 123–125 °C.
IR (KBr): 3133, 1710, 1595, 1486, 1264, 1016, 919, 757 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

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Synthesis
1H NMR (400 MHz, CDCl3): δ = 1.56 (t, J = 7.4 Hz, 3 H, CH3), 3.49 (q, J =
7.4 Hz, 2 H, SCH2), 7.21–7.26 (m, 1 H, Ar-H), 7.35 (dd, J = 2.8, 8.8 Hz, 1
H, Ar-H), 7.38–7.45 (m, 4 H, Ar-H), 7.59 (d, J = 8.8 Hz, 1 H, Ar-H), 7.74
(d, J = 2.8 Hz, 1 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 8.1, 49.4, 120.6, 121.7, 122.9, 125.7,
127.4, 129.7, 131.4, 134.0, 137.2, 142.8, 168.5.
2,3-Diphenyl-2λ4,1,3-benzothiadiazin-4(3H)-one 2-Oxide (8a);
Typical Procedure
To a stirred solution of 7a (704 mg, 2.0 mmol) in CH2Cl2 (10 mL) was
added Et3N (505 mg, 0.69 mL, 5.0 mmol) at r.t. To this mixture was
then added EDCI (570 mg, 3.0 mmol) and HOBt (459 mg, 3.0 mmol).
The mixture was stirred for 12 h at r.t. under N2 atmosphere. The re-
action mass was diluted with H2O (10 mL) and extracted with CH2Cl2
(3 × 50 mL). The combined organic layers were dried (Na2SO4), fil-
tered, and concentrated under reduced pressure. The crude product
was purified by CombiFlash chromatography (silica gel, n-hex-
ane/EtOAc, 7:3) to afford the desired product 8a as an off-white solid;
yield: 534 mg (80%); mp 116–118 °C.
HRMS (EI): m/z calcd for C15H15ClN2O3S: 338.0492; found: 338.0496.
2-{[Anilino(ethyl)oxo-λ6-sulfanylidene]amino}-5-bromobenzoic
Acid (7m)
Cream solid; yield: 609 mg (80%); mp 114–116 °C.
IR (KBr): 3142, 1713, 1595, 1484, 1264, 1017, 919, 763 cm–1
.
IR (KBr): 3062, 1680, 1604, 1473, 1359, 1315, 1268, 1125, 1084, 814,
753 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.56 (t, J = 7.4 Hz, 3 H, CH3), 3.46–3.53
(m, 2 H, SCH2), 7.22–7.26 (m, 1 H, Ar-H), 7.38–7.43 (m, 4 H, Ar-H),
7.47–7.51 (m, 1 H, Ar-H), 7.51–7.55 (m, 1 H, Ar-H), 7.93 (d, J = 2.3 Hz,
1 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 8.0, 49.4, 114.8, 121.1, 121.2, 122.5,
125.8, 129.7, 134.5, 136.8, 137.1, 143.3, 168.3.
1H NMR (400 MHz, CDCl3): δ = 7.01 (d, J = 4.8 Hz, 1 H, Ar-H), 7.13
(ddd, J = 1.1, 7.2, 8.0 Hz, 2 H, Ar-H), 7.23 (dd, J = 0.8, 8.3 Hz, 1 H, Ar-H),
7.27–7.39 (m, 3 H, Ar-H), 7.41–7.46 (m, 2 H, Ar-H), 7.55–7.64 (m, 2 H,
Ar-H), 7.70 (d, J = 7.7 Hz, 2 H, Ar-H), 8.12 (dd, J = 1.4, 7.9 Hz, 1 H, Ar-
H).
13C NMR (100 MHz, CDCl3): δ = 114.8, 121.6, 123.1, 128.8, 128.9,
HRMS (EI): m/z calcd for C15H15BrN2O3S: 381.9987; found: 381.9992.
129.1, 129.5, 130.5, 132.3, 134.3, 135.6, 137.8, 145.9, 161.9.
3-{[Anilino(benzyl)oxo-λ6-sulfanylidene]amino}pyridine-2-car-
HRMS (EI): m/z calcd for C19H14N2O2S: 334.0776; found: 334.0778.
boxylic Acid (7n)
Compounds 8b–o were prepared similarly following the above proce-
White solid; yield: 513 mg (70%); mp 139–141 °C.
dure.
IR (KBr): 3068, 1730, 1585, 1458, 1421, 1263, 1028, 925, 777 cm–1
.
2-Ethyl-3-phenyl-2λ4,1,3-benzothiadiazin-4(3H)-one 2-Oxide (8b)
1H NMR (400 MHz, CDCl3): δ = 4.65 (d, J = 13.8 Hz, 1 H, SCH2), 4.82 (d,
J = 13.8 Hz, 1 H, SCH2), 7.01 (dd, J = 4.9, 7.7 Hz, 1 H, Ar-H), 7.16 (d, J =
7.5 Hz, 2 H, Ar-H), 7.23–7.33 (m, 6 H, Ar-H), 7.37–7.44 (m, 2 H, Ar-H),
8.21–8.29 (m, 1 H, Ar-H), 8.41–8.52 (m, 1 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 58.9, 115.7, 117.5, 122.3, 126.0, 126.5,
128.9, 129.5, 129.8, 130.9, 136.0, 142.5, 150.5, 155.7, 165.7.
Off-white solid; yield: 503 mg (88%); mp 159–161 °C.
IR (KBr): 3070, 1681, 1604, 1470, 1353, 1295, 1049, 816, 751 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.39 (t, J = 7.3 Hz, 3 H, CH3), 3.30 (q, J =
7.3 Hz, 2 H, SCH2), 7.02–7.08 (m, 1 H, Ar-H), 7.11 (dd, J = 0.6, 8.2 Hz, 1
H, Ar-H), 7.44–7.49 (m, 2 H, Ar-H), 7.40–7.58 (m, 4 H, Ar-H), 8.05 (dd,
J = 1.7, 8.0 Hz, 1 H, Ar-H).
HRMS (EI): m/z calcd for C19H17N3O3S: 367.0991; found: 367.0993.
13C NMR (100 MHz, CDCl3): δ = 8.2, 49.4, 114.3, 121.2, 122.6, 129.2,
129.7, 129.9, 130.0, 132.3, 135.6, 145.8, 162.5.
2-{[(Benzylamino)(oxo)phenyl-λ6-sulfanylidene]amino}benzoic
Acid (7o)
HRMS (EI): m/z calcd for C15H14N2O2S: 286.0776; found: 286.0773.
White solid; yield: 366 mg (50%); mp 115–117 °C.
IR (KBr): 3165, 1712, 1593, 1471, 1269, 1103, 1043, 750 cm–1
.
2-Benzyl-3-phenyl-2λ4,1,3-benzothiadiazin-4(3H)-one 2-Oxide
(8c)
1H NMR (400 MHz, CDCl3): δ = 4.25 (d, J = 14.3 Hz, 1 H, NCH2), 4.42 (d,
J = 14.3 Hz, 1 H, NCH2), 6.91–6.94 (m, 1 H, Ar-H), 7.32 (s, 5 H, Ar-H),
7.34–7.43 (m, 1 H, Ar-H), 7.54–7.58 (m, 3 H, Ar-H), 7.64–7.68 (m, 1 H,
Ar-H), 7.83 (d, J = 7.8 Hz, 1 H, Ar-H), 8.11 (d, J = 7.5 Hz, 2 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 47.1, 120.6, 121.3, 122.1, 127.1, 127.7,
128.2, 128.5, 129.4, 132.2, 133.2, 133.7, 135.8, 139.3, 144.3, 169.2.
Off-white solid; yield: 591 mg (85%); mp 188–190 °C.
IR (KBr): 2950, 1697, 1603, 1468, 1336, 1080, 829, 756 cm–1
1H NMR (400 MHz, CDCl3): δ = 4.51 (s, 2 H, SCH2), 6.94–6.98 (m, 1 H,
Ar-H), 7.05 (d, J = 8.3 Hz, 1 H, Ar-H), 7.28–7.35 (m, 5 H, Ar-H), 7.44–
7.50 (m, 3 H, Ar-H), 7.53–7.59 (m, 3 H, Ar-H), 7.89 (dd, J = 1.6, 7.9 Hz,
1 H, Ar-H).
.
HRMS (EI): m/z calcd for C20H18N2O3S: 366.1038; found: 366.1038.
13C NMR (100 MHz, CDCl3): δ = 60.8, 114.5, 121.2, 122.5, 128.7, 129.2,
129.4, 129.6, 129.9, 130.5, 131.1, 132.0, 135.5, 145.5, 162.7.
2-{[(tert-Butoxycarbonylamino)(oxo)phenyl-λ6-sulfa-
nylidene]amino}benzoic Acid (7p)
HRMS (EI): m/z calcd for C20H16N2O2S: 348.0932; found: 348.0933.
Cream solid; yield: 601 mg (80%); mp 133–135 °C.
IR (KBr): 3091, 1715, 1597, 1492, 1278, 1161, 941, 761 cm–1
.
2-Benzyl-7-fluoro-3-phenyl-2λ4,1,3-benzothiadiazin-4(3H)-one
2-Oxide (8d)
1H NMR (400 MHz, CDCl3): δ = 1.35 s, 9 H, C(CH3)3], 7.03–7.11 (m, 1 H,
Ar-H), 7.41 (ddd, J = 1.6, 7.2, 8.5 Hz, 1 H, Ar-H), 7.47–7.53 (m, 3 H, Ar-
H), 7.55–7.61 (m, 1 H, Ar-H), 8.02–8.07 (m, 3 H, Ar-H),
13C NMR (100 MHz, CDCl3): δ = 27.9, 81.8, 117.0, 119.2, 123.2, 127.9,
129.2, 132.2, 133.4, 134.5, 138.6, 140.2, 156.0, 170.0.
Colorless oil; yield: 644 mg (88%).
IR (film): 1692, 1613, 1443, 1309, 1277, 1168, 760 cm–1
1H NMR (400 MHz, CDCl3): δ = 4.51 (s, 2 H, SCH2), 6.65 (td, J = 2.4, 8.5
Hz, 1 H, Ar-H), 6.71 (dd, J = 2.3, 10.0 Hz, 1 H, Ar-H), 7.28–7.37 (m, 5 H,
Ar-H), 7.46–7.52 (m, 2 H, Ar-H), 7.54–7.62 (m, 3 H, Ar-H), 7.87 (dd, J =
6.4, 8.9 Hz, 1 H, Ar-H).
.
HRMS (EI): m/z calcd for C18H20N2O5S: 376.1093; found: 376.1095.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

H
I. Sen et al.
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Synthesis
13C NMR (100 MHz, CDCl3): δ = 61.0, 108.4, 108.6, 109.4, 109.6, 125.9,
128.8, 129.6, 129.7, 130.0, 130.5, 131.1, 131.7, 131.8, 131.9, 147.8,
147.9, 161.7, 166.0, 168.6.
2-Benzyl-5-methyl-3-phenyl-2λ4,1,3-benzothiadiazin-4(3H)-one
2-Oxide (8i)
Yellow solid; yield: 579 mg (80%); mp 154–156 °C.
HRMS (EI): m/z calcd for C20H15FN2O2S: 366.0838; found: 366.0839.
IR (KBr): 3054, 1696, 1590, 1465, 1356, 1266, 1098, 1015, 836, 772
cm–1
.
2-Ethyl-3-(2-methylphenyl)-2λ4,1,3-benzothiadiazin-4(3H)-one
2-Oxide (8e)
1H NMR (400 MHz, CDCl3): δ = 2.32 (s, 3 H, Ar-CH3), 4.45–4.54 (m, 2
H, SCH2), 6.85–6.91 (m, 1 H, Ar-H), 7.27–7.33 (m, 5 H, Ar-H), 7.33–
7.37 (m, 1 H, Ar-H), 7.47–7.59 (m, 5 H, Ar-H), 7.77 (dd, J = 1.1, 7.9 Hz,
1 H, Ar-H).
White solid; yield: 450 mg (75%); mp 104–106 °C.
IR (KBr): 2962, 1683, 1602, 1471, 1458, 1350, 1296, 1126, 1083, 1049,
995, 817, 756 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 17.2, 60.2, 114.1, 120.5, 126.0, 126.5,
1H NMR (400 MHz, CDCl3): δ = 1.39 (t, J = 7.4 Hz, 3 H, CH3), 2.28 (s, 3
H, Ar-CH3), 3.28 (quint, J = 7.1, 17.8 Hz, 2 H, SCH2), 7.04–7.09 (m, 1 H,
Ar-H), 7.14–7.11 (m, 1 H, Ar-H), 7.33–7.44 (m, 3 H, Ar-H), 7.51–7.56
(m, 1 H, Ar-H), 7.56–7.60 (m, 1 H, Ar-H), 8.05–8.10 (m, 1 H, Ar-H).
128.3, 129.1, 129.3, 129.5, 130.1, 130.7, 131.8, 135.7, 143.7, 162.8.
HRMS (EI): m/z calcd for C21H18N2O2S: 362.1089; found: 362.1088.
2-Ethyl-8-methyl-3-phenyl-2λ4,1,3-benzothiadiazin-4(3H)-one
2-Oxide (8j)
13C NMR (100 MHz, CDCl3): δ = 7.8, 18.1, 50.1, 114.8, 121.2, 122.7,
127.3, 129.2, 130.0, 130.7, 131.2, 131.4, 135.5, 137.2, 145.5, 161.1.
Yellow solid; yield: 504 mg (84%); mp 132–134 °C.
IR (KBr): 3065, 1679, 1597, 1474, 1343, 1270, 1097, 899, 752 cm–1
.
HRMS (EI): m/z calcd for C16H16N2O2S: 300.0933; found: 300.0932.
1H NMR (400 MHz, CDCl3): δ = 1.39 (t, J = 7.3 Hz, 3 H, CH3), 2.65 (s, 3
H, Ar-CH3), 3.24–3.33 (m, 2 H, SCH2), 6.86 (d, J = 7.5 Hz, 1 H, Ar-H),
6.98 (d, J = 7.8 Hz, 1 H, Ar-H), 7.36 (t, J = 7.8 Hz, 1 H, Ar-H), 7.44–7.52
(m, 2 H, Ar-H), 7.53–7.57 (m, 3 H, Ar-H).
3-(2,6-Dimethylphenyl)-2-ethyl-2λ4,1,3-benzothiadiazin-4(3H)-
one 2-Oxide (8f)
White solid; yield: 439 mg (70%); mp 87–89 °C.
IR (KBr): 3007, 1679, 1603, 1472, 1350, 1043, 759 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 6.4, 22.2, 47.4, 111.4, 119.4, 123.3,
1H NMR (400 MHz, CDCl3): δ = 1.42 (t, J = 7.4 Hz, 3 H, CH3), 2.29 (s, 3
H, Ar-CH3), 2.35 (s, 3 H, Ar-CH3), 3.27–3.49 (m, 2 H, SCH2), 7.06 (td, J =
1.1, 7.6 Hz, 1 H, Ar-H), 7.13 (d, J = 8.3 Hz, 1 H, Ar-H), 7.18–7.25 (m, 2
H, Ar-H), 7.27–7.32 (m, 1 H, Ar-H), 7.54 (ddd, J = 1.6, 7.1, 8.3 Hz, 1 H,
Ar-H), 8.07 (dd, J = 1.6, 7.9 Hz, 1 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 7.5, 18.7, 19.4, 50.6, 114.9, 121.2,
122.8, 128.9, 129.4, 129.7, 129.8, 130.5, 135.7, 137.3, 140.0, 145.7,
161.9.
127.9, 128.0, 128.3, 130.6, 132.6, 141.4, 145.5, 160.8.
HRMS (EI): m/z calcd for C16H16N2O2S: 300.0932; found: 300.0932.
2-Ethyl-3-(4-methoxyphenyl)-2λ4,1,3-benzothiadiazin-4(3H)-one
2-Oxide (8k)
Yellow solid; yield: 537 mg (85%); mp 157–159 °C.
IR (KBr): 3010, 1679, 1606, 1511, 1354, 1252, 1112, 1048, 834, 722
cm–1
.
HRMS (EI): m/z calcd for C17H18N2O2S: 314.1089; found: 314.1096.
1H NMR (400 MHz, CDCl3): δ = 1.39 (t, J = 7.3 Hz, 3 H, CH3), 3.31 (q, J =
7.3 Hz, 2 H, SCH2), 3.87 (s, 3 H, OCH3), 7.01–7.07 (m, 3 H, Ar-H), 7.07–
7.12 (m, 1 H, Ar-H), 7.37 (d, J = 8.5 Hz, 2 H, Ar-H), 7.51 (t, J = 7.7 Hz, 1
H, Ar-H), 8.04 (dd, J = 1.5, 8.0 Hz, 1 H, Ar-H).
2-Benzyl-6-methoxy-3-phenyl-2λ4,1,3-benzothiadiazin-4(3H)-one
2-Oxide (8g)
White solid; yield: 604 mg (80%); mp 154–156 °C.
IR (KBr): 3059, 1692, 1486, 1314, 1053, 840, 763 cm–1
13C NMR (100 MHz, CDCl3): δ = 6.2, 49.3, 55.5, 114.3, 115.0, 121.1,
122.6, 124.3, 129.2, 131.1, 135.5, 145.8, 160.6, 162.7.
.
1H NMR (400 MHz, CDCl3): δ = 3.78 (s, 3 H, OCH3), 4.45–4.53 (m, 2 H,
SCH2), 7.00 (d, J = 8.8 Hz, 1 H, Ar-H), 7.04–7.15 (m, 1 H, Ar-H), 7.27–
7.33 (m, 5 H, Ar-H), 7.35 (d, J = 3.0 Hz, 1 H, Ar-H), 7.44–7.49 (m, 2 H,
Ar-H), 7.52–7.59 (m, 3 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 55.7, 60.5, 110.3, 114.7, 123.9, 124.6,
126.3, 128.7, 129.4, 129.5, 129.9, 130.4, 131.1, 132.1, 139.5, 154.1,
162.7.
HRMS (EI): m/z calcd for C16H16N2O3S: 316.0882; found: 316.0882.
6-Chloro-2-ethyl-3-phenyl-2λ4,1,3-benzothiadiazin-4(3H)-one
2-Oxide (8l)
Yellow solid; yield: 512 mg (80%); mp 146–148 °C.
IR (KBr): 3051, 1681, 1602, 1469, 1417, 1313, 1028, 877, 815, 748 cm–1
1H NMR (400 MHz, CDCl3): δ = 1.39 (t, J = 7.3 Hz, 3 H, CH3), 3.26–3.36
(m, 2 H, SCH2), 7.06 (d, J = 8.8 Hz, 1 H, Ar-H), 7.42–7.49 (m, 3 H, Ar-H),
7.53–7.58 (m, 3 H, Ar-H), 8.00 (d, J = 2.6 Hz, 1 H, Ar-H).
.
HRMS (EI): m/z calcd for C21H18N2O3S: 378.1038; found: 378.1032.
2-Ethyl-6-nitro-3-phenyl-2λ4,1,3-benzothiadiazin-4(3H)-one
2-Oxide (8h)
13C NMR (100 MHz, CDCl3): δ = 8.2, 49.5, 115.2, 124.2, 126.4, 128.3,
129.9, 130.0, 130.2, 132.0, 135.6, 144.4, 161.5.
Yellow solid; yield: 542 mg (82%); mp 207–209 °C.
HRMS (EI): m/z calcd for C15H13ClN2O2S: 320.0386; found: 320.0387.
IR (KBr): 3005, 1685, 1612, 1477, 1326, 1117, 1019, 802, 744 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 1.25 (t, J = 7.2 Hz, 3 H, CH3), 3.60–
3.74 (m, 2 H, SCH2), 7.24 (d, J = 9.0 Hz, 1 H), 7.53–7.65 (m, 5 H, Ar-H),
8.38 (dd, J = 2.9, 9.2 Hz, 1 H, Ar-H), 8.65 (d, J = 2.8 Hz, 1 H, Ar-H).
13C NMR (100 MHz, DMSO-d6): δ = 7.4, 49.9, 113.4, 123.4, 124.7,
129.7, 129.9, 130.3, 130.4, 131.3, 140.5, 151.1, 160.3.
6-Bromo-2-ethyl-3-phenyl-2λ4,1,3-benzothiadiazin-4(3H)-one
2-Oxide (8m)
White solid; yield: 580 mg (80%); mp 138–140 °C.
IR (KBr): 3100, 1683, 1597, 1466, 1419, 1311, 1026, 880, 813, 748 cm–1
.
HRMS (EI): m/z calcd for C15H13N3O4S: 331.0627; found: 331.0630.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

I
I. Sen et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 1.39 (t, J = 7.3 Hz, 3 H, CH3), 3.25–3.35
(m, 2 H, SCH2), 7.00 (d, J = 8.7 Hz, 1 H, Ar-H), 7.40–7.50 (m, 2 H, Ar-H),
7.53–7.57 (m, 3 H, Ar-H), 7.59 (dd, J = 2.4, 8.7 Hz, 1 H, Ar-H), 8.15 (d,
J = 2.4 Hz, 1 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 8.2, 49.6, 113.5, 115.7, 124.6, 129.9,
130.0, 130.3, 131.4, 132.0, 138.4, 8.2, 144.9, 161.4.
Acknowledgment
We thank Dr. Bhanu Manjunath, Director, Syngenta Goa Research &
Technology Centre for his support. This work has been completed as a
part of the Ph.D. Thesis (I. Sen) affiliated to the University of Manga-
lore with guidance from Dr. Sitaram Pal at Syngenta Goa Research &
Technology Centre.
HRMS (EI): m/z calcd for C15H13BrN2O2S: 363.9881; found: 363.9876.
2-Benzyl-3-phenyl-2λ4-pyrido[2,3-c][1,2,6]thiadiazin-4(3H)-one
2-Oxide (8n)
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561657.
Yellow solid; yield: 558 mg (80%); mp 138–140 °C.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
IR (KBr): 3061, 1678, 1585, 1463, 1427, 1359, 1276, 1064, 1029, 829,
773 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 4.49–4.63 (m, 2 H, SCH2), 6.91 (dd, J =
4.9, 7.7 Hz, 1 H, Ar-H), 7.22–7.27 (m, 2 H, Ar-H), 7.35–7.41 (m, 3 H,
Ar-H), 7.47–7.52 (m, 2 H, Ar-H), 7.54–7.60 (m, 3 H, Ar-H), 8.12 (dd, J =
2.0, 7.8 Hz, 1 H, Ar-H), 8.49 (dd, J = 1.9, 4.6 Hz, 1 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 61.3, 109.7, 117.4, 128.8, 129.7, 129.8,
130.2, 130.4, 130.7, 131.2, 131.5, 138.3, 155.3, 155.4, 162.1.
References
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HRMS (EI): m/z calcd for C19H15BrN3O2S: 349.0885; found: 349.0886.
3-Benzyl-2-phenyl-2λ4,1,3-benzothiadiazin-4(3H)-one 2-Oxide
(8o)
Yellow solid; yield: 570 mg (82%); mp 116–118 °C.
IR (KBr): 3062, 1670, 1604, 1471, 1460, 1354, 1309, 1276, 1143, 1047,
1026, 947, 850, 759 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 4.81 (d, J = 16.0 Hz, 1 H, NCH2), 4.98 (d,
J = 16.0 Hz, 1 H, NCH2), 7.05–7.13 (m, 2 H, Ar-H), 7.12–7.18 (m, 5 H,
Ar-H), 7.41–7.47 (m, 2 H, Ar-H), 7.50–7.55 (m, 1 H, Ar-H), 7.55–7.61
(m, 1 H, Ar-H), 7.78–7.86 (m, 2 H, Ar-H), 8.11 (dd, J = 1.5, 8.1 Hz, 1 H,
Ar-H).
13C NMR (100 MHz, CDCl3): δ = 46.5, 114.5, 121.5, 122.9, 127.5, 128.1,
128.2, 128.3, 129.0, 129.3, 134.2, 135.1, 135.5, 138.9, 145.6, 162.4.
HRMS (EI): m/z calcd for C20H16N2O2S: 348.0932; found: 348.0933.
2-Phenyl-2λ4,1,3-benzothiadiazin-4(3H)-one 2-Oxide (8p)
To a stirred solution of 7p (500 mg, 1.39 mmol) in CH2Cl2 (10 mL) was
added Et3N (350 mg, 0.48 mL, 3.47 mmol) at r.t. To this mixture was
then added EDCI (399 mg, 2.08 mmol) and HOBt (321 mg, 2.08
mmol). The mixture was stirred for 12 h at r.t. under N2 atmosphere.
The reaction mass was acidified to pH 2 using 2 M HCl solution and
extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were
dried (Na2SO4), filtered, and concentrated under reduced pressure.
The crude product was purified by CombiFlash chromatography (sili-
ca gel, n-hexane/EtOAc, 5:5) to afford the desired product 8p (179 mg,
50%) as a pale solid; mp 113–115 °C.
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1H NMR (400 MHz, CDCl3): δ = 7.02–7.14 (m, 2 H, Ar-H), 7.52–7.65
(m, 4 H, Ar-H), 7.90–7.92 (m, 2 H, Ar-H), 8.06 (d, J = 8.1 Hz, 1 H, Ar-H)
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J