Copper-catalyzed N[sbnd]H/S[sbnd]H functionalization: A strategy for the synthesis of benzothiadiazine derivatives

Article abstract of DOI:10.1016/j.tet.2017.02.063

A copper-mediated N[sbnd]S bond-forming reaction via N[sbnd]H/S[sbnd]H activation is described. This reaction occurs under mild conditions with high efficiency, step economy, and tolerates a wide variety of functional groups, providing an efficient means of accessing biologically important 1,2,4-benzothiadiazin-3(4H)-ones.

Full text of DOI:10.1016/j.tet.2017.02.063

Accepted Manuscript
Copper-catalyzed N–H/S–H functionalization: A strategy for the synthesis of
benzothiadiazine derivatives
Şengül Dilem Doğan
PII:
S0040-4020(17)30212-0
10.1016/j.tet.2017.02.063
TET 28504
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 4 November 2016
Revised Date: 16 February 2017
Accepted Date: 27 February 2017
Please cite this article as: Doğan ED, Copper-catalyzed N–H/S–H functionalization: A strategy for the
synthesis of benzothiadiazine derivatives, Tetrahedron (2017), doi: 10.1016/j.tet.2017.02.063.
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Copper-Catalyzed N-H/S-H Functionalization:
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A Strategy for the Synthesis of Benzothiadiazine
Derivatives
Şengül Dilem Doğan
Department of Pharmaceutical Basic Sciences, Faculty of Pharmacy, Erciyes University,Kayseri, 03839 Turkey

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1
Tetrahedron
journal homepage: www.elsevier.com
Copper-Catalyzed N-H/S-H Functionalization: A Strategy for the
Synthesis of Benzothiadiazine Derivatives
Şengül Dilem Doğan
Department of Pharmaceutical Basic Sciences, Faculty of Pharmacy, Erciyes University,Kayseri, 03839 Turkey
ARTICLE INFO
ABSTRACT
A copper-mediated N-S bond-forming reaction via N-H/S-H activation is described. This
reaction occurs under mild conditions with high efficiency, step economy, and tolerates a wide
variety of functional groups, providing an efficient means of accessing biologically important
1,2,4-benzothiadiazin-3(4H)-ones.
Article history:
Received
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Benzothiadiazine
Copper-catalyzed
NH-SH functionalization
N-S bond formation
Diphenylurea
1. Introduction
catalyzed functionalization of N-H/S-H bonds has not been
reported.
The direct construction of N–S bonds is an interesting approach
for the synthesis of a wide range of biologically important
molecules and functional materials. In recent years, there have
been numerous examples related to C–C,1 C–N,2 C–S3, and C–O4
bond formation via copper-catalyzed functionalization of C–H
bonds. However, copper-catalyzed direct heteroatom-heteroatom
bond (N–S, N–N, N–O)5 formation has remained undeveloped.
N–S bond formation has immense importance in synthetic
chemistry because of its wide existence in natural products,
biologically active compounds, and drug molecules. To the best
of our knowledge, only a few examples of copper-catalyzed N-S
bond formation reactions have been reported in the literature.
Punniyamurthy et al.6 and Shi et al.7 reported a one-pot copper-
promoted N-S bond formation using benzamides as starting
compounds in the presence of sulfur powder (Scheme 1). A
variety of benzoisothiazolones were synthesized in two steps.
The first step was a C-S cross coupling reaction. The second step
was N-S bond formation. Kanai8 synthesized via a copper-
catalyzed one-pot process benzo[d]isothiazol-3-(2H)-ones
starting from 2-mercapto-N-phenylbenzamide in one step
(Schema 1). To date, copper-catalyzed dehydrogenative cross-
coupling reactions between N–H and S–H bonds have been seen
as the only direct method for the synthesis of
benzoisothiazolones (Figure 1). It was interesting that the
synthesis of 1,2,4-benzothiadiazine derivatives via copper-
(a) Previous work
O
O
Cu
NH
R
N
R
S
X
X=SH, CI, Br, I, H
Benzoisothiazolones
Punniyamurthy (2012)6: X=I, S source
Kanai (2014)8: X= SH
Shi (2014)7: X=H, S source
(b) This work
H
N
O
O
R
NH
SH
NH R
Cu
N
S
Benzothiadiazines
Scheme1. Copper-mediated N-S bond formation
Benzothiadiazine derivatives, found in pharmaceuticals, have
attracted the attention of researchers.9 Various benzothiadiazine
derivatives including chlorothiazide, diazoxide, cyclothiazide,

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2
Tetrahedron
and bendroflumethiazide are widely used as diuretic and
of benzoic acid derivatives with ethylchloroformate in the
presence of triethylamine followed by the addition of a solution
of NaN3 in water. The desired ureas were obtained in high yields.
antihypertensive drugs10 (Figure 1). In addition to the
aforementioned activities, benzothiadiazine derivatives have
shown anti-HIV (human immunodeficiency virus), anti-HCMV
(human cytomegalovirus), anti-VZV (varicella zoster virus), anti-
HCV (hepatitis C), and anti-RSV (respiratory syncytial viral)
activities.11
Scheme 3. Synthesis of N-(2-mercaptophenyl)-N'-substituted-
ureas from 2-aminobenzenethiol
Entry
1
2
3
4
5
6
7
8
catalyst
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
solvent
DMF
DMSO
CH3CN
Toluene
2-Propanol
H2O
MeOH
1,4-Dioxane
DCE
DMF
DMF
DMF
DMF
DMF
DMF
conversion (%)a
Figure 1. Representative drugs with 1,2,4-benzothiadiazine
skeletons.
99
97
56
n.r
n.r
n.r
n.r
n.r
n.r
70
60
18
31
89
n.r
Benzothiadiazine derivatives have traditionally been synthesized
using classical methods including Diels-Alder reactions, [3+2]
cycloaddition, and Friedel-Crafts reactions. Besides these
methods, transition metal catalyzed transformation has received
increasing attention in recent years.12 The methods reported for
the synthesis of benzothiadiazines have various disadvantages
such as isomer formation, strong acid conditions, long reaction
time, and over-substitution. Thus, it is desirable to synthesize
various benzothiadiazines derivative starting from readily
available materials via an efficient and easily applicable protocol.
Herein, a new one-pot copper catalyzed methodology for the
synthesis of 1,2,4-benzothiadiazin-3(4H)-ones from N-(2-
mercaptophenyl)-N'-(phenyl)-ureas in the presence of molecular
oxygen (Scheme 1) is reported.
9
CuI
CuI
10
11
12
13
14
15
CuBr
CuO
Cu2O
Cu(OAc)2
–
aDetermined by 1H NMR spectroscopy.
n.r=no reaction.
Table 1. Optimization for synthesis of N-substituted-1,2,4-
benzothiadiazin-3(4H)-ones
For the cyclization reaction, N-(2-mercaptophenyl)-N'-(4-
phenyl)-urea (1a) was chosen as a model compound. To optimize
the reaction conditions 1a was reacted with different copper
catalysts and in different solvents (Table 1). Several copper
sources were investigated and the conversion ratio was
determined by 1H-NMR spectroscopy: CuCl (70%), CuBr (60%),
CuO (18%), Cu2O (31%), and Cu(OAc)2 ( 89%) (Table 1, entries
10-14). High conversion was also obtained in DMSO, but the S-
oxidation products were observed in a ratio of 3-5% depending
on the reaction time. Control experiments clearly indicated that
copper was indispensable for the reaction (entries 15, Table 1).
Finally, the desired product, 2-phenyl-2H-1,2,4-benzothiadiazin-
3(4H)-ones (2a) was formed in a yield of 99% when the reaction
was carried out with 10 mol% copper (I) iodide in N,N-
dimethylformamide (DMF) at 80 °C for 4–5 h under molecular
oxygen (Table 1, entry 1).
Scheme 2. Strategy for the synthesis of N-substituted-1,2,4-
benzothiadiazin-3(4H)-ones
2. Result and Discussion
The starting materials (1a-1p) were prepared from the reaction
between 2-aminobenzenethiol (3) and isocyanate13 (Scheme 3).
Commercially available isocyanates were used for the synthesis
of 1a, 1e, 1f, 1i, 1j, 1o, and 1p. The remaining isocyanates (1b,
1c, 1d, 1g, 1h, 1k, 1l, 1m, 1n) were generated by Curtius
rearrangement of acyl azides,14 which were obtained by treatment

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2a: 53%
2e: 50%
2i: 59%
2b: 55%
2f: 40%
2j: 68%
2c: 68%
2g: 55%
2k: 51%
2d: 60%
2h: 61%
2l: 59%
2m: 48%
2n: 66%
2o: 53%
2p: 73%
* isolated yields after purification by column chromatography
Table 2. Substrate scope for the synthesis of benzoisothiadiazines (2a-2p)
With having the optimized conditions in hand, we tested the
scope of this cyclization reaction and submitted various starting
materials including N'-aromatic- and N'-aliphatic substituents
under the same reactions conditions to Cu-catalyzed cyclization
(Table 2). Neither electron-donating (e.g., -Me, -OMe) (1h-o),
nor electron-withdrawing substituents (e.g., -F, -Cl, -Br, -NO2
and –CN) (1b-g) on the N'-phenyl group had any significant
effect.
Furthermore, the ortho-, meta- and para- positions of the
substituents (1f, 1j, 1k-l) also showed no effects on the mode of
cyclization reactions (Table 2). It was concluded that the
electronegativity and the positions of the substituents attached to
the phenyl ring had no effect on the intramolecular cross
coupling reaction. Additionally, N'-alkyl urea (1p) afforded the
corresponding benzothiadiazine 2p with the highest yield (Table
2). Contrary to our expectation, no loss of halogen atom was
observed during the reaction with 1b-d (Table 2).

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Tetrahedron
a
b
Figure 2. (a) The molecular structure of compound 2a showing the atom numbering scheme; thermal ellipsoids are drawn at the
40% probability level. (b) Observed key HMBC (H C) correlations for compound 2k.
Scheme 3. Possible reactions pathways for the formation of 2.
It was expected that N-(2-mercaptophenyl)-N'-phenyl-substituted
4. Experimental
ureas (1) would undergo two different cyclizations reaction to
give the six-membered cyclization product 2 as well as the four-
membered cyclization product 8 (Scheme 3). NMR spectral
studies clearly indicated the exclusive formation of a six-
4.1. General methods
membered ring. To show the formation of a six-membered ring
compound, 2k was chosen as model compound. The HMBC
spectrum of 2k showed strong correlation between the –NH
protons resonating at 10.16 ppm as a singlet and the quaternary
carbon atoms (C-4a) and aromatic carbon atoms (C-5) resonating
at 121.6 and 116.1 ppm, respectively (Figure 2b). The key
correlations supported the direct connection of the NH group to
the benzene ring. The structure was further confirmed by single
crystal X-ray diffraction studies performed on compound 2a
(Figure 2a). These results indicated that the cyclization proceeded
via N'H/SH activation. The suggested mechanism occurred as
follows (Scheme 3). The first step was the coordination of N-(2-
mercaptophenyl)-N'-(4-methylphenyl)-urea (1) to a copper atom.
The second step was the Cu–S oxidative bond formation via the
elimination of water. Third was Cu–N oxidative bond formation
via the elimination of water. (The order of steps second and third
could be reversed). The formation of benzoisothiadiazine and the
regeneration of the copper catalyst occurred in the last step via
reductive elimination.
THF, benzene, toluene were distilled from sodium-benzophenone
just prior to use. All reagents were purchased and used as
received. All volatiles were removed under the reduced pressure.
All reaction mixtures and column eluents were monitored by
TLC using commercial glass backed thin layer chromatography
(TLC) plates. Melting points were measured using, open glass
capillaries and are uncorrected. Infrared (IR) spectra were
recorded in the range 4000–600 cm-1 via ATR diamond. MS
spectra were recorded on a LC/MS High Resolution Time of
Flight (TOF) Agilent 1200/6530 instrument at the Bilkent
University. 1H- and 13C-NMR spectra were recorded on a Bruker
AM 400 spectrometer (at 400 and 100 MHz, respectively) in
DMSO-d6 or CDCl3 solution. Coupling constants, J, are reported
in hertz to the nearest 0–5 Hz. Deuterated solvents were used for
the homonuclear lock, and the signals are referenced to the
deuterated solvents peaks.
4.1. General procedure 1 for the synthesis of 1a, 1e, 1f, 1i, 1j, 1o,
1p (1a as an example)
3. Conclusion
2-Aminothiophene (7.9 mmol, 0.85 mL) was added to phenyl
isocyanate solution (8.7 mmol, 0.9 mL) in 5 mL toluene. The
mixture was stirred at 80 °C until complete, and then cooled to
room temperature. The precipitate was filtered off and washed
with toluene. The resulting residue was purified by crystallization
from EtOH to afford urea 1a (1.2 g, 62% yield) as a white solid.
Efficient regioselective one-pot copper-catalyzed N-H/S-H
functionalization forming
a
N–S bond provided 1,2,4-
benzothiadiazin-3(4H)-ones from readily available ureas in high
yields. This approach has numerous advantages including the use
of a low-toxic and relatively cheap catalyst (copper iodide) and,
easily available oxidant (molecular oxygen) and its tolerance of a
variety of functional groups. Further work is underway to expand
the scope of direct heteroatom-heteroatom (N–N, N–S) bond
formation.
4.2. General procedure 2 for the synthesis of 1b, 1c, 1d, 1g, 1h,
1k, 1l, 1m, 1n 1 (1g as an example)
To a solution of 4-methoxy benzoic acid (0.5 g, 3.3 mmol) in 10
mL THF at –5 °C, triethylamine (0.46 mL, 3.3 mmol) in 5 mL

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THF was added drop wise and stirred. After 30 min., the cooled
ethyl chloroformate solution (0.31 mL, 3.3 mmol) in 5 mL THF
was added slowly and was stirred at at –5 °C for 30 min. In the
last step, the solution of sodium azide (0.42 g, 6.6 mmol) in 5 mL
water was added drop-wise and stirred at room temperature
overnight. The resulting mixture was extracted with ethyl acetate
(3x15 mL) and the organic phase was washed with saturated
sodium bicarbonate (3x30 mL) and with water (2x25 mL) and
dried over MgSO4. After the ethyl acetate was removed, 0.47 g
azide (80%) was obtained. Without any purification, the obtained
acyl azide was used immediately. Acyl azide (0.47 g, 2.7 mmol)
and 2-aminothiophene (0.34 g, 2.7 mmol) in benzene (20 mL)
was stirred at 70–80 °C for 24 h under nitrogen. The formed
precipitate was filtered off and washed with benzene. The
resulting residue was purified by crystallization from EtOH and
urea 1g was obtained as a white solid.
Hz, ArH); 13C NMR (100 MHz, DMSO) δ 152.7 (CO), 139.8,
139.4, 134.1, 132.0, 130.6, 125.5, 123.8, 122.3, 120.6, 113.8;
HRMS (EI): [M–H]–, found 320.97027. C13H1079BrN2OS requires
320.96751.
4.7. N-(2-mercaptophenyl)-N'-4-cyanophenylurea (1e)
According to the general procedure 1, urea 1e was obtained as a
white solid in 81% yield after crystallization from EtOH: mp
253–255 °C; Rf (90% EtOAc/hexane): 0.71; IR (ATR) 3321,
1
2987, 1644, 1549, 1406, 1054; H NMR (400 MHz, DMSO) δ
9.81 (1H, s, NH), 8.55 (1H, s, NH), 7.90 (1H, d, J = 8.0 Hz,
ArH), 7.75 (2H, d, J = 8.5 Hz, ArH), 7.62 (2H, d, J = 8.5 Hz,
ArH), 7.38 (1H, d, J = 7.5 Hz, ArH), 7.29 (1H, t, J = 7.0 Hz,
ArH), 7.00 (1H, t, J = 7.5 Hz, ArH); 13C NMR (100 MHz,
DMSO) δ 152.5 (CO), 144.5, 139.4, 134.0, 133.8, 130.6, 125.9,
124.2, 122.6, 119.7, 118.5, 103.9 (CN); HRMS (EI): [M–H]–,
found 268.05421. C14H10N3OS requires 268.05446.
4.3. N-(2-mercaptophenyl)-N'-phenylurea (1a)
According to the general procedure 1, the urea 1a was obtained
as a white solid in 62% yield after purification by crystallization
from EtOH: mp 216–217 °C; Rf (50% EtOAc/hexane): 0.78; IR
(ATR) 3663, 3269, 2987, 2324, 1639, 1538; 1H NMR (400 MHz,
DMSO) δ 9.36 (1H, s, NH), 8.39 (1H, s, NH), 7.96 (1H, d, J =
8.0 Hz, ArH), 7.46 (2H, d, J = 7.5 Hz, ArH), 7.38-7.18 (4H, m,
ArH), 7.07-6.78 (2H, m, ArH ); 13C NMR (100 MHz, DMSO) δ
152.9 (CO), 140.0, 140.0, 134.1, 130.6, 129.3, 125.30, 123.6,
4.8. N-(2-mercaptophenyl)-N'-3-cyanophenylurea (1f)
According to the general procedure 1, urea 1f was obtained as a
white solid in 86% yield after crystallization from EtOH: mp
225–226 °C; Rf (50% EtOAc/hexane): 0.62; IR (ATR) 2973,
1
1660, 1528, 1408, 1252, 1056; H NMR (400 MHz, DMSO) δ
9.67 (1H, s, NH), 8.51 (1H, s, NH), 7.98 (1H, s, ArH), 7.90 (1H,
d, J = 7.5 Hz, ArH), 7.63 (1H, d, J = 7.5 Hz, ArH), 7.50 (1H, t, J
= 8.0 Hz, ArH), 7.44 (1H, d, J = 7.5 Hz, ArH), 7.37 (1H, d, J =
8.0 Hz, ArH), 7.30 (1H, t, J = 7.5 Hz, ArH), 6.99 (1H, t, J = 7.0
Hz, ArH); 13C NMR (100 MHz, DMSO) δ 152.8 (CO), 140.9,
139.5, 133.9, 130.7, 130.6, 125.9, 125.8, 124.1, 123.3, 122.5,
121.1, 119.3, 112.1; HRMS (EI): [M–H]–, found 268.05196.
C14H10N3OS requires 268.05446.
–
122.4, 122.3, 118.7; HRMS (EI): [M–H] , found 244.06369.
C13H12N2OS requires 244.06703).
4.4. N-(2-mercaptophenyl)-N'-4-fluorophenylurea (1b)
According to the general procedure 2, urea 1b was obtained as a
white solid in 66% yield after the purification by crystallization
from EtOH: mp 229–230 °C; Rf (50% EtOAc/hexane): 0.80; IR
(ATR) 3259, 2989, 2086, 1633, 1556, 1209; 1H NMR (400 MHz,
DMSO) δ 9.39 (1H, s, NH), 8.37 (1H, s, NH), 7.94 (1H, d, J =
8.0 Hz, ArH), 7.49-7.40 (2H, m, ArH), 7.31 (2H, dd, J = 16.5,
7.5 Hz, ArH), 7.14 (2H, dd, J = 12.0, 5.5 Hz, ArH), 6.95 (1H, td,
J = 7.5, 1.0 Hz, ArH); 13C NMR (100 MHz, DMSO) δ 157.8 (d,
J=238 Hz), 152.9 (CO), 140.0, 136.3 (d, J=2.0 Hz), 134.1, 130.6,
125.3, 123.7, 122.3, 120.4 (d, J=7.5 Hz), 115.8 (d, J=22.0 Hz);
HRMS (EI): [M–H]–, found 261.05138. C13H10FN2OS requires
261.04979.
4.9. N-(2-mercaptophenyl)-N'-4-nitrophenylurea (1g)
According to the general procedure 2, urea 1g was obtained as a
white solid in 77% yield after crystallization from EtOH: mp
252–254 °C; Rf (50% EtOAc/hexane): 0.76; IR (ATR) 3289,
1
2987, 2888, 1645, 1549, 1343; H NMR (400 MHz, DMSO) δ
10.02 (1H, s, NH), 8.60 (1H, s, NH), 8.20 (2H, d, J = 9.0 Hz,
ArH), 7.91 (1H, d, J = 8.0 Hz, ArH), 7.67 (2H, d, J = 9.0 Hz,
ArH), 7.39 (1H, d, J = 7.5 Hz, ArH), 7.30 (1H, t, J = 7.5 Hz,
ArH), 7.01 (1H, t, J = 7.0 Hz, ArH); 13C NMR (100 MHz,
DMSO) δ 152.4 (CO), 146.6, 141.5, 139.3, 134.1, 130.7, 125.9,
125.6, 124.4, 122.6, 117.9; HRMS (EI): [M–H]–, found
288.04371. C13H10N3O3S requires 288.04429.
4.5. N-(2-mercaptophenyl)-N'-4-chlorophenylurea (1c)
According to the general procedure 2, urea 1c was obtained as a
white solid in 75% yield after the purification by crystallization
from EtOH: mp 263–265 °C; Rf (50% EtOAc/hexane): 0.85; IR
(ATR) 3253, 2988, 2104, 1885, 1634, 1488; 1H NMR (400 MHz,
DMSO) δ 9.49 (1H, s, NH), 8.41 (1H, s, NH), 7.92 (1H, d, J =
8.0 Hz, ArH), 7.47 (2H, d, J = 9.0 Hz, ArH), 7.38-7.24 (4H, m,
ArH), 6.96 (1H, t, J = 7.5 Hz, ArH); 13C NMR (100 MHz,
DMSO) δ 152.8 (CO), 139.8, 139.0, 134.1, 130.6, 129.1, 125.9,
125.5, 123.8, 122.3, 120.2; HRMS (EI): [M–H]–, found
277.02078. C13H1035ClN2OS requires 277.02024.
4.10. N-(2-mercaptophenyl)-N'-4-methoxyphenylurea (1h)
According to the general procedure 2, urea 1h was obtained as a
white solid in 80% yield after crystallization from EtOH: mp
200–202 °C; Rf (50% EtOAc/hexane): 0.75; IR (ATR) 3273,
1
2958, 2834, 1640, 1552, 1242; H NMR (400 MHz, DMSO) δ
9.20 (1H, s, NH), 8.31 (1H, s, NH), 7.97 (1H, d, J = 8.5 Hz,
ArH), 7.36 (2H, d, J = 8.5 Hz, ArH), 7.30 (2H, d, J = 7.5 Hz,
ArH), 6.93 (1H, t, J = 7.5 Hz, ArH), 6.88 (2H, d, J = 8.5 Hz,
ArH), 3.71 (3H, s, OMe); 13C NMR (100 MHz, DMSO) δ 155.0
(CO), 153.0, 140.3, 134.2, 133.0, 130.7, 124.9, 123.3, 122.0,
120.4, 114.4, 55.6; HRMS (EI): [M–H]–, found 275.08487.
C14H15N2O2S requires 275.08514.
4.6. N-(2-mercaptophenyl)-N'-4-bromoophenylurea (1d)
According to the general procedure 2, urea 1d was obtained as a
white solid in 70% yield after the purification by crystallization
from EtOH: mp 233–235 °C; Rf (50% EtOAc/hexane): 0.92; IR
(ATR) 3257, 2987, 2095, 1633, 1578, 1485; 1H NMR (400 MHz,
DMSO) δ 9.48 (1H, s, NH), 8.41 (1H, s, NH), 7.92 (1H, d, J =
8.2 Hz, ArH), 7.49-7.39 (4H, m, ArH), 7.34 (1H, dd, J = 7.5, 1.0
Hz, ArH), 7.29 (1H, t, J = 7.5 Hz, ArH), 6.96 (1H, td, J = 7.5, 1.0
4.11. N-(2-mercaptophenyl)-N'-4-tollylphenylurea (1i)
According to the general procedure 1, urea 1i was obtained as a
white solid in 75% yield after crystallization from EtOH: mp
224–226 °C (Et2O); Rf (50% EtOAc/hexane): 0.89; IR (ATR)
2971, 1641, 1544, 1406, 1229, 1064; 1H NMR (400 MHz,

ACCEPTED MANUSCRIPT
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Tetrahedron
DMSO) δ 9.27 (1H, s, NH), 8.35 (1H, s, NH), 7.96 (1H, d, J =
165–168 °C; Rf (50% EtOAc/hexane): 0.62; IR (ATR) 2970,
1
8.0 Hz, ArH), 7.42-7.18 (4H, m, ArH), 7.10 (2H, d, J = 7.5 Hz,
ArH), 6.94 (1H, t, J = 7.0 Hz, ArH), 2.25 (3H, s, Me); 13C NMR
(100 MHz, DMSO) δ 152.9 (CO), 140.2, 137.4, 134.1, 131.3,
130.6, 129.6, 125.1, 123.5, 122.2, 118.8, 20.8; HRMS (EI): [M–
H]–, found 257.07514. C14H13N2OS requires 257.33082.
1640, 1500, 1407, 1250, 1056; H NMR (400 MHz, DMSO) δ
8.79 (1H, s, NH), 8.61 (1H, s, NH), 7.82 (2H, t, J = 9.0 Hz, ArH),
7.39 (1H, d, J = 7.5 Hz, ArH), 7.28 (1H, t, J = 7.5 Hz, ArH), 6.99
(1H, t, J = 7.0 Hz, ArH), 6.61 (1H, d, J = 2.5 Hz, ArH), 6.47 (1H,
dd, J = 8.5, 2.5 Hz, ArH), 3.85 (3H, s, OMe), 3.73 (3H, s, OMe);
13C NMR (100 MHz, DMSO) δ 155.7 (CO), 153.3, 150.3, 139.5,
132.6, 129.8, 126.7, 123.9, 123.3, 121.9, 121.3, 104.6, 99.2, 56.2,
55.7; HRMS (EI): [M–H]–, found 303.08257. C15H15N2O3S
requires 303.08034.
4.12. N-(2-mercaptophenyl)-N'-3-tollylphenylurea (1j)
According to the general procedure 1, urea 1j was obtained as a
white solid in 60% yield after crystallization from EtOH: mp
192–194 °C; Rf (50% EtOAc/hexane): 0.92; IR (ATR) 3252,
4.17. N-(2-mercaptophenyl)-N'-2-naphthylurea (1o)
1
2972, 1636, 1407, 1228, 1071; H NMR (400 MHz, DMSO) δ
9.31 (1H, s, NH), 8.38 (1H, s, NH), 7.96 (1H, d, J = 8.0 Hz,
ArH), 7.35-7.27 (3H, m, ArH), 7.24 (1H, d, J = 8.0 Hz, ArH),
7.17 (1H, t, J = 7.5 Hz, ArH), 6.95 (1H, t, J = 7.5 Hz, ArH), 6.80
(1H, d, J = 7.0 Hz, ArH), 2.28 (3H, s, Me); 13C NMR (100 MHz,
DMSO) δ 152.9 (CO), 140.1, 139.9, 138.4, 134.1, 130.6, 129.1,
125.2, 123.63, 123.2, 122.3, 119.3, 115.9, 21.6; HRMS (EI): [M–
H]–, found 257.07448. C14H13N2OS requires 257.33082.
According to the general procedure 1, urea 1o was obtained as a
white solid in 78% yield after crystallization from EtOH: mp
233–234 °C; Rf (90% EtOAc/hexane): 0.92; IR (ATR) 3249,
1
2988, 1638, 1544, 1213; H NMR (400 MHz, DMSO) δ 9.39
(1H, s, NH), 8.86 (1H, s, NH), 8.18 (1H, d, J = 8.0 Hz, ArH),
8.00 (1H, d, J = 8.0 Hz, ArH), 7.95 (2H, t, J = 7.0 Hz, ArH), 7.67
(1H, d, J = 8.0 Hz, ArH), 7.63-7.51 (2H, m, ArH), 7.48 (1H, t, J
= 7.5 Hz, ArH), 7.42 (1H, d, J = 7.5 Hz, ArH), 7.32 (1H, t, J =
7.5 Hz, ArH), 7.00 (1H, t, J = 7.5 Hz, ArH); 13C NMR (100
MHz, DMSO) δ 153.5 (CO), 140.1, 134.5, 134.2, 133.9, 130.5,
128.8, 126.8, 126.4, 126.2, 126.1, 125.6, 123.8, 123.8, 122.6,
122.2, 118.8; HRMS (EI): [M–H]–, found 293.07477.
C17H13N2OS requires 293.07486.
4.13. N-(2-mercaptophenyl)-N'-3,4,5-trimethoxyphenylurea (1k)
According to the general procedure 2, urea 1k was obtained as a
white solid in 61% yield after crystallization from EtOH: mp
170–171 °C; Rf (50% EtOAc/hexane): 0.67; IR (ATR) 3253,
1
2972, 1643, 1446, 1410, 1128; H NMR (400 MHz, DMSO) δ
9.37 (1H, s, NH), 8.36 (1H, s, NH), 7.98 (1H, d, J = 8.0 Hz,
ArH), 7.30 (2H, d, J = 7.5 Hz, ArH), 6.95 (1H, t, J = 7.5 Hz,
ArH), 6.80 (2H, s, ArH), 3.75 (6H s, OMe), 3.61 (3H, s, OMe);
13C NMR (100 MHz, DMSO) δ 153.3 (CO), 152.8, 140.1, 136.1,
134.2, 132.9, 130.7, 124.9, 123.5, 122.1, 96.3, 60.5, 56.0; HRMS
(EI): [M–H]–, found 333.09294. C16H17N2O4S requires
333.09090.
4.18. 1-(Tert-butyl)-3-(2-mercaptophenyl)urea (1p)
According to the general procedure 1, urea 1p was obtained as a
white solid in 88% yield after crystallization from EtOH: mp
242–243 °C; Rf (90% EtOAc/hexane): 0.81; IR (ATR) 3292,
1
2968, 1641, 1546, 1427, 1263; H NMR (400 MHz, DMSO) δ
7.93 (1H, d, J = 8.0 Hz, ArH), 7.90 (1H, s, NH), 7.25 (2H, dd, J
= 14.0, 7.0 Hz, ArH), 6.91-6.78 (2H, m, NH and ArH ), 1.29 (9H,
s, Me); 13C NMR (100 MHz, DMSO) δ 154.6 (CO), 141.1, 134.1,
130.5, 124.2, 122.5, 121.7, 50.0, 29.3; HRMS (EI): [M–H]–,
found 223.09336. C11H15N2OS requires 223.09051.
4.14. N-(2-mercaptophenyl)-N'-2,3,4-trimethoxyphenylurea (1l)
According to the general procedure 2, urea 1l was obtained as a
white solid in 66% yield after crystallization from EtOH: mp
193–195 °C; Rf (50% EtOAc/hexane): 0.71; IR (ATR) 3248,
4.19. Typical Procedure
3
for the synthesis of 1,2,4-
1
2972, 1643, 1528, 1489, 1263; H NMR (400 MHz, DMSO) δ
benzothiadiazines 2a-2p (1a as an example)
8.87 (1H, s, NH), 8.73 (1H, s, NH), 7.79 (1H, d, J = 8.0 Hz,
ArH), 7.71 (1H, d, J = 9.0 Hz, ArH), 7.41 (1H, dd, J = 7.5, 1.0
Hz, ArH), 7.29 (1H, t, J = 7.5 Hz, ArH), 7.01 (1H, t, J = 7.5 Hz,
ArH), 6.73 (1H, d, J = 9.0 Hz, ArH), 3.80 (3H, s, OMe), 3.77
(3H, s, OMe), 3.75 (3H, s, OMe); 13C NMR (100 MHz, DMSO) δ
153.3 (CO), 148.7, 143.5, 142.2, 139.3, 132.5, 129.8, 127.0,
126.8, 124.1, 123.6, 114.9, 108.0, 61.4, 60.9, 56.4; HRMS (EI):
[M–H]–, found 333.09360. C16H17N2O4S requires 333.09090.
The mixture of N-(2-mercaptophenyl)-N'-(4-methylphenyl)-urea
(1a, 50 mg, 0.21 mmol), CuI (10 mol%), and DMF (5 mL) was
stirred 80 °C for 5h under oxygen. Upon completion of the
reaction, the mixture was cooled to room temperature and mixed
with water (15 mL). The product was then extracted with
ethylacetate (4x15 mL). The combined organic layers were dried
over anhydrous MgSO4 and concentrated under reduced pressure.
The resulting product was purified over a column of silica gel
(EtOAc/hexane (1:1) as eluents) to give product 2a in 53% yield.
4.15. N-(2-mercaptophenyl)-N'-3,4-dimethoxyphenylurea (1m)
According to the general procedure 2, urea 1m was obtained as a
white solid in 74% yield after crystallization from EtOH: mp
156–158 °C; Rf (50% EtOAc/hexane): 0.70; IR (ATR) 3260,
4.20. 2-Phenyl-2H-1,2,4-benzothiadiazin-3(4H)-one (2a)
White solid; Mp: 212–213 °C; Rf (50% EtOAc/hexane): 0.68; IR
(ATR) 3194, 2970, 1667, 1575, 1469, 1336; 1H NMR (400 MHz,
DMSO) δ 10.28 (1H, s, NH), 7.40-7.25 (6H, m, ArH), 7.20 (1H,
dd, J = 7.0, 6.0 Hz, ArH), 7.13-7.01 (2H, m, ArH); 13C NMR
(100 MHz, DMSO) δ 157.9 (CO), 142.5, 138.9, 129.4, 129.3,
126.2, 125.3, 124.8, 123.5, 121.5, 116.2; HRMS (EI): [M–H]–,
found 241.04649. C13H9N2OS requires 241.04356.
1
2832, 1635, 1549, 1505, 1225; H NMR (400 MHz, DMSO) δ
9.26 (1H, s, NH), 8.32 (1H, s, NH), 7.98 (1H, d, J = 8.0 Hz,
ArH), 7.37-7.24 (2H, m, ArH), 7.17 (1H, d, J = 1.5 Hz, ArH),
7.03-6.73 (3H, m, ArH), 3.73 (3H, s, OMe), 3.70 (3H, s, OMe);
13C NMR (100 MHz, DMSO) δ 153.0 (CO), 149.2, 144.6, 140.2,
134.2, 133.6, 130.7, 124.9, 123.4, 122.1, 113.0, 110.7, 104.3,
56.3, 55.8; HRMS (EI): [M–H]–, found 303.08174. C15H15N2O3S
requires 303.08034.
4.21. 2-(4-Fluorophenyl)-2H-1,2,4-Benzothiadiazin-3(4H)-one
(2b)
4.16. N-(2-mercaptophenyl)-N'-2,4-dimethoxyphenylurea (1n)
Pink solid; Mp: 199–201 °C; Rf (50% EtOAc/hexane): 0.71; IR
(ATR) 2973, 1672, 1506, 1394, 1240, 1055, 1H NMR (400 MHz,
DMSO) δ 10.26 (1H, s, NH), 7.41-7.26 (4H, m, ArH), 7.19 (2H,
According to the general procedure 2, urea 1n was obtained as a
white solid in 74% yield after crystallization from EtOH: mp

ACCEPTED MANUSCRIPT
7
t, J = 8.5 Hz, ArH), 7.08 (2H, d, J = 7.5 Hz, ArH); 13C NMR (100
4.27. 2-(4-Metoksiphenyl)-2H-1,2,4-Benzothiadiazin-3(4H)-one
(2h)
MHz, DMSO) δ 160.2 (d, J= 243.5Hz), 158.0, 138.9, 138.7 (d,
J=2 Hz), 129.4, 127.9 (d, J =8.0 Hz), 124.8, 123.5, 121.4, 116.2
(d, J=12.0 Hz), 115.9; HRMS (EI): [M–H]–, found 259.03698.
C13H8FN2OS requires 259.03414.
°
White solid; Mp: 222–224 C; Rf (50% EtOAc/hexane): 0.68; IR
(ATR) 3179, 2970, 1668, 1506, 1352, 1241; 1H NMR (400 MHz,
DMSO) δ 10.12 (1H, s, NH), 7.28 (2H, t, J = 7.5 Hz, ArH), 7.19
(2H, d, J = 8.5 Hz, ArH), 7.05 (2H, t, J = 7.5 Hz, ArH), 6.90 (2H,
d, J = 9.0 Hz, ArH), 3.74 (3H, s, OMe); 13C NMR (100 MHz,
DMSO) δ 158.3(CO), 157.9, 139.1, 135.2, 129.2, 127.7, 124.6,
123.4, 121.7, 116.1, 114.5, 55.8; HRMS (EI): [M–H]–, found
273.06922. C14H13N2O2S requires 273.07169.
4.22. 2-(4-Chlorophenyl)-2H-1,2,4-Benzothiadiazin-3(4H)-one
(2c)
Light brown solid; Mp: 218–219 °C; Rf (50% EtOAc/hexane):
1
0.54; IR (ATR) 3202, 2965, 1673, 1580, 1490, 1352; H NMR
(400 MHz, DMSO) δ 10.37 (1H, s, NH), 7.41 (2H, d, J = 8.7 Hz,
ArH), 7.34 (3H dd, J = 8.0, 4.5 Hz, ArH), 7.30 (1H, d, J = 7.5
Hz, ArH), 7.09 (2H, d, J = 8.0 Hz, ArH); 13C NMR (100 MHz,
DMSO) δ 157.6 (CO), 141.3, 138.8, 130.1, 129.5, 129.1, 126.8,
125.0, 123.6, 121.3, 116.3; HRMS (EI): [M–H]–, found
275.00513. C13H835ClN2OS requires 275.00361.
4.28. 2-(4-Metilphenyl)-2H-1,2,4-Benzothiadiazin-3(4H)-one (2i)
Brown solid; Mp: 230–232 °C; Rf (50% EtOAc/hexane): 0.76; IR
(ATR) 3150, 2971, 1673, 1582, 1471, 1341; 1H NMR (400 MHz,
DMSO) δ 10.20 (1H, s, NH), 7.29 (2H, t, J = 9.0 Hz, ArH), 7.19-
7.12 (4H, m, ArH), 7.11-6.97 (2H, m, ArH), 2.27 (3H, s, Me);
13C NMR (100 MHz, DMSO) δ 158.8 (CO), 139.98, 139.0,
135.8, 129.7, 129.3, 125.6, 124.7, 123.5, 121.5, 116.2, 20.9;
HRMS (EI): [M–H]–, found 255.06357. C14H11N2OS requires
255.05921.
4.23. 2-(4-Bromophenyl)-2H-1,2,4-Benzothiadiazin-3(4H)-one
(2d)
Light gray solid; Mp: 228–230 °C; Rf (50% EtOAc/hexane):
1
0.72; IR (ATR) 3196, 2962, 1668, 1577, 1349, 1249; H NMR
(400 MHz, DMSO) δ 10.37 (1H, s, NH), 7.53 (2H, d, J = 8.5 Hz,
ArH), 7.34 (1H, d, J = 8.0 Hz, ArH), 7.30 (3H, d, J = 8.5 Hz,
ArH), 7.09 (2H, d, J = 8.5 Hz, ArH); 13C NMR (100 MHz,
DMSO) δ 157.5 (CO), 141.8, 138.7, 132.0, 129.5, 127.0, 125.0,
123.6, 121.3, 118.2, 116.4; HRMS (EI): [M–H]–, found
318.95778. C13H879BrN2OS requires 318.95407.
4.29. 2-(3-Methylphenyl)-2H-1,2,4-Benzothiadiazin-3(4H)-one
(2j)
Brown-red solid; Mp: 132–134 °C; Rf (50% EtOAc/hexane):
1
0.80; IR (ATR) 3062, 2949, 1675, 1580, 1474, 1350; H NMR
(400 MHz, DMSO) δ 10.26 (1H, s, NH), 7.34-7.26 (2H, m, ArH),
7.26-7.20 (1H, m, ArH), 7.12-7.06 (3H, m, ArH), 7.06-6.98 (2H,
m, ArH), 2.29 (3H, s, Me); 13C NMR (100 MHz, DMSO) δ 158.2
(CO), 142.4, 138.9, 138.8, 129.3, 129.1, 127.03, 125.9, 124.8,
123.5, 122.5, 121.5, 116.2, 21.2; HRMS (EI): [M–H]–, found
255.06318. C14H11N2OS requires 255.05921.
4.24. 2-(4-Cyanophenyl)-2H-1,2,4-Benzothiadiazin-3(4H)-one
(2e)
Light brown solid; Mp: 166–168 °C; Rf (50% EtOAc/hexane):
1
0.72; IR (ATR) 3269, 2969, 1667, 1585, 1474, 1322; H NMR
(400 MHz, DMSO) δ 10.65 (1H, s, NH), 7.80 (2H, d, J = 6.5 Hz,
ArH), 7.57 (2H, d, J = 6.5 Hz, ArH), 7.39 (1H, d, J = 7.6 Hz,
ArH), 7.33 (1H, t, J = 8.1 Hz, ArH), 7.11 (2H, d, J = 7.0 Hz,
ArH); 13C NMR (100 MHz, DMSO) δ 156.8 (CO), 146.6, 138.35,
133.4, 129.7, 125.3, 123.9, 123.6, 121.2, 119.1, 116.6, 106.9;
HRMS (EI): [M+H]–, found 268.05733. C14H10N3OS requires
268.05446.
4.30. 2-(3,4,5-Trimetoksiphenyl)-2H-1,2,4-Benzothiadiazin-
3(4H)-one (2k)
Light brown solid; Mp: 219–221 °C; Rf (50% EtOAc/hexane):
1
0.52; IR (ATR 3145, 2971, 1668, 1505, 1352, 1241; H NMR
(400 MHz, DMSO) δ 10.16 (1H, s, NH), 7.34-7.25 (2H, m, ArH),
7.07 (2H, d, J = 7.5 Hz, ArH), 6.59 (2H, s, ArH), 3.74 (6H, s,
OMe), 3.63 (3H, s, OMe); 13C NMR (100 MHz, DMSO) δ 158.0
(CO), 153.1, 153.1, 139.0, 138.0, 129.3, 124.7, 123.4, 121.6,
116.2, 104.1, 60.5, 56.5; HRMS (EI): [M–H]–, found 331.07951.
C16H15N2O4S requires 331.07525.
4.25. 2-(3-Cyanophenyl)-2H-1,2,4-Benzothiadiazin-3(4H)-one
(2f)
Light brown solid; Mp: 189–191 °C; Rf (50% EtOAc/hexane):
0.73; IR (ATR) 3201, 2973, 1688, 1579, 1479, 1342, 1262; 1H
NMR (400 MHz, DMSO) δ 10.49 (1H, s, NH), 7.86 (1H, s,
ArH), 7.70 (1H, d, J = 8.0 Hz, ArH), 7.65 (1H, d, J = 7.5 Hz,
ArH), 7.56 (1H, t, J = 8.0 Hz, ArH), 7.37 (1H, d, J = 7.5 Hz,
ArH), 7.32 (1H, t, J = 7.5 Hz, ArH), 7.11 (2H, d, J = 8.0 Hz,
ArH); 13C NMR (100 MHz, DMSO) δ 157.3 (CO), 143.2, 138.6,
130.65, 129.6, 129.3, 129.3, 127.9, 125.1, 123.7, 121.1, 118.6,
116.5, 112.1; HRMS (EI): [M–H]–, found 266.03881. C14H8N3OS
requires 266.03881.
4.31. 2-(2,3,4 -Trimetokhoxyphenyl)-2H-1,2,4-Benzothiadiazin-
3(4H)-one (2l)
Light brown solid; Mp: 163–165 °C; Rf (100% EtOAc): 0.90; IR
(ATR) 3200, 2912, 1672, 1583, 1470, 1301; 1H NMR (400 MHz,
DMSO) δ 10.05 (1H, s, NH), 7.34-7.19 (2H, m, ArH), 7.14-6.99
(2H, m, ArH), 6.92 (1H, d, J = 9.0 Hz, ArH), 6.75 (1H, d, J = 9.0
Hz, ArH), 3.79 (3H, s, OMe), 3.72 (3H, s, OMe), 3.58 (3H, s,
OMe); 13C NMR (100 MHz, DMSO) δ 158.5 (CO), 153.55,
150.2, 142.4, 139.4, 129.4, 129.0, 124.3, 124.1, 123.3, 121.9,
116.1, 107.7, 61.1, 60.8, 56.4; HRMS (EI): [M–H]–, found
331.08031. C16H15N2O4S requires 331.07525.
4.26. 2-(4-Nitro)-2H-1,2,4-Benzothiadiazin-3(4H)-one (2g)
Gray solid; Mp: 128–130 °C; Rf (50% EtOAc/hexane): 0.76; IR
(ATR) 3076, 2950, 1690, 1585, 1504, 1309; 1H NMR (400 MHz,
DMSO) δ 10.75 (1H, s, NH), 8.21 (2H, d, J = 9.0 Hz, ArH), 7.65
(2H, d, J = 9.0 Hz, ArH), 7.41 (1H, d, J = 7.5 Hz, ArH), 7.34
4.32. 2-(3,4 -Dimethoxyphenyl)-2H-1,2,4-Benzothiadiazin-3(4H)-
one (2m)
(1H, t, J = 7.5 Hz, ArH), 7.12 (2H, dd, J = 7.5, 2.0 Hz, ArH); 13
C
Brown solid; Mp: 146–148 °C; Rf (100% EtOAc): 0,67; IR
(ATR) 3063, 2901, 1678, 1579, 1512, 1362; 1H NMR (400 MHz,
DMSO) δ 10.09 (1H, s, NH), 7.28 (2H, t, J = 8.0 Hz, ArH), 7.11-
6.98 (2H, m, ArH), 6.91 (1H, d, J = 8.5 Hz, ArH), 6.86 (1H, d, J
= 2.0 Hz, ArH), 6.79 (1H, dd, J = 8.5, 2.0 Hz, ArH), 3.74 (3H, s,
NMR (100 MHz, DMSO) δ 156.5 (CO), 148.4, 143.5, 138.3,
129.8, 125.4, 124.9, 123.9, 123.0, 121.2, 116.7; HRMS (EI): [M–
H]–, found 286.03288. C13H8N3O3S requires 286.02864.

ACCEPTED MANUSCRIPT
8
Tetrahedron
OMe), 3.71 (3H, s, OMe); 13C NMR (100 MHz, DMSO) δ
0.403 e Å-3 . CCDC-1511675 contains the supplementary
crystallographic data for this paper. These data can be obtained
158.3(CO), 149.0, 147.8, 138.9, 135.2, 129.2, 124.6, 123.5,
121.6, 118.6, 116.1, 112.0, 110.8, 56.1, 56.0; HRMS (EI): [M–
H]–, found 301.06939. C15H13N2O3S requires 301.06469.
free
of
charge
via
http://www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033; e-mail:
deposit@ccdc.cam.ac.uk).
4.33. 2-(2,4 -Dimethoxyphenyl)-2H-1,2,4-Benzothiadiazin-3(4H)-
one (2n)
Gray solid; Mp: 156–159 °C; Rf (50% EtOAc/hexane): 0.58; IR
(ATR) 3050, 2919, 1680, 1582, 1505, 1360; 1H NMR (400 MHz,
DMSO) δ 9.94 (1H, s, NH), 7.30-7.15 (2H, m, ArH), 7.11-6.94
(3H, m, ArH), 6.60 (1H, d, J = 2.5 Hz, ArH), 6.46 (1H, dd, J =
8.5, 2.5 Hz, ArH), 3.76 (3H, s, OMe), 3.67 (3H, s, OMe); 13C
NMR (100 MHz, DMSO) δ 160.2 (CO), 158.4, 156.7, 139.4,
130.2, 128.8, 124.2, 123.1, 122.0, 115.9, 105.2, 99.9, 99.8, 56.31,
55.9; HRMS (EI): [M–H]–, found 301.06917. C15H13N2O3S
requires 301.06469.
Acknowledgments
The author is indebted to the Scientific and Technological
Research Council of Turkey (Grant No: 115Z261 and the Faculty
of Pharmacy at Erciyes University for their financial support of
this work. The author would like to acknowledge the contribution
of the COST (European Cooperation in Science and Technology)
Action CA 15106.
References and notes
4.34. 2-(2-Naphtyl)-2H-1,2,4-Benzothiadiazin-3(4H)-one (2o)
1. (a) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215-1292. (b)
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5566.
Pink solid; Mp: 189–201 °C; Rf (90% EtOAc/hexane): 0.85; IR
(ATR) 3050, 2913, 1668, 1581, 1472, 1342; 1H NMR (400 MHz,
DMSO) δ 10.24 (1H, s, NH), 8.01 (1H, d, J = 8.0 Hz, ArH), 7.96
(1H, d, J = 7.5 Hz, ArH), 7.63 (1H, d, J = 8.0 Hz, ArH), 7.59-
7.45 (4H, m, ArH), 7.40-7.26 (2H, m, ArH), 7.17 (1H, d, J = 7.5
Hz, ArH), 7.10 (1H, t, J = 7.5 Hz, ArH); 13C NMR (100 MHz,
DMSO) δ 158.5 (CO), 139.4, 138.2, 134.5, 130.1, 129.4, 129.01,
128.8, 127.5, 127.2, 126.9, 126.3, 124.7, 123.6, 122.6, 121.8,
116.3; HRMS (EI): [M+Na]–, found 315.05735. C17H12N2NaOS
requires 315.05680.
4.35. 2-(Tert-butyl)-2H-1,2,4-Benzothiadiazin-3(4H)-one (2p)
5. Anand, D.; Patel, O. P.; Maurya, R. K.; Kant, R.; Yadav, P. P. J. Org.
Chem. 2015, 80, 12410-12419.
6. Paul, R.; Punniyamurthy, T. RSC Adv. 2012, 2, 7057-7060.
7. Chen, F.-J.; Liao, G.; Li, X.; Wu, J.; Shi, B.-F. Org. Lett. 2014, 16,
5644-5647.
Brown solid; Mp: 153–155 °C; Rf (50% EtOAc/hexane): 0,79; IR
(ATR) 3193, 2908, 1661, 1586, 1332, 1189; 1H NMR (400 MHz,
DMSO) δ 9.85 (1H, s, NH), 7.27 (1H, d, J = 7.5 Hz, ArH), 7.22
(1H, t, J = 7.5 Hz, ArH), 6.98 (2H, m, ArH), 1.35 (9H, s, Me);
13C NMR (100 MHz, DMSO) δ 159.7 (CO), 139.6, 129.0, 124.6,
122.9, 122.8, 115.51, 59.4, 29.5; HRMS (EI): [M–H]–, found
221.07862. C11H13N2OS requires 221.07486.
8. Wang, Z.; Kuninobu, Y.; Kanai, M. J. Org. Chem. 2013, 78, 7337-7342.
9. Novello, F. C.; Sprague, J. M. J. Am. Chem. Soc.1957, 79, 2028-2029.
10. (a) Convay, J.; Lauwers, P. Circulation 1960, 21, 21-27. (b) Beyer, K. H.
Annals of the New York Academy of Sciences, 1958, 71, 363-379. (c)
Partin, K.; Patneau, D.; Winters, C.; Mayer, M.; Buonanno, A. Neuron,
1993, 11, 1069-1082. (d) Dahlöf, B.; Sever, P. S.; Poulter, N. R.; Wedel,
H.; Beevers, D. G.; Caulfield, M.; Collins, R.; Kjeldsen, S. E.;
Kristinsson, A.; McInnes, G. T. Lancet, 2005, 366, 895-906. (e) Lysaa,
R.; Giverhaug, T.; Wold, H. L.; Aarbakke, J. Eur. J. Clin. Pharmacol,
1996, 49, 393-396. (f) Freis, E. D. Am J Cardiol, 1988, 61, 117-121.
11. (a) Martinez, A.; Gil, C.; Perez, C.; Castro, A.; Prieto, C.; Otero, J.;
Andrei, G.; Snoeck, R.; Balzarini, J.; De Clercq, E. J. Med. Chem. 2000,
43, 3267-3273. (b) Nguyen, T. T.; Gates, A. T.; Gutshall, L. L.; Johnston,
V. K.; Gu, B.; Duffy, K. J.; Sarisky, R. T. Antimicrob. Agents
Chemother. 2003, 47, 3525-3530. (c) Buckheit, R. W.; Fliakas-Boltz, V.;
Decker, W. D.; Roberson, J. L.; Pyle, C. A.; White, E. L.; Bowdon, B. J.;
McMahon, J. B.; Boyd, M. R.; Bader, J. P. Antiviral Res. 1994, 25, 43-
56. (d) Martinez, A.; Gil, C.; Castro, A.; Bruno, A. M.; Pérez, C.; Prieto,
C.; Otero, Antiviral Chem. Chemother. 2003, 14, 107-114. (e) Zhan, P.;
Liu, X.; Clercq, E. D. Curr. Med. Chem. 2008, 15, 1529-1540.
12. (a) Rolfe, A.; Hanson, P. R. Tetrahedron Lett. 2009, 50, 6935-6937. (b)
Cherepakha, A.; Kovtunenko, V. O.; Tolmachev, A.; Lukin, O.;
Nazarenko, K. G. Synth. Commun. 2011, 41, 1977-1989. (c) Kim, J.; Lee,
S. Y.; Lee, J.; Do, Y.; Chang, S. J. Org. Chem. 2008, 73, 9454-9457. (d)
Greig, I. R.; Tozer, M. J.; Wright, P. T. Org. Lett. 2001, 3, 369-371. (e)
Girard, Y.; Atkinson, J. G.; Rokach, J. J. Chem. Soc., Perkin Trans. 1,
1979, 1043-1047. (f) Yang, D.; Fu, H.; Hu, L.; Jiang, Y.; Zhao, Y. J.
Comb. Chem. 2009, 11, 653-657.
4.36. X-ray crystal structure analysis of 2a
For the crystal structure determination, single-crystal of
compound 2a was used for data collection on a four-circle
Rigaku R-AXIS RAPID-S diffractometer (equipped with a two-
dimensional area IP detector). Graphite-monochromated Mo-Kα
radiation (λ = 0.71073 Å) and oscillation scans technique with
∆w = 5º for one image were used for data collection. The lattice
parameters were determined by the least-squares methods on the
basis of all reflections with F2 > 2 (F2). Integration of the
σ
intensities, correction for Lorentz and polarization effects and
cell refinement was performed using CrystalClear (Rigaku/MSC
Inc. 2005) software.15 The structures were solved by direct
methods using SHELXS-9716 and refined by a full-matrix least-
squares procedure using the program SHELXL-9716 H atoms
were positioned geometrically and refined using a riding model.
The final difference Fourier maps showed no peaks of chemical
significance. Crystal data for 2a: C13H10N2OS, crystal system,
space group: monoclinic, P21/n; (no:14); unit cell dimensions: a
= 14.1123(9), b = 5.5822 (5), c = 14.7842(9) Å, α= 90, β =
102.412(3), γ = 90º ; volume: 1137.4(2) Å3; Z = 4; calculated
density: 1.415 g/cm3; absorption coefficient: 0.267 mm-1; F(000):
504; θ-range for data collection 1.8–26.6º; refinement method:
full matrix least-square on F2; data/parameters: 2300/155;
goodness-of-fit on F2: 1.028; final R-indices [I > 2σ(I)]: R1 =
0.0385, wR2 = 0.058; largest diff. peak and hole: 0.393 and -
13. (a) Özcan, S.; Balci, M. Tetrahedron, 2008, 64, 5531-5540. (b) Doğan, S.
D.; Demirpolat, E.; Aycan, M. B. Y.; Balci, M. Tetrahedron, 2015, 71,
252-258.
14. Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297-368.
15. Rigaku/MSC, Inc., 9009 new Trails Drive, The Woodlands, TX 77381.
16. Sheldrick GM. SHELXS-97 and SHELXL-97, Program for Crystal
Structure Solution and Refinement. Germany: University of Gottingen;
1997.

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9
Supplementary Material
Supplementary data associated with this article can be found in
the online version, at

ACCEPTED MANUSCRIPT
Table 1. Optimization for synthesis of N-substituted-1,2,4-benzothiadiazin-3(4H)-ones
Entry
1
2
3
4
5
6
7
8
catalyst
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
solvent
DMF
DMSO
CH3CN
Toluene
2-Propanol
H2O
MeOH
1,4-Dioxane
DCE
DMF
DMF
DMF
DMF
DMF
DMF
conversion (%)a
99
97
56
n.r
n.r
n.r
n.r
n.r
n.r
70
60
18
31
89
n.r
9
CuI
CuI
10
11
12
13
14
15
CuBr
CuO
Cu2O
Cu(OAc)2
–
aDetermined by 1H NMR spectroscopy.
n.r=no reaction.
Table 2. Substrate scope for the synthesis of benzoisothiadiazines (2a-2p)

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H
N
O
N
S
F
2a: 53%
2b: 55%
2c: 68%
2d: 60%
2e: 50%
2f: 40%
2g: 55%
2h: 61%
H
O
N
N
S
2i: 59%
2j: 68%
2k: 51%
2l: 59%
2m: 48%
2n: 66%
2o: 53%
2p: 73%
* isolated yields after purification by column chromatography

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Scheme 3. Possible reactions pathways for the formation of 2.