Synthesis of 4-unsubstituted 2H-1,2,3-benzothiadiazine 1,1-dioxides via ortho lithiation of protected benzaldehyde derivatives

Article abstract of DOI:10.1016/j.tet.2013.11.058

Variously substituted 2-phenyl-1,3-dioxolanes and 2-(2-bromophenyl)-1,3- dioxolanes, prepared from the corresponding benzaldehydes, were lithiated ortho to the acetal group. Reaction of the lithio derivatives with sulfur dioxide led to the lithium sulfinate salts, which gave, upon oxidative chlorination with sulfuryl chloride, the corresponding benzenesulfonyl chlorides. Then, depending on the aromatic substitution pattern of the molecule, several protocols were elaborated for the functional group transformations leading to the target compounds. Ring closure was performed with hydrazine hydrate or acetylhydrazine, in the latter case with one-pot removal of the acetyl group. The 4-unsubstituted 2H-1,2,3-benzothiadiazine 1,1-dioxides thus obtained are potential drug candidates based on their structural similarity to biologically active phthalazinones.

Full text of DOI:10.1016/j.tet.2013.11.058

Tetrahedron 70 (2014) 286e293
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 4-unsubstituted 2H-1,2,3-benzothiadiazine 1,1-dioxides
via ortho lithiation of protected benzaldehyde derivatives
*
ꢀ
ꢀ
ꢀ
ꢀ
Marta Porcs-Makkay, Gyula Lukacs, Angela Pandur, Gyula Simig, Balazs Volk
Egis Pharmaceuticals Plc., Chemical Research Division, PO Box 100, H-1475 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 October 2013
Received in revised form 10 November 2013
Accepted 18 November 2013
Available online 22 November 2013
Variously substituted 2-phenyl-1,3-dioxolanes and 2-(2-bromophenyl)-1,3-dioxolanes, prepared from
the corresponding benzaldehydes, were lithiated ortho to the acetal group. Reaction of the lithio de-
rivatives with sulfur dioxide led to the lithium sulfinate salts, which gave, upon oxidative chlorination
with sulfuryl chloride, the corresponding benzenesulfonyl chlorides. Then, depending on the aromatic
substitution pattern of the molecule, several protocols were elaborated for the functional group trans-
formations leading to the target compounds. Ring closure was performed with hydrazine hydrate or
acetylhydrazine, in the latter case with one-pot removal of the acetyl group. The 4-unsubstituted 2H-
1,2,3-benzothiadiazine 1,1-dioxides thus obtained are potential drug candidates based on their structural
similarity to biologically active phthalazinones.
Keywords:
Lithiation
Ring closure
Protecting group
Sulfur heterocycles
Nitrogen heterocycles
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
and phosphodiesterase-4 (PDE-4) inhibitors.3 Also, they can
potentially be used for the treatment of protein-kinase mediated
Biological efficacy of compounds bearing a phthalazine (1,
Scheme 1) or phthalazinone (2) skeleton is discussed in several
papers and patent applications. Compounds 1 are known as active
antiparasital agents,1 AMPA/kainate receptor allosteric modulators2
diseases4 and depression.5 Various pharmacological and thera-
peutic effects are also described for compounds 2 ranging from poly
(ADP-ribose) polymerase (PARP) inhibition6 to antagonism of
chemoattractant receptor-homologous molecule expressed on T
O
X
X
O
O
R1
R2
R1
R2
X
R1
R2
S
R
N
N
N
N
N
N
R
R
1
2
3
R1, R2, R3: H, alkyl, aryl; X: various substituents
O
O
O
O
X
X
X
X
SO2Cl
O
SO2Cl
O
S
S
NH
NH
N
N
O
O
R
H
R
6
5
4
7
R: alkyl, aryl
R: alkyl, aryl
Scheme 1.
helper type 2 cells (CRTH-2).7 Other members of the family 2
exhibit anti-inflammatory effect,8 cytoprotective properties9 and
antihistamine efficacy.10 Certain representatives of the 1,2,3-
benzothiadiazine 1,1-dioxide (3) family, structurally related to
* Corresponding author. Tel.: þ36 1 8035874; fax: þ36 1 8035613; e-mail
address: volk.balazs@egis.hu (B. Volk).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.11.058

M. Porcs-Makkay et al. / Tetrahedron 70 (2014) 286e293
287
compounds 2, also act as antagonists of the CRTH-2 receptor7 or as
bactericides and fungicides.11
and 6-methoxy substituted (5d) target compounds. In the former
case, literature data on the unsuccessful attempts for the direct
lithiation of the unsubstituted derivative, 2-phenyl-1,3-dioxolane
(11a)26 suggested the use of the commercially available 2-
bromobenzaldehyde (12a, route B) as the starting material
instead.27 In the latter case, lithiation of 2-(3-methoxyphenyl)-1,3-
dioxolane (11d) with butyllithium is expected to occur primarily at
the doubly activated position between the substituents,28 therefore
bromo derivative 12d was used to achieve the required regiose-
lective lithiation leading to the key intermediate 8d, which could
ultimately result in target compound 5d.
While the syntheses of phthalazines (1) and phthalazinones (2)
are wellelaborated,12 theliterature on the preparation andchemistry
of compounds 3e5 (Scheme 1) is rather scarce. Apart from the
unsubstituted, C]N double bond containing congener, 2H-1,2,3-
benzothiadiazine 1,1-dioxide (5, X¼H),13 only a few representatives
of family 4 are described, bearing a substituted amino,14 a hydra-
zino15 or a substituted phenyl16 moiety at position 4 (substituent R in
4). 4-Unsubstituted congeners with various substitution patterns on
the aromatic ring (5, XsH) are unknown in the literature.
In the course of our earlier efforts to explore 4-alkyl- (4, R¼alkyl)17
and 4-aryl-2H-1,2,3-benzothiadiazine 1,1-dioxides (4, R¼Ph or
substituted phenyl) with anxiolytic effect, we elaborated the syn-
thesis of the precursors of the target compounds: acetophenone and
benzophenone derivatives masked as 1,3-dioxolanes were chlor-
osulfonylated ortho to the protected keto group (6, Scheme 1) via
ortho-lithiation chemistry.18,19
Now, we aimed at elaborating a versatile synthetic route for the
preparation of 4-unsubstituted 2H-1,2,3-benzothiadiazine 1,1-
dioxides (5). The syntheses of sodium 2-formylbenzenesulfonate as
the key intermediate of the only described representative (5, X¼H),13b
involving either oxidation of 2-methylsulfonic acid20 or introduction
of the sulfonic acid function to 2-chlorobenzaldehyde by nucleophilic
substitutionwith sodium sulfite21 are not generalizable. Therefore, an
alternative method was sought, which could be extended to other
derivatives with various aromatic substitution patterns. ortho-Lith-
iation and subsequent chlorosulfonylation of benzaldehydes, which
are temporarily protected and at the same time transformed into an
ortho-directing group, promised to be a suitable route for the syn-
thesis of the key intermediates of the target compounds.
Thus, benzaldehydes 10 were transformed into the correspond-
ing 1,3-dioxolanes 11 by reaction with ethylene glycol in toluene at
reflux temperature, in the presence of para-toluenesulfonic acid
(Scheme 2, route A). 2-Bromobenzaldehyde derivatives 12 were
transformed to ortho-brominated acetal-protected benzaldehydes
13 analogously or under microwave conditions29 (route B). Lith-
iation of compounds 11 and 13 with butyllithium in THF and
quenching with sulfur dioxide led to lithium sulfinates 9. Treatment
with sulfuryl chloride resulted in the formation of benzenesulfonyl
chloride derivatives. This oxidative chlorination step and the sub-
sequent work-up procedure could in certain cases be performed
without hydrolysis of the dioxolane moiety, thus compounds 7a,b,d
were isolated (route C). Reaction of 2,3-dichloro (7b) and 4-methoxy
(7d) derivatives with acetylhydrazine in IPA resulted in the forma-
tion of sulfonyl-acetohydrazides 14b and 14d, respectively (route E).
Under acidic reflux conditions, removal of the acetal protecting
group, deacetylation and ring closure took place in one pot giving
rise to the formation of target compounds 5b and 5d.
An alternative method was carried out with 7a: the dioxolane
protecting group was removed by stirring with concentrated sul-
furic acid in the presence of Kieselgel (route F), leading to 2-
formylbenzenesulfonyl chloride (15a). The same protocol could
also be applied for 7b and 7d. However, in the case of the 2-chloro-
3-methoxyphenyl (9c) lithium sulfinate, chlorination with sulfuryl
chloride gave after work-up a mixture of acetal 7c and its hydro-
lyzed derivative 15c. Hydrolysis of the mixture to pure 15c was
completed by stirring with Kieselgel and concentrated sulfuric acid.
Compounds 15aed were then treated with hydrazine hydrate to
give benzothiadiazine derivatives 5aed.
Contrary to our expectations based on the former results
obtained in the lithiation of 2-(4-chlorophenyl)-2-methyl-18 and
2-(4-chlorophenyl)-2-phenyl-1,3-dioxolane19 with butyllithium, 2-
(4-chlorophenyl)-1,3-dioxolane (11e) could not be lithiated at the
2-position of the 4-chlorophenyl ring under the same or even
harsher conditions (THF, from ꢀ78 up to þ50 ꢁC). Therefore, an
alternative approach had to be elaborated for the preparation of
target compound 7-chloro-2H-1,2,3-benzothiadiazine 1,1-dioxide
(5e, Scheme 3). Considering that the sulfonamide moiety is
a strong ortho-directing group,30,31 chlorineelithium exchange in
7,8-dichloro-2H-1,2,3-benzothiadiazine 1,1-dioxide (5b) was
attempted. Indeed, reaction of 5b with BuLi (ꢀ78 ꢁC, 2 h) and
subsequent quenching with water led to 5e in 69% yield. Quenching
of the lithium salt with dry ice gave 8-carboxy-7-chloro congener
5f, a useful building block also for further functionalizations. When
starting from the 8-chloro-7-methoxy derivative 5c, aqueous work-
up of the lithio intermediate led to the 7-methoxy target compound
5g. Nevertheless, only a poor yield could be achieved in this latter
reaction. When lithiations were carried out at ꢀ78 ꢁC, a significant
amount of the starting material could be recovered even if a fivefold
excess of BuLi and a longer reaction time (5 h) was applied. If the
temperature was elevated to 0 ꢁC, 4-butyl derivative 16a was
formed as the main product, due to the addition of BuLi to the C]N
double bond. It is to be noted that the formation of an analogous
BuLi adduct (16b) could also be detected by 1H NMR in crude
products 5e and 5f as a minor impurity.
Several methods are known for such an ortho-functionalization
of benzaldehydes. Benzaldehydes protected as cyclohexylimines
exhibit ortho directing potential in lithiation reactions.22,23 1,3-
Dimethyl-2-phenylimidazolidine, prepared from benzaldehyde
and N,N0-dimethylethylenediamine, also led to ortho-lithio in-
termediates upon reaction with butyllithium and TMEDA.24 A more
general method was described by Comins et al., who reported on
the ortho lithiation of various lithium
a-amino(phenyl)meth-
anolates.25 These latter were generated in situ from aromatic
aldehydes and lithium dialkylamides (e.g., lithium morpholin-4-ide
or lithium 4-methylpiperazin-1-ide).
Nevertheless, our synthetic approach necessitated such an ortho
directing group that was expected to protect the carbonyl group not
only in the lithiation reaction but also in the planned chlorination
step leading to intermediates 7 (Scheme 1), and at the same time
could be hydrolyzed under mild conditions so that the chlor-
osulfonyl moiety of 7 remains stable. 1,3-Dioxolanes prepared by
acetalization of the corresponding benzaldehydes with ethylene
glycol seemed suitable for this purpose.
2. Results and discussion
In continuation of our earlier work dealing with the lithiation of
acetophenones18 and benzophenones19 protected as 1,3-dioxolanes
we report here on the synthesis (Scheme 2) of ortho-chlorosulfonyl
benzaldehyde acetals 7 (via ortho-lithio intermediates 8 and lith-
ium sulfinates 9) and their transformation to the corresponding 2H-
1,2,3-benzothiadiazine 1,1-dioxides (5). Depending on which
approach seemed more promising, two strategies were applied for
the preparation of lithiated intermediate 8: directed ortho-metal-
ation (route A) or bromineelithium exchange (route B). We will
also show various alternatives for the transformation of acetal-
protected lithium sulfinates 9 to target compounds 5 (routes CeF).
The bromineelithium exchange approach (route B) proved to be
more advantageous for the preparation of the unsubstituted (5a)

288
M. Porcs-Makkay et al. / Tetrahedron 70 (2014) 286e293
R1
R1
R2
R3
R2
route A
a
O
R3
CHO
R1
O
c
R2
R3
10b,c,e
H
Li
O
11b,c,e
e
R1
R1
O
R2
R3
R2
R3
Br
Br
H
route B
b
d
8a-d
O
CHO
O
H
12a,d
13a,d
R1
R1
R2
R3
SO2NHNHAc
O
R2
R3
SO2Cl
O
route E
h
O
j
route C
O
R1
R1
H
H
7a,b,d
O
O
14b,d
f
R2
R3
SO2Li
R2
R3
S
NH
O
i
route F
R1
N
route D
g
O
H
5a-d
9a-d
k
R2
R3
SO2Cl
CHO
15a-d
5, 7-15
a
R1
H
R2
R3
H
Synthetic sequence applied
H
route B + route C + route F
route A + route C + route E or
b
c
Cl
Cl
H
Cl
H
H
route A + route C + route F
OMe
H
route A + route D
route B + route C + route E or
d
e
OMe
H
route B + route C + route F
H
Cl
alternative method (see Scheme 3)
Scheme 2. Reagents and conditions: (a) HOe(CH2)2eOH, toluene, reflux, 6e12 h, 84e100%; (b) HOe(CH2)2eOH, toluene, reflux, 5 h, 90%; or MW, 2 h, 77%; (c,d) BuLi, THF, e78 ꢁC;
(e) SO2, THF, e78 ꢁC to rt, 69e100% calculated for 11 or 13; (f) SO2Cl2, hexane, e5 to 0 ꢁC, 1 h, 74e98%; (g) step 1: SO2Cl2, hexane, e5 to 0 ꢁC, 1.5 h; step 2: H2SO4, CHCl3, Kieselgel, rt,
3 h, 3278% calculated for 11c; (h) H2NeNHAc, IPA, 0 ꢁC rt, 2e12 h, 76e96%; (i) H2SO4, CHCl3, Kieselgel, rt, 20e30 h, 54e88%; (j) 10% aq HCl, reflux, 2.5e3 h, 56e87%; (k) N2H4$H2O,
THF, rt or reflux, 1e2 h, 20e89%.
R1
Cl
H O
O
O
O
O
Li
R2
O
O
R2
or
S
R2
S
S
CO , then H
NH
NH
BuLi/THF
NLi
N
N
-78 C, 2 h
24-69 %
N
5e: R1 = H, R2 = Cl
5b: R2 = Cl
5c: R2 = OMe
5f: R1 = COOH, R2 = Cl
5g: R1 = H, R2 = OMe
R1
O
O
R2
S
NH
NH
16a: R1=Cl, R2=OMe
16b: R1=Cl, R2=Cl
Scheme 3.
3. Conclusions
benzaldehyde derivatives protected as dioxolanes or bromi-
neelithium exchange of their ortho-bromo congeners, followed by
introduction of the sulfinate group by using sulfur dioxide as the
electrophile for quenching the aromatic lithium salt. Thereafter, the
slightly different behavior of the analogues variously substituted on
A new, versatile synthetic route is disclosed here for the syn-
thesis 4-unsubstituted 2H-1,2,3-benzothiadiazine 1,1-dioxides. The
key step of the synthetic route is directed ortho lithiation of

M. Porcs-Makkay et al. / Tetrahedron 70 (2014) 286e293
289
the aromatic ring necessitated the development of alternative
4.3. 2-(4-Chlorophenyl)-1,3-dioxolane (11e)
methods for the further conversion of the lithium sulfinate salts to
the target compounds. According to one procedure, the sulfinate
group was transformed to sulfonyl-acetohydrazide via the corre-
sponding sulfonyl chloride, while the dioxolane protecting group
was kept intact until the final cyclization reaction leading to the
target compounds. In the course of the other variant, the primarily
prepared ortho-formylbenzenesulfonyl chloride was cyclized to the
corresponding 2H-1,2,3-benzothiadiazine 1,1-dioxide. Thanks to
the novel, versatile intermediates, i.e., the ortho-chlorosulfonylated
benzaldehydes and their dioxolane counterparts, the significance of
the synthetic route described above goes beyond the preparation of
these particular compounds, by rendering possible the synthesis of
various new compound families.
A solution of 4-chlorobenzaldehyde (10e, 29.0 g, 0.20 mol),
ethylene glycol (40 mL, 44.5 g, 0.72 mol) and p-toluenesulfonic acid
(0.4 g, 0.002 mol) in toluene (120 mL) was refluxed in a DeaneStark
apparatus for 6 h. The reaction mixture was washed with aqueous
sodium hydrogen carbonate solution (5 w/w%, 150 mL) and water
(3ꢂ150 mL), dried over MgSO4 and the solvent was evaporated. The
crude pale yellow oil was distilled under reduced pressure (0.2 bar)
at 88e100 ꢁC to give 11e (30.9 g, 84%) as a colorless oil. Analytical
data are in accord with the literature.33
4.4. 2-(2-Bromophenyl)-1,3-dioxolane (13a)34
A solution of 2-bromobenzaldehyde (12a, 37.1 g, 0.20 mol),
ethylene glycol (50 mL, 55.6 g, 0.90 mol) and p-toluenesulfonic acid
(1.0 g, 0.005 mol) in toluene (200 mL) was refluxed in a DeaneStark
apparatus (bp 118e120 ꢁC) in a microwave reactor under irradiation
with a constant 650 W energy for 2 h.29 The reaction mixture was
washed with aqueous sodium hydrogen carbonate solution (5 w/w
%, 200 mL) and water (200 mL), dried over MgSO4 and the solvent
was evaporated. The crude pale yellow oil was distilled under re-
duced pressure (0.04 mbar) at 86e88 ꢁC to give 13a (35.15 g, 77%) as
4. Experimental section
€
All melting points were determined on a Buchi 535 capillary
melting point apparatus. IR spectra were obtained on a Bruker IFS-
113v FT spectrometer in KBr pellets. 1H NMR and 13C NMR spectra
were recorded on a Varian Gemini 200 (200 and 50 MHz for 1H and
13C NMR spectra, respectively), Bruker Avance III (400 and 100 MHz
for 1H and 13C NMR spectra, respectively) or a Varian Unity Inova
500 spectrometer (500 and 125 MHz for 1H and 13C NMR spectra,
respectively). CDCl3 or DMSO-d6 was used as solvent and tetra-
methylsilane (TMS) as internal standard. Chemical shifts (
coupling constants (J) are given in parts per million and in Hertz,
respectively. Elemental analyses were performed on Per-
a colorless oil. 1H NMR (DMSO-d6, 500 MHz)
d
7.63 (1H, dd, J¼8.1,
1.2 Hz), 7.58 (1H, dd, J¼7.3, 1.8 Hz), 7.43 (1H, td, J¼8.1, 1.2 Hz), 7.34
(1H, td, J¼7.3, 1.8 Hz), 5.95 (1H, s), 4.08 (2H, m), 3.98 (2H, m). 13
C
d) and
NMR (DMSO-d6, 100 MHz)
d 136.7, 132.9, 131.2, 128.3, 127.8, 122.3,
101.9, 65.1. IR (KBr, cmꢀ1) 2889,1472,1352. Anal. Calcd for C9H9BrO2
(229.07): C 47.19, H 3.96, Br 34.88%. Found: C 46.69, H 4.07, Br 34.83%.
a
kineElmer 2400 analyzer. The reactions were followed by analyt-
ical thin layer chromatography on silica gel 60 F254. All unspecified
reagents were purchased from commercial sources. The yields have
not been optimized.
4.5. 2-(2-Bromo-5-methoxyphenyl)-1,3-dioxolane (13d)35
A solution of 2-bromo-5-methoxybenzaldehyde (12d, 5.38 g,
25 mmol), ethylene glycol (6.45 mL, 7.17 g, 0.115 mol) and p-tolue-
nesulfonic acid (0.25 g,1.3 mmol) in toluene (25 mL) was refluxed in
a DeaneStark apparatus for 5 h. The reaction mixture was washed
with aqueous sodium hydrogen carbonate solution (5 w/w%,
2ꢂ20 mL) and water (20 mL), dried over MgSO4 and the solvent was
evaporated to give 13d (5.85 g, 90%) as a pale yellowoil.1H NMR data
are in accord with the literature.35b 13C NMR (DMSO-d6, 100 MHz)
4.1. 2-(3,4-Dichlorophenyl)-1,3-dioxolane (11b)32
A solution of 3,4-dichlorobenzaldehyde (10b, 52.5 g, 0.30 mol),
ethylene glycol (33 mL, 36.7 g, 0.59 mol) and p-toluenesulfonic acid
(1.0 g, 0.005 mol) in toluene (300 mL) was refluxed in a DeaneStark
apparatus for 6 h. The reaction mixture was washed with aqueous
sodium hydrogen carbonate solution (5 w/w%, 120 mL) and water
(150 mL), dried over MgSO4 and the solvent was evaporated to give
11b (67.4 g, 100%) as colorless crystals, mp 42e47 ꢁC. 1H NMR
d
158.8, 137.7, 134.9, 128.4, 116.7, 113.8, 101.8, 65.0, 55.5. IR (KBr,
cmꢀ1) 2890,1474,1293. Anal. Calcd for C10H11BrO3 (259.11): C 46.35,
H 4.28, Br 30.84%. Found: C 46.24, H 4.24, Br 30.64%.
(DMSO-d6, 200 MHz)
d
7.58 (1H, d, J¼1.8 Hz), 7.45 (1H, d, J¼8.1 Hz),
7.30 (1H, dd, J¼8.1, 1.8 Hz), 5.77 (1H, s), 4.06 (4H, m). 13C NMR
4.6. 2-(1,3-Dioxolan-2-yl)benzenesulfonyl chloride (7a)
(DMSO-d6, 125 MHz) d 138.4, 133.0, 132.4, 130.3, 128.5, 125.8, 102.1,
65.2. IR (KBr, cmꢀ1) 2880, 1472, 1359. Anal. Calcd for C9H8Cl2O2
(219.08): C 49.34, H 3.68, Cl 32.37%. Found: C 49.41, H 3.76, Cl
32.04%.
Butyllithium (15 mL of a 2.5 M solution in hexane, 37.5 mmol)
was added to a solution of 2-(2-bromophenyl)-1,3-dioxolane (13a,
6.87 g, 30.0 mmol) in THF (60 mL) under argon at ꢀ78 ꢁC and the
mixture was stirred for 40 min at ꢀ50 ꢁC. The resulting suspension
was added to
a stirred solution of sulfur dioxide (13.7 g,
4.2. 2-(3-Chloro-4-methoxyphenyl)-1,3-dioxolane (11c)
214.0 mmol) in THF (36 mL) cooled to ꢀ78 ꢁC. The mixture was
stirred at ambient temperature for 2 h and the solid product was
filtered to give lithium sulfinate 9a (5.92 g, 90%) as colorless crys-
A solution of 3-chloro-4-methoxybenzaldehyde (10c, 11.72 g,
0.068 mol), ethylene glycol (7.56 mL, 8.39 g, 0.135 mol) and p-tol-
uenesulfonic acid (0.23 g, 1.3 mmol) in toluene (70 mL) was
refluxed in a DeaneStark apparatus for 12 h. The reaction mixture
was washed with aqueous sodium hydrogen carbonate solution (5
w/w%, 100 mL) and water (2ꢂ100 mL), dried over MgSO4 and the
solvent was evaporated to give 11c (13.60 g, 93%) as a pale yellow
tals. 1H NMR (DMSO-d6, 500 MHz)
d
7.71 (1H, dd, J¼7.6, 0.8 Hz), 7.39
(1H, d, J¼7.5 Hz), 7.34 (1H, td, J¼7.4, 0.8 Hz), 7.23 (1H, td, J¼7.4,
0.8 Hz), 6.58 (1H, s), 3.99 (4H, m).
Sulfuryl chloride (2.3 mL, 3.75 g, 28.0 mmol) in hexane (30 mL)
was added dropwise over a period of 10 min to the suspension of
the lithium sulfinate 9a (4.40 g, 20.0 mmol) in hexane (54 mL) at
ꢀ5 ꢁC. After addition of sulfuryl chloride, the solvent was imme-
diately evaporated in vacuo. The residue was stirred for 30 min at
0e5 ꢁC with water (50 mL) and the crystalline product was filtered
to give 7a (4.88 g, 98%) as colorless crystals, mp 59e60 ꢁC. 1H NMR
oil. 1H NMR (DMSO-d6, 500 MHz)
dd, J¼8.4, 2.1 Hz), 7.13 (1H, d, J¼8.4 Hz), 5.69 (1H, s), 4.05 (2H, m),
d
7.48 (1H, d, J¼2.1 Hz), 7.38 (1H,
3.93 (2H, m), 3.87 (3H, s). 13C NMR (DMSO-d6, 100 MHz)
d
155.3,
131.6, 128.1, 126.9, 121.1, 122.5, 102.1, 64.9, 56.2. IR (KBr, cmꢀ1) 2890,
1507, 1265. Anal. Calcd for C10H11ClO3 (214.65): C 55.96, H 5.17, Cl
16.52%. Found: C 55.56, H 5.23, Cl 16.40%.
(DMSO-d6, 500 MHz)
J¼7.5, 1.1 Hz), 7.33 (2H, m), 6.64 (1H, s), 4.08 (2H, m) 3.85 (2H, m).
d
7.74 (1H, dd, J¼7.5, 1.1 Hz), 7.49 (1H, dd,

290
M. Porcs-Makkay et al. / Tetrahedron 70 (2014) 286e293
13C NMR
d
(DMSO-d6, 100 MHz) 150.2, 133.2, 132.7, 129.3, 127.0,
this solution acetylhydrazine (8.15 g, 0.11 mol) was added at 0 ꢁC.
After stirring at room temperature for 2 h, the solvent was evapo-
rated in vacuo, to the residue ice-water (100 g) was added, the
precipitate was filtered to give 14b (13.5 g, 76%) as colorless crys-
tals, mp 141e143 ꢁC (2-propanol). 1H NMR (DMSO-d6, 400 MHz)
126.5, 63.0. IR (KBr, cmꢀ1) 2884, 1475, 1381. Anal. Calcd for
C9H9ClO4S (248.69): C 43.47, H 3.65, Cl 14.26, S 12.89%. Found C
43.03, H 3.70, Cl 13.62, S 12.27%.
4.7. 6-(1,3-Dioxolan-2-yl)-2,3-dichlorobenzenesulfonyl chlo-
ride (7b)
d
10.06 (2H, br s), 7.89 (1H, d, J¼8.8 Hz), 7.69 (1H, d, J¼8.8 Hz), 6.63
(1H, s), 4.02 (2H, m), 3.93 (2H, m), 1.68 (3H, s). 13C NMR (DMSO-d6,
125 MHz): 168.6, 140.1, 139.0, 134.9, 133.5, 132.0, 127.2, 99.0, 65.1,
20.2. IR (KBr, cmꢀ1) 3306, 3145, 1686, 1517. Anal. Calcd for
11H12Cl2N2O5S (355.20): C 37.20, H 3.41, Cl 19.96, N 7.89, S 9.03%.
d
Butyllithium (140 mL of a 2.5 M solution in hexane, 0.35 mol)
was added to a solution of 2-(3,4-dichlorophenyl)-1,3-dioxolane
(11b, 63.4 g, 0.29 mol) in THF (155 mL) under argon at ꢀ78 ꢁC
and the mixture was stirred for 2 h at this temperature. The
resulting suspension was added to a stirred solution of sulfur di-
oxide (56.1 g, 0.87 mol) in THF (105 mL) cooled to ꢀ78 ꢁC. The
mixture was stirred at ambient temperature for 2 h and the solid
product was filtered to give lithium sulfinate 9b (77.2 g, 92%) as
C
Found: C 37.24, H 3.45, Cl 19.88, N 7.82, S 8.93%.
4.10. N0-{[2-(1,3-Dioxolan-2-yl)-4-methoxyphenyl]sulfonyl}
acetohydrazide (14d)
2-(1,3-Dioxolan-2-yl)-4-methoxybenzenesulfonyl chloride (7d,
25.1 g, 0.09 mol) was dissolved in 2-propanol (270 mL) and to this
solution acetylhydrazine (26.6 g, 0.36 mol) was added at 10 ꢁC.
After stirring for 12 h, the solid was filtered to give 14d (27.3 g, 96%)
as colorless crystals, mp 153e154 ꢁC (ethanol). 1H NMR (DMSO-d6,
colorless crystals. 1H NMR (DMSO-d6, 500 MHz)
d 7.41 (2H, s), 7.35
(1H, s), 3.86 (4H, m).
Sulfuryl chloride (43.3 mL, 72.1 g, 0.534 mol) in hexane (100 mL)
was added dropwise over a period of 70 min to the suspension of
the lithium sulfinate 9b (77.2 g, 0.267 mol) in hexane (600 mL) at
ꢀ5 ꢁC. After stirring at 0 ꢁC for 1 h, the solvent was evaporated,
water (500 mL) was added to the residue and the mixture was
stirred for 30 min. The crystalline product was filtered to give 7b
(62.7 g, 74%) as colorless crystals. An analytical sample was
recrystallized from acetonitrile to give colorless crystals, mp
400 MHz)
d
10.06 (1H, br s), 9.26 (1H, br s) 7.79 (1H, d, J¼8.8 Hz),
7.15 (1H, d, J¼2.7 Hz), 7.08 (1H, dd, J¼8.8, 2.7 Hz), 6.48 (1H, s), 4.08
(2H, m), 3.95 (2H, m), 3.84 (3H, s), 1.69 (3H, s). 13C NMR (DMSO-d6,
400 MHz)
20.1. IR (KBr, cmꢀ1) 3223, 3010, 1667, 1595. Anal. Calcd for
12H16N2O6S (316.34): C 45.56, H 5.10, N 8.86, S 10.14%. Found: C
d 167.9, 162.5, 139.8, 132.3, 128.6, 113.5, 98.7, 64.8, 55.7,
C
68e72 ꢁC. 1H NMR (DMSO-d6, 400 MHz)
d
7.57 (1H, d, J¼8.5 Hz),
45.25, H 5.13, N 8.74, S 10.02%.
7.52 (1H, d, J¼8.5 Hz), 7.02 (1H, s), 4.03 (2H, m), 3.88 (2H, m). 13
C
NMR (DMSO-d6, 100 MHz)
d
147.0, 137.4, 134.2, 131.0, 130.0, 127.7,
4.11. 2-Formyl-benzenesulfonyl chloride (15a)36
99.2, 65.1. IR (KBr, cmꢀ1) 2879, 1430, 1384. Anal. Calcd for
C8H7Cl3O4S (317.59): C 34.04, H 2.22, Cl 33.49, S 10.10%. Found: C
34.12, H 2.29, Cl 33.21, S 9.98%.
To a suspension of Kieselgel (11.0 g) in chloroform (170 mL),
concentrated sulfuric acid (3.8 mL) was added and stirred at room
temperature for 10 min. After the addition of 2-(1,3-dioxolan-2-yl)
benzenesulfonyl chloride (7a, 5.52 g, 22.4 mmol) the suspension
was stirred for 30 h at room temperature. After filtration, the filtrate
was washed with aqueous sodium hydrogen carbonate solution
(5 w/w%, 50 mL) and water (50 mL), dried, and concentrated in
vacuo to give pure 15a (2.50 g, 54%) as a yellow oil. 1H NMR (DMSO-
4.8. 2-(1,3-Dioxolan-2-yl)-4-methoxybenzenesulfonyl chlo-
ride (7d)
Butyllithium (100 mL of a 2.5 M solution in hexane, 0.25 mol)
was added to a solution of 2-(2-bromo-5-methoxyphenyl)-1,3-
dioxolane (13d, 40.5 g, 0.156 mol) in THF (150 mL) under argon at
ꢀ78 ꢁC and the mixture was stirred for 2 h at this temperature. The
resulting suspension was added to a stirred solution of sulfur di-
oxide (41.7 g, 0.65 mol) in THF (155 mL) cooled to ꢀ78 ꢁC. The
mixture was stirred at ambient temperature for 2 h and the solid
product was filtered to give crude lithium sulfinate (9d, 45.2 g,
d6, 500 MHz)
d
10.90 (1H, s), 7.83 (1H, dd, J¼7.7,1.3 Hz), 7.77 (1H, dd,
J¼7.7, 1.4 Hz), 7.63 (1H, dd, J¼7.5, 1.4 Hz), 7.50 (1H, dt, J¼7.5, 1.3 Hz).
13C NMR (DMSO-d6, 100 MHz)
d 194.6, 150.2, 134.4, 133.8, 130.7,
128.0, 127.9. IR (KBr, cmꢀ1) 3096, 1704, 1376, 1183. Anal. Calcd for
C7H5ClO3S (204.63): C 41.09, H 2.46, Cl 17.33, S 15.67%. Found: C
41.00, H 2.44, Cl 17.40, S 15.51%.
>100%) as colorless crystals. 1H NMR (DMSO-d6, 200 MHz)
d 7.65
(1H, d, J¼9.1 Hz), 7.91 (2H, m), 6.54 (1H, s), 4.07 (2H, m), 3.90 (2H,
4.12. 2-Formyl-5,6-dichlorobenzenesulfonyl chloride (15b)
m), 3.73 (3H, s).
Sulfuryl chloride (18.7 mL, 31.1 g, 0.23 mol) in hexane (225 mL)
was added dropwise over a period of 70 min to the suspension of
the lithium sulfinate 9d (45.2 g) in hexane (330 mL) at ꢀ5 ꢁC. After
stirring at 0 ꢁC for 1 h, the solvent was evaporated in vacuo, hexane
(200 mL) was added to the residue and the mixture was stirred for
30 min. The crystalline product was filtered to give 7d (42.2 g, 97%)
as pale yellow crystals, mp 53e56 ꢁC. 1H NMR (DMSO-d6, 400 MHz)
To a suspension of Kieselgel (11.0 g) in chloroform (224 mL),
concentrated sulfuric acid (3.8 mL) was added and stirred at room
temperature for 10 min. After the addition of 6-(1,3-dioxolan-2-yl)-
2,3-dichlorobenzenesulfonyl chloride (7b, 5.62 g, 17.7 mmol) the
suspensionwas stirred for 30 h at room temperature. After filtration,
the filtrate was washed with aqueous sodium hydrogen carbonate
solution (5 w/w%, 50 mL) and water (50 mL), dried, and concen-
trated in vacuo to give pure 15b (4.49 g, 88%) as yellow crystals, mp
d
7.66 (1H, d, J¼8.6 Hz), 6.97 (1H, d, J¼2.7 Hz), 6.86 (1H, dd, J¼8.6,
2.7 Hz), 6.53 (1H, s), 4.07 (2H, m), 3.85 (2H, m), 3.75 (3H, s). 13C NMR
(DMSO-d6, 125 MHz) 159.7, 139.5, 137.5, 128.5, 118.6, 113.4, 99.3,
65.1, 55.5. IR (KBr, cmꢀ1) 2888, 1601, 1571, 1364. Anal. Calcd for
10H11ClO5S (278.71): C 43.09, H 3.98, Cl 12.72, S 11.51%. Found: C
53e54 ꢁC (hexane). 1H NMR (DMSO-d6, 400 MHz)
d 10.51 (1H, s),
d
7.79 (1H, d, J¼8.2 Hz), 7.38 (1H, d, J¼8.2 Hz). 13C NMR (DMSO-d6,
100 MHz) d )
192.1,147.2,137.2,136.9,131.0,130.0,127.0. IR (KBr, cmꢀ1
C
3392, 1705, 1373, 1178. Anal. Calcd for C7H3Cl3O3S (273.52): C 30.74,
H 1.11, Cl 38.88, S 11.72%. Found: C 30.93, H 1.19, Cl 38.78, S 11.99%.
43.16, H 4.04, Cl 12.67, S 11.41%.
4.9. N0-{[2,3-Dichloro-6-(1,3-dioxolan-2-yl)phenyl]sulfonyl}
acetohydrazide (14b)
4.13. 2-Chloro-6-formyl-3-methoxybenzenesulfonyl chloride
(15c)
2,3-Dichloro-6-(1,3-dioxolane-2-yl)benzenesulfonyl
(7b, 15.88 g, 0.05 mol) was dissolved in 2-propanol (100 mL) and to
chloride
Butyllithium (10 mL of a 2.5 M solution in hexane, 25.0 mmol)
was added to a solution of 2-(3-chloro-4-methoxyphenyl)-1,3-

M. Porcs-Makkay et al. / Tetrahedron 70 (2014) 286e293
291
dioxolane (11c, 4.50 g, 21.0 mmol) in THF (11 mL) under argon at
4.16. 7,8-Dichloro-2H-1,2,3-benzothiadiazine 1,1-dioxide
(5b)17
ꢀ78 ꢁC and the mixture was stirred for 2 h at this temperature.
The resulting suspension was added to a stirred solution of sulfur
dioxide (5.10 g, 80 mmol) in THF (9 mL) cooled to ꢀ78 ꢁC. The
mixture was stirred at ambient temperature for 2 h and the solid
product was filtered to give lithium sulfinate 9c (4.11 g, 69%) as
4.16.1. Route E. N0-{[2,3-Dichloro-6-(1,3-dioxolan-2-yl)phenyl]sul-
fonyl}acetohydrazide (14b, 67.5 g, 0.19 mol) was refluxed with
aqueous HCl (10 w/w%, 400 mL) for 2.5 h and filtered to give 5b
(41.52 g, 87%) as colorless crystals, mp 183e185 ꢁC (2-propanol). 1H
colorless crystals. 1H NMR (DMSO-d6, 500 MHz)
d 7.38 (1H, d,
J¼8.4 Hz), 7.33 (1H, s), 6.90 (1H, d, J¼8.4 Hz), 3.86 (4H, m), 3.80
NMR (DMSO-d6, 400 MHz): d 8.46 (1H, br s), 7.94 (1H, s), 7.83 (1H, d,
(3H, s).
J¼8.4 Hz), 7.45 (1H, d, J¼8.4 Hz). 13C NMR (DMSO-d6, 100 MHz):
Sulfuryl chloride (2.30 mL, 3.88 g, 28.8 mmol) in hexane (30 mL)
was added dropwise over a period of 70 min to the suspension of
the lithium sulfinate 9c (4.11 g, 14.4 mmol) in hexane (5 mL) at
ꢀ5 ꢁC. After stirring for 15 min at 0 ꢁC the solvent was evaporated,
water (40 mL) was added, the mixture extracted with ethyl acetate
(2ꢂ20 mL), dried, and concentrated in vacuo to give a mixture of 7c
and 15c (ca. 3.0 g) as an oil.
d
141.8, 136.2, 134.4, 132.9, 129.0, 128.2, 124.9. IR (KBr, cmꢀ1) 3242,
1361, 1175. Anal. Calcd for C7H4Cl2N2O2S (251.09): C 33.48, H 1.61, Cl
28.24, N 11.16, S 12.77%. Found: C 33.88, H 1.64, Cl 27.98, N 11.06, S
12.63%.
4.16.2. Route F. 2,3-Dichloro-6-formylbenzenesulfonyl chloride
(15b, 4.04 g, 14.0 mmol) was dissolved in THF (32 mL) and hydra-
zine monohydrate (1.4 mL, 1.44 g, 28.8 mmol) was added dropwise
to the solution. The reaction mixture was refluxed for 1 h. There-
after the mixture was poured into water, acidified with aqueous HCl
(10 w/w%, 1 mL) and the precipitate was filtered to give 5b (0.70 g,
20%) as colorless crystals, mp 184e186 ꢁC identical with compound
obtained via Route E.
To a suspension of Kieselgel (2.9 g) in chloroform (30 mL),
concentrated sulfuric acid (1.6 mL) was added and stirred at room
temperature for 10 min. After the addition of the mixture of 7c
and 15c (3.0 g) obtained above, the suspension was stirred for 3 h
at room temperature. After filtration, the filtrate was washed with
aqueous sodium hydrogen carbonate solution (5 w/w%, 2ꢂ20 mL)
and water (2ꢂ20 mL), dried, and concentrated in vacuo. The res-
idue was crystallized from a 1:1 mixture of hexane and ethyl ac-
etate to give 15c (1.47 g, 38% calculated for 11c as starting
material) as colorless crystals, mp 106e109 ꢁC (hexaneeethyl ac-
4.17. 8-Chloro-7-methoxy-2H-1,2,3-benzothiadiazine 1,1-
dioxide (5c)
etate 1:1). 1H NMR (CDCl3, 200 MHz)
d 10.62 (1H, s), 7.90 (1H, d,
J¼8.8 Hz), 7.32 (1H, d, J¼8.8 Hz), 4.06 (3H, s). 13C NMR (CDCl3,
2-Chloro-6-formyl-3-methoxybenzenesulfonyl chloride (15c,
2.69 g, 0.01 mol) was dissolved in THF (28 mL) and hydrazine
monohydrate (2.45 mL, 2.50 g, 0.05 mol) was added dropwise to the
solution. The reaction mixture was refluxed for 2 h. It was poured
into water (15 mL) and acidified with aqueous HCl (10 w/w%,
10 mL). The mixture was extracted with ethyl acetate (20 mL) and
the solvent was evaporated in vacuo. The residue was stirred with
hexane (10 mL) and the crystals formed were filtered to give 5c
(2.0 g, 77%) as yellow crystals, mp 189e191 ꢁC (ethyl acetate). 1H
125 MHz)
d )
187.7, 159.8, 142.7, 129.7, 116.4, 57.3. IR (KBr, cmꢀ1
2946, 1683, 1578, 1470, 1182. Anal. calcd for C8H6Cl2O4S (269.12): C
35.70, H 2.25, Cl 26.35, S 11.92%. Found: C 36.23, H 2.08, Cl 25.81, S
12.21%.
4.14. 2-Formyl-4-methoxybenzenesulfonyl chloride (15d)
To a suspension of Kieselgel (9.4 g) in chloroform (68 mL),
concentrated sulfuric acid (1.15 mL) was added and stirred at room
temperature for 10 min. After the addition of 2-(1,3-dioxolan-2-yl)-
4-methoxybenzenesulfonyl chloride (7d, 2.37 g, 8.5 mmol) the
suspension was stirred for 20 h at room temperature. After filtra-
tion, the filtrate was washed with aqueous sodium hydrogen car-
bonate solution (5 w/w%, 30 mL) and water (30 mL), dried, and
concentrated in vacuo. The residue was crystallized from diethyl
ether to give pure 15d (1.30 g, 65%) as colorless crystals, mp
NMR (DMSO-d6, 200 MHz): d 12.29 (1H, br s), 8.19 (1H, s), 7.84 (1H,
d, J¼8.8 Hz), 7.65 (1H, d, J¼8.8 Hz), 3.35 (3H, s). 13C NMR (DMSO-d6,
125 MHz): d 157.4,142.5,133.1,129.5,121.9,116.7,114.4, 57.4. IR (KBr,
cmꢀ1): 3292, 1481, 1282. Anal. Calcd for C8H7ClN2O3S (246.67): C
38.95, H 2.86, Cl 14.37, N 11.36, S 13.00%. Found: C 39.23, H 2.80, Cl
14.38, N 11.13, S 13.04%.
4.18. 6-Methoxy-2H-1,2,3-benzothiadiazine 1,1-dioxide (5d)17
89e91 ꢁC. 1H NMR (DMSO-d6, 400 MHz)
J¼8.5 Hz), 7.25 (1H, d, J¼2.8 Hz), 7.16 (1H, dd, J¼8.5, 2.8 Hz), 3.79
d 10.88 (1H, s), 7.79 (1H, d,
4.18.1. Route E. N0-{[2-(1,3-Dioxolan-2-yl)-4-methoxyphenyl]sul-
fonyl}acetohydrazide (14d, 6.33 g, 0.02 mol) was refluxed with
aqueous HCl (10 w/w%, 60 mL) for 3 h and filtered to give 5d (2.37 g,
56%) as colorless crystals. An analytical sample was recrystallized
from ethanol to give pure 5d, mp 163e164 ꢁC. 1H NMR (DMSO-d6,
(3H, s). 13C NMR (DMSO-d6, 100 MHz)
d 193.5, 159.8, 142.9, 134.1,
129.1, 118.6, 110.8, 55.7. IR (KBr, cmꢀ1) 1713, 1566, 1407. Anal. Calcd
for C8H7ClO4S (234.67): C 40.95, H 3.00, Cl 15.11, S 13.66%. Found: C
40.63, H 3.05, Cl 15.02, S 13.68%.
400 MHz):
d
12.20 (1H, s), 8.21 (1H, s), 7.89 (1H, d, J¼8.6 Hz), 7.41
4.15. 2H-1,2,3-Benzothiadiazine 1,1-dioxide (5a)13b,13c,17
(1H, d, J¼2.6 Hz), 7.38 (1H, dd, J¼8.7, 2.6 Hz), 3.90 (3H, s). 13C NMR
(DMSO-d6, 100 MHz): 162.3, 141.6, 129.6, 126.0, 122.3, 119.3, 111.6,
56.2. IR (KBr, cmꢀ1): 3215, 1311, 1141. Anal. Calcd for C8H8N2O3S
(212.23): C 45.28, H 3.80, N 13.20, S 15.11%. Found: C 45.36, H 3.84,
N 12.94, S 14.96%.
2-Formylbenzenesulfonylchloride (15a, 2.15 g, 10.5 mmol) was
dissolved in THF (35 mL) and hydrazine monohydrate (3.1 mL,
3.17 g, 63.4 mmol) was added dropwise to the solution. The reaction
stirred at room temperature for 1 h. Thereafter the mixture was
poured into ice-water (150 mL), acidified with aqueous HCl (10 w/w
%, 15 mL) and the precipitate was filtered to give 5a (1.70 g, 89%) as
yellow crystals, mp 143e146 ꢁC (lit.13b mp 142e143 ꢁC). 1H NMR
4.18.2. Route F. 2-Formyl-4-methoxybenzenesulfonyl chloride
(15d, 1.64 g, 7.0 mmol) was dissolved in THF (13 mL) and hydrazine
monohydrate (0.70 mL, 0.70 g, 14.0 mmol) was added dropwise to
the solution. The reaction mixture was stirred at room temperature
for 1 h. Thereafter the mixture was poured into ice-water, acidified
with aqueous HCl (10 w/w%, 5 mL) and the precipitate was filtered
to give 5d (1.10 g, 74%) as colorless crystals, mp 164e166 ꢁC, iden-
tical with compound obtained via Route E.
(DMSO-d6, 400 MHz):
d 12.43 (1H, br s), 8.31 (1H, s), 7.98 (1H, m),
7.87 (3H, m). 13C NMR (DMSO-d6, 125 MHz):
d 142.2, 133.1, 132.7,
128.0, 127.5, 119.9. IR (KBr, cmꢀ1) 3243, 1322, 1178. Anal. Calcd for
C7H6N2O2S (180.20): C 46.15, H 3.32, N 15.35, S 17.60%. Found: C
46.41, H 3.43, N 15.16, S 17.48%.

292
M. Porcs-Makkay et al. / Tetrahedron 70 (2014) 286e293
4.19. 7-Chloro-2H-1,2,3-benzothiadiazine 1,1-dioxide (5e)17
4.22. 4-Butyl-8-chloro-7-methoxy-3,4-dihydro-1,2,3-
benzothiadiazine 1,1-dioxide (16a)
7,8-Dichloro-2H-1,2,3-benzothiadiazine 1,1-dioxide (5b, 8.03 g,
0.032 mol) was dissolved in THF (140 mL) and the solution was
cooled to ꢀ78 ꢁC. At this temperature, a solution of butyllithium in
hexane (2.5 M, 40 mL, 0.10 mol) was added dropwise. The reaction
mixture was stirred at ꢀ78 ꢁC for 4 h, thereafter it was poured into
the mixture of ice and water (160 g). The mixture was extracted
with diethyl ether (2ꢂ100 mL). The aqueous layer was acidified
with aqueous HCl (10 w/w%, 50 mL) and the precipitate was filtered
to give crude 5e (6.44 g, 93%). It was recrystallized from ethanol
(150 mL) to give pure 5e (4.80 g, 69%) as colorless crystals, mp
8-Chloro-7-methoxy-2H-1,2,3-benzothiadiazine 1,1-dioxide (5c,
0.50 g, 2.0 mmol) was dissolved in THF (10 mL) and the solution was
cooled to ꢀ78 ꢁC. At this temperature, a solution of butyllithium in
hexane (2.5 M, 4.0 mL, 10.0 mmol) was added dropwise. The re-
action mixture was stirred at 0 ꢁC for 1 h, thereafter it was poured
into the mixture of ice and water (20 g). The mixture was extracted
with diethyl ether (2ꢂ20 mL). The aqueous layer was acidified with
aqueous HCl (10 w/w%, 10 mL), extracted with ethyl acetate and
dried. The solvent was evaporated in vacuo, the residue (0.37 g,
60%) was crystallized from ethanol (4 mL) to give 16a (0.05 g, 8%) as
colorless crystals, mp 209e211 ꢁC (ethanol). 1H NMR (DMSO-d6,
221e223 ꢁC (ethanol). 1H NMR (DMSO-d6, 500 MHz):
d 12.63 (1H,
br s), 8.35 (1H, s), 8.07 (1H, d, J¼2.1 Hz), 7.89 (1H, dd, J¼8.3, 2.1 Hz),
7.91 (1H, d, J¼8.3 Hz). 13C NMR (DMSO-d6, 125 MHz):
d
141.7, 136.9,
400 MHz):
d
8.57 (1H, br s), 7.37 (1H, d, J¼8.8 Hz), 7.33 (1H, d,
134.3, 133.4, 130.4, 126.3, 119.9. IR (KBr, cmꢀ1): 3230, 1331, 1170.
Anal. Calcd for C7H5ClN2O2S (216.65): C 38.80, H 2.33, Cl 16.37, N
12.93, S 14.80%. Found: C 39.16, H 2.28, Cl 16.29, N 12.69, S 14.52%.
J¼8.8 Hz), 5.92 (1H, br s), 4.03 (1H, br s), 3.89 (3H, s), 1.84 (1H, br s),
1.67 (1H, br s), 1.28 (4H, m), 0.86 (3H, t, J¼6.6 Hz), 13C NMR (DMSO-
d6, 125 MHz): d 153.7, 136.0, 134.7, 127.1, 117.9, 115.7, 56.9, 55.7, 32.9,
27.2, 22.2, 14.1. IR (KBr, cmꢀ1): 3294, 3189, 1289, 1192, 1173. Anal.
Calcd for C12H17N2O3S (304.80): C 47.29, H 5.62, Cl 11.63, N 9.19, S
10.52%. Found: C 46.93, H 5.39, Cl 11.36, N 9.36, S 10.52%.
4.20. 7-Chloro-2H-1,2,3-benzothiadiazine-8-carboxylic acid
1,1-dioxide (5f)
7,8-Dichloro-2H-1,2,3-benzothiadiazine 1,1-dioxide (5b, 5.02 g,
20.0 mmol) was dissolved in THF (87.5 mL) and the solution cooled
to ꢀ78 ꢁC. At this temperature, a solution of butyllithium in hexane
(2.5 M, 25 mL, 62.5 mmol) was added dropwise. The reaction
mixture was stirred at ꢀ78 ꢁC for 5 h, thereafter it was poured into
dry ice (ca. 300 g) and it was left at room temperature overnight.
The mixture was diluted with water (100 mL) and extracted with
diethyl ether (2ꢂ30 mL). To the aqueous layer was added aqueous
HCl solution (10 w/w%, 20 mL), it was extracted with ethyl acetate
(3ꢂ40 mL), dried and evaporated in vacuo. The crystalline residue
was stirred with hexane (20 mL) and filtered to give crude 5f
(4.30 g), which furnished after recrystallization from a mixture
ethyl acetate and hexane (1:3) pure 5f (3.13 g, 60%) as colorless
crystals, mp 283e284 ꢁC (hexaneeethyl acetate). 1H NMR (DMSO-
Acknowledgements
ꢀ
The authors thank Dr. Tibor Bako for the NMR spectra and Ms.
€ €
Tímea Toro for the help in the preparation of the manuscript.
References and notes
1. Fred, M. BE 646344 Belg. Pat. Appl.; Chem. Abstr. 1968, 68, 39638.
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ꢀ
ꢀ
2. Lukacs, G.; Szabo, G.; Simig, G.; Florian, E.; Gigler, G.; Levay, G.; Mezei, T.; Porcs-
ꢀ
Makkay, M.; Tihanyi, K.; Vegh, M.; Egyed, A. WO 0039100 PCT Intern. Pat. Appl.;
Chem. Abstr. 2000, 133, 89535.
3. (a) Napoletano, M.; Norcini, G.; Grancini, G.; Pellacini, F.; Morazzoni, G. WO
0005219 PCT Intern. Pat. Appl.; Chem. Abstr. 2000, 132, 122627. (b) Napoletano,
M.; Norcini, G.; Botta, D.; Grancini, G.; Morazzoni, G.; Santangelo, F.; Siro, H.;
Jorge, G.; Garcia Navio, J. L.; Alvarez-Builla, J. G. WO 9932456 PCT Intern. Pat.
Appl.; Chem. Abstr. 1999, 131, 73662.
4. Tasker, A.; Falsey, J. R.; Rzasa, R. M.; Herberich, B. J.; Zhang, D. WO 2010042649
PCT Intern. Pat. Appl.; Chem. Abstr. 2010, 152, 454124.
5. Sigal, M. V., Jr.; Marchini, P.; Poet, B. L. US 3274185 US Pat. Appl.; Chem. Abstr.
1966, 65, 99390.
6. Compounds 2: Li, J. -H.; Tays, K. L.; Zhang, J. WO 9911624 PCT Intern. Pat. Appl.;
d6, 200 MHz):
d
12.73 (1H, br s), 8.37 (1H, s), 8.06 (1H, d, J¼8.6 Hz),
7.94 (1H, d, J¼8.6 Hz). 13C NMR (DMSO-d6, 100 MHz):
d 164.4, 142.2,
133.9, 132.7, 130.7, 130.5, 128.4, 126.7. IR (KBr, cmꢀ1): 3297, 1763,
1452, 1178. Anal. Calcd for C8H5ClN2O4S (260.66): C 36.86, H 1.93, Cl
13.60, N 10.75, S 12.30%. Found: C 36.81, H 1.89, Cl 13.53, N 10.64, S
12.10%.
Chem. Abstr. 1999, 130, 218328.
7. Compounds 2 and 3: Bennani, Y.; Tumey, L. N.; Gleason, E. A.; Robarge, M. J. WO
2006034419 PCT Intern. Pat. Appl.; Chem. Abstr. 2006, 144, 350540.
8. Thomas, T. L.; Radov, L. A. EP 0164593 PCT Intern. Pat. Appl.; Chem. Abstr. 1986,
104, 207293.
9. Radov, L. A.; Thomas, T. L. EP 0309765 Eur. Pat. Appl.; Chem. Abstr. 1989, 111,
153822.
4.21. 7-Methoxy-2H-1,2,3-benzothiadiazine 1,1-dioxide hemi-
hydrate (5g)
10. Vogelsang, D.; Scheffer, G.; Brock, N.; Lenke, D. US 3813384 US Pat. Appl.; Chem.
Abstr. 1974, 81, 63654.
8-Chloro-7-methoxy-2H-1,2,3-benzothiadiazine 1,1-dioxide (5c,
0.50 g, 2.0 mmol) was dissolved in THF (10 mL) and the solution was
cooled to ꢀ78 ꢁC. At this temperature, a solution of butyllithium in
hexane (2.5 M, 4.0 mL, 10.0 mmol) was added dropwise. The re-
action mixture was stirred at ꢀ78 ꢁC for 5 h, thereafter it was
poured into the mixture of ice and water (20 g). The mixture was
extracted with diethyl ether (2ꢂ20 mL). The aqueous layer was
acidified with aqueous HCl (10 w/w%,10 mL). The crystals separated
by filtration after stirring at 0 ꢁC for 30 min were identified as
starting material (0.30 g, 60% recovered) containing traces of the
product (5g) and 4-butyl substituted by-product (16a). The filtrate
was extracted with ethyl acetate and dried. The solvent evaporated
in vacuo, and the residue was crystallized from ethanol (1.5 mL) to
give 5g (0.10 g, 24%) as colorless crystals, mp 153e155 ꢁC (ethanol).
11. (a) Aoki, K.; Sasatake, K.; Kimura, T.; Hatakeyama, N. JP 49094832 Japanese Pat.
Appl.; Chem. Abstr. 1975, 82, 165882. (b) Aoki, K.; Sasatake, K.; Kimura, T.; Ha-
taheyama, N. JP 49094833 Japanese Pat. Appl.; Chem. Abstr. 1975, 82, 120070. (c)
Aoki, K.; Sasatake, K.; Kimura, T.; Yamazaki, S. JP 49094838 Japanese Pat. Appl.;
Chem. Abstr. 1975, 82, 150500. (d) Aoki, K.; Sasatake, K.; Kimura, T.; Yamazaki, S.
JP 49094839 Japanese Pat. Appl.; Chem. Abstr. 1975, 82, 150499.
12. Brown, D. J. The Chemistry of Heterocyclic Compounds InTaylor, E. C., Wipf, P.,
Weissberger, A., Eds.. Cinnolines and Phthalazines: Supplement II; John Wiley &
Sons: 2005; Vol. 64, pp 109e171.
13. (a) King, J. F.; Hawson, A.; Deaken, D. M.; Komery, J. Chem. Commun. 1969, 1,
33e34; (b) The synthesis of 2H-1,2,3-benzothiadiazine 1,1-dioxide (5a) was
described in a low yield in: King, J. F.; Huston, B. L.; Hawson, A.; Komery, J.;
Deaken, D. M.; Harding, D. R. K. Can. J. Chem. 1971, 49, 936e942; (c) King, J. F.;
Hawson, A.; Huston, B. L.; Danks, L. J.; Komery, J. Can. J. Chem. 1971, 49,
943e955.
14. Nabar, U. V.; Mayadeo, M. S.; Deodhar, K. D. Indian J. Chem., Sect. B 1988,
109e111.
15. Robertson, J. E.; Biel, J. H. US 3153614 US Pat. Appl.; Chem. Abstr. 1965, 62, 9171.
16. (a) Wright, J. B. US 3407197 US Pat. Appl.; Chem. Abstr. 1969, 70, 57914. (b)
Wright, J. B. J. Heterocycl. Chem. 1968, 5, 453e459.
1H NMR (DMSO-d6, 500 MHz):
(1H, d, J¼8.5 Hz), 7.42 (1H, dd, J¼8.5, 2.4 Hz), 7.40 (1H, d, J¼2.4 Hz),
d 12.20 (1H, br s), 8.20 (1H, s), 7.81
3.94 (3H, s). 13C NMR (DMSO-d6, 125 MHz):
d 162.0, 142.2, 135.2,
ꢀ
ꢀ
ꢀ
17. Porcs-Makkay, M.; Lukacs, G.; Kapus, G.; Gacsalyi, I.; Simig, G.; Levay, G.; Mezei,
ꢀ
ꢀ
ꢀ
ꢀ
130.4, 120.8, 120.2, 103.3, 56.4. IR (KBr, cmꢀ1): 3266, 1313, 1168.
Anal. Calcd for C8H8N2O3S$0.5H2O (220.23): C 43.43, H 4.10, N
12.66, S 14.49%. Found: C 43.58, H 4.08, N 12.47, S 14.00%.
T.; Vegh, M.; Kertesz, S.; Barkoczy, J.; Leveleki, C.; Harsing, L. WO 2008020255;
Chem. Abstr. 2008, 148, 262627.
ꢀ
18. Lukacs, G.; Porcs-Makkay, M.; Simig, G. Tetrahedron Lett. 2003, 44, 3211e3214.
ꢀ
19. Lukacs, G.; Porcs-Makkay, M.; Simig, G. Eur. J. Org. Chem. 2004, 20, 4130e4140.

M. Porcs-Makkay et al. / Tetrahedron 70 (2014) 286e293
293
20. Imamura, H.; Nagao, S.; Hasegawa, R. JP 54100343 Japanese Pat. Appl.; Chem.
Abstr. 1980, 92, 41574.
21. Hichri, H.; Lesins, V.; Sommer, C. C. US 6040477 US Pat. Appl.; Chem. Abstr.
Trans. 2012, 41, 5060e5070; (d) Dumoulin, D.; Lebrun, S.; Deniau, E.; Couture,
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Creaser, C. S.; Malkov, A. V.; Mojovic, L.; Stephenson, G. R. J. Organomet. Chem.
2003, 101e122.
2000, 132, 207658.
22. Lithiation (BuLi, e78 ꢁC) of the Schiff base formed from piperonal and cyclo-
hexylamine led to compounds deuterated or iodinated adjacent to the imine
moiety in: Ziegler, F. E.; Fowler, K. W. J. Org. Chem. 1976, 41, 1564e1566.
23. High-yielding reactions for a broader range of cyclohexyl imines of benzalde-
hydes using lithium 2,2,6,6-tetramethylpiperidin-1-ide as the lithiating agent
are described in: Flippin, L. A.; Muchowski, J. M.; Carter, D. S. J. Org. Chem. 1993,
58, 2463e2467.
28. In the case of methoxy- and other alkoxybenzaldehydes, the number of alkoxy
groups and their positions relative to the acetal-protected formyl moiety de-
termines the rate of the lithiation reaction.
29. A general procedure for the preparation of dioxolanes of acetophenones and
benzophenones in a microwave reactor was elaborated at our laboratory, see:
ꢀ
ꢀ
Lukacs, G.; Porcs-Makkay, M.; Komaromi, A.; Simig, G. ARKIVOC 2008, iii, 17e24.
30. Meyers, I. A.; Lutomski, K. J. Org. Chem. 1979, 44, 4464e4466.
31. Blanchet, J.; Macklin, T.; Ang, P.; Metallinos, C.; Snieckus, V. J. Org. Chem. 2007,
72, 3199e3206.
24. Harris, T. D.; Roth, G. P. J. Org. Chem. 1979, 44, 2004e2007.
25. (a) Comins, D. L.; Roth, G. P.; Mantlo, N. B. Tetrahedron Lett. 1982, 23,
3979e3982; (b) Comins, D. L.; Brown, J. D. J. Org. Chem. 1984, 49, 1078e1083;
(c) Comins, D. L. Synlett 1992, 615e625.
32. Compound 11b is mentioned but not characterized in: Zhi, H.-Z.; Luo, J.; Ma,
W.; Lu, C.-X. Gaodeng Xuexiao Huaxue Xuebao 2008, 29, 2007e2010 Chem. Abstr.
2008, 151, 173294.
26. (a) 2-Phenyl-1,3-dioxolane (11a) is described in: Soderquist, J. A.; Kock, I.; Es-
trella, M. E. Org. Process Res. Dev. 2006, 10, 1076e1079 but its lithiation is un-
precedented in the literature (b) Only one literature reference is known where
unsubstituted benzaldehyde (10a) was converted to an acetal (dimethyl acetal)
and subjected to lithiation (with n-Buli no reaction, with t-BuLi, 34% yield):
Plaumann, H. B.; Keay, B. A.; Rodrigo, R. Tetrahedron Lett. 1979, 51, 4921e4924.
27. Ortho lithiation of various acetals of unsubstituted benzaldehyde (10a) was
also described via bromine-elithium exchange in: (a) Robinson, R. P. EP 400916
Eur. Pat. Appl.; Chem. Abstr. 1991, 114, 228883. (b) Mugesh, G.; Panda, A.; Singh,
H. B.; Narayan, S.; Punekar, N. S.; Butcher, R. J. J. Am. Chem. Soc. 2001, 123,
33. Khan, A. T.; Mondal, E.; Ghosh, S.; Islam, S. Eur. J. Org. Chem. 2004, 9,
2002e2009.
34. Barbasiewicz, M.; Makosza, M. Org. Lett. 2006, 8, 3745e3748.
35. (a) Tsoungas, P. G.; Searcey, M. Tetrahedron Lett. 2001, 42, 6589e6592; (b)
Koepf, M.; Melin, F.; Jaillard, J.; Weiss, J. Tetrahedron Lett. 2005, 46, 139e142.
36. (a) Shashidhar, M. S.; Bhatt, M. V. J. Chem. Soc., Chem. Commun. 1987, 654e656;
(b) Rajeev, K. G.; Shashidhar, S. M.; Pius, K.; Bhatt, V. M. Tetrahedron 1994, 50,
5425e5438; (c) Fish, P. V.; Cook, A. S.; Phillips, C.; Bent, A. F.; Mills, J. E. J;
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390017.
€
839e850; (c) Pollnitz, A.; Silvestru, C.; Carpentier, J.-F.; Silvestru, A. Dalton