Oxidative Annulation of 3-Aryl-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxides with Aryl Aldehydes: An Easy Access to Hydroxyisoindolo[1,2-b] benzothiadiazinedioxide Scaffolds

Article abstract of DOI:10.1002/ejoc.201901509

A novel and efficient approach has been developed for the synthesis of a diverse range of hydroxyisoindolo[1,2-b]benzothiadiazinedioxide derivatives through a sequential palladium catalyzed cross-dehydrogenative coupling (CDC) and intramolecular cyclizati

Full text of DOI:10.1002/ejoc.201901509

A Journal of
Accepted Article
Title: Oxidative Annulation of 3-Aryl-2H-benzo[e][1,2,4]thiadiazine-1,1-
dioxides with Aryl Aldehydes: Direct Access to Angularly Fused
N-Heterocycles
Authors: G. Ravi Kumar, Swarnayu Banik, Boora Ramesh,
Balasubramanian Sridhar, and Basireddy Venkata Subba
Reddy
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901509
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901509
Supported by

10.1002/ejoc.201901509
European Journal of Organic Chemistry
FULL PAPER
Oxidative Annulation of 3-Aryl-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxides with
Aryl Aldehydes: An Easy Access to Hydroxyisoindolo[1,2-b]
benzothiadiazinedioxide Scaffolds
G. Ravi Kumar,a Swarnayu Banik,a Boora Ramesh,a Dr B Sridhar,b Dr B. V. Subba Reddy.a
[a]Fluoro-Agrochemicals, [b]Laboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical
Technology, Hyderabad –500 007, India. E-mail: basireddy@iict.res.in; Fax: 91-40-27160512.
Abstract: A novel and efficient approach has
been developed for the synthesis of a diverse
range
of
hydroxyisoindolo[1,2-
b]benzothiadiazinedioxide derivatives through a
sequential
dehydrogenative
palladium
catalyzed
(CDC)
cross-
and
coupling
intramolecular cyclization. This method works not
only with aryl aldehydes and alcohols but also
with toluene to generate angularly fused
heterocycles in good to excellent yields.
Introduction
The benzothiadiazine-1,1-dioxide moiety is
frequently found in natural products and
biologically active molecules.1 They are being
used as anti-hypertensive,2 anti-microbial,3 and
anti-viral agents.4 Specifically, benzothiadiazine-
1,1-dioxide derivatives (I-II) are known to display
a diverse range of biological activities.5 A few of
them are used for the treatment of Alzheimer's at
early stages.6
Figure 1. Examples of biologically active
benzothiadiazine-1,1-dioxide frameworks
In addition, benzothiadiazine dioxide II is known
to exhibit potent NS5B inhibition and useful for
the treatment of obesity and diabetes (Figure 1).7
On the other hand, sulfonyl moieties like
sulfonamide, sulfonylurea, and sultam are core
structures of many drugs and pharmaceuticals.8 In
recent years, fused N-heterocycles, in particular,
quinazolinones have proved to be an important
class of alkaloids because of their existence in
natural products such as phaitanthrins A & B and
cruciferane and are found to exhibit anti-
tubercular and anti-mycobacterial activity.9,10
[a] Fluoro & Agrochemicals, CSIR-Indian Institute of
Chemical Technology, Hyderabad-500 007, India.
E-mail: basireddy@iict.res.in; www.iictindia.org
[b] Laboratory of X-ray Crystallography, CSIR-Indian
Institute of Chemical Technology, Hyderabad–500 007,
India. Home page: www.iictindia.org
Electronic supplementary information (ESI) available.
CCDC 1954833. For ESI and crystallographic data in
CIF or other electronic format, see DOI:
Recently,
transition
metal-catalyzed
C-H
activation reactions have attracted much attention
in organic synthesis.11 Indeed, transition metals
facilitate the formation of C-C and C-N bonds
without any pre-functionalization.12 However, the
transition-metal catalyzed cross-dehydrogenative
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901509
European Journal of Organic Chemistry
FULL PAPER
coupling between aromatic C-H bond and conducted in different solvents like DMA,
aldehyde C-H bond to form the respective aryl dioxane, water and DMF (Table 1, entries 6-9).
ketone remains relatively unexplored.13,14 Among them, DMSO gave the product 3a in good
Therefore, we attempted the oxidative annulation yield (Table 1, entry 2). Further, we studied the
of
3-aryl-2H-benzo[e][1,2,4]thiadiazine-1,1- effect of oxidants like K2S2O8, molecular oxygen,
dioxides with aryl aldehydes, benzyl alcohols and hydrogen peroxide and oxone (Table 1, entries 10-
alkylated arenes.
13). Of these oxidants, TBHP gave the best results
(Table 1, entries 11- 13).
Results and discussion
Table 1. Optimization of reaction conditions
Following our interest on C-H bond
functionalization,15 we herein report a novel
strategy for the synthesis of hydroxyisoindole[1,2-
b]quinazosulfone derivatives through a sequential
Pd catalyzed CDC reaction16 followed by
intramolecular cyclization. This method is useful
for the synthesis of substituted hydroxyisoindole
[1,2-b]quinazosulfone derivatives by means of C-
H activation. Accordingly, we attempted the
reaction
of
3-phenyl-2H-benzo[e][1,2,4]
thiadiazine-1,1-dioxide (1a) with benzaldehyde
(2a) using 5 mol% Pd(OAc)2 and TBHP (2 equiv)
under air at 100 C in DMSO. After 14h, the
formation of 3a was observed only in 20% yield
(Table 1, entry 1) instead of product 4, which is
known to form from arylquinazolinones and
aldehyde (Scheme 1).17a
Scheme 1. Annulation of benzothiadiazine-1,1-
dioxide with benzaldehyde
In order to understand the effect of catalysts, the
reaction was carried out using other catalysts like
Co(OAc)2, Ni(OAc)2, PdCl2, and Ru(p-cymene)Cl2
(Table 1, entries 14-17). These catalysts failed to
promote the reaction under present conditions. To
improve the yield, we gradually increased the
quantity of TBHP from 2 to 4 equiv (Table 1,
entry 18). Interestingly, the desired product 3a
To improve the conversion, the reaction was
performed with different additives like AgOAc,
NaOAc, CsOAc and Cu(OAc)2 (Table 1, entries 2-
5). Notably, the yield was improved to 50% when
AgOAc was used as an additive (Table 1, entry 2).
To know the effect of solvent, the reaction was
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901509
European Journal of Organic Chemistry
FULL PAPER
was obtained in 65% yield. However, in the 70% yields respectively. Whereas aryl aldehyde
absence of catalyst, the reaction failed to give the having electron-donating substituents like
product 3a (Table 1, entry 19). Similarly, the isopropyl- and methoxy- gave the products 3e, 3f
reaction did not proceed without an oxidant, and 3g in 78%, 65% and 70% yields respectively.
TBHP (Table 1, entry 20). This clearly indicates However, the aryl aldehyde having strong
that Pd(OAc)2 and TBHP are essential for the electron-withdrawing groups such as -NO2, and -
success of CDC/annulation. To further improve, CN failed to give the desired product. However, a
the temperature was increased to 130 °C (Table 1, sterically hindered 2,3,4-trimethoxybenzaldehyde
entry 21). Remarkably, the product 3a was gave the product 3h in 55% yield. Similarly, 6-
obtained in 75% yield. Indeed, 5 mol% of bromopiperonal afforded the product 3i in 50%
Pd(OAc)2, 1.2 equiv of AgOAc and 4 equiv of yield. Due to steric hindrance, the substituted
aromatic aldehydes gave the products in low
yields.
TBHP at 130 C are optimal to get the maximum
conversion (Table 1, entry 21). No further
improvement was observed even by increasing the
temperature to 150 C (Table 1, entry 22).
In order to extend the scope, we examined the
effect of substituents like o-fluoro-, m-chloro-, p-
methoxy-, p-cyano-, and p-phenyl groups on the
Inspired by above results, we investigated the
scope of CDC/annulation reaction by varying
substituents on aromatic aldehyde and the results
are summarized in Scheme 2.
phenyl
ring
of
3-phenyl-2H-
benzo[1,2,4]thiadiazine-1,1-dioxide (1a). These
substrates are well tolerated under optimized
conditions and the results are summarized in
Scheme 3. For example, the reaction of p-
methoxy-3-phenyl-2H-benzo[1,2,4]thiadiazine-
1,1-dioxide with benzaldehyde gave the product
3j in 72% yield. Whereas o-fluoro substituted
benzaldehyde afforded the product 3k in 65%
yield. Furthermore, aryl aldehyde bearing electro-
rich substituents such as o-methyl-, p-ethyl-, p-
tert-butyl gave the products 3l, 3m and 3n in 71%,
78% and 76% yields respectively. Aryl aldehyde
with a CF3 group at para position furnished the
product 3o in 63% yield. In addition,
heteroaromatic substrate like thiophene-2-
carboxaldehyde afforded the product 3p in 58%
yield. Eventually, the effect of ortho-, meta- and
para- substitution on phenyl ring of 3-phenyl-2H-
benzo[1,2,4]thiadiazine-1,1-dioxide was examined.
Scheme 3. Substrate scope with various
substituents
on
the
phenyl
ring
of
benzothiadiazinedioxidea, b
Aromatic aldehydes bearing high electronegative
groups such as o-fluoro-, m-chloro-, and p-bromo-
gave the products 3b, 3c and 3d in 60%, 65%, and
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901509
European Journal of Organic Chemistry
FULL PAPER
products 3ab and 3ac under similar conditions
(Scheme 3).
Scheme 4. Substrate scope with benzyl alcoholsa,b
The scope of this method was further extended to
benzyl alcohols under standard reaction conditions
(Scheme 4). Accordingly, treatment of substrate
1a with benzyl alcohol 5a afforded the desired
product 3a in 30% yield. To improve the yield, we
further performed the reaction using 6 equiv. of
TBHP. Indeed, the desired product was obtained
in 58% yield. Further we investigated the effect of
substituents on aromatic ring of benzyl alcohol.
Specifically, the benzyl alcohol bearing
electronegative groups such as o-fluoro- and o-
chloro- on the aromatic ring furnished the
The presence of o-fluoro-, m-chloro- and p-fluoro
groups on 3-phenyl-2H-benzo[1,2,4]thiadiazine-
1,1-dioxide gave the products 3q, 3r, 3s and 3t in
54%, 65%, 70% and 62% yields respectively.
Moreover, the presence of a bulky group at the
para-position of a phenyl ring of 1a gave the
product 3u in 56% yield. Similarly, the -CN
substituted 1a afforded the product 3v in 51%
yield. However, ortho-methyl- and ortho-
methoxy-substituted
3-phenyl-2H-benzo[1,2,4]
thiadiazine-1,1-dioxide failed to give the desired
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901509
European Journal of Organic Chemistry
FULL PAPER
products 3b and 3w in 50% and 47% yields
respectively. Other substituted benzyl alcohols
like m-methoxy- and p-methyl- gave the products
3g and 3x in 55% and 68% yields respectively.
Next we examined the effect of substituent on the
phenyl
benzo[1,2,4]thiadiazine-1,1-dioxide. Interestingly,
the reaction of p-methoxy-3-phenyl-2H-
benzo[1,2,4]thiadiazine1,1-dioxide with p-
ring
of
3-phenyl-2H-
ethylbenzyl alcohol gave the product 3m in 62%
yield. Whereas the benzyl alcohol having the
electron-withdrawing p-CF3 group afforded the
product 3o in 45% yield. Furthermore, 2-thienyl
carbinol gave the product 3p in 60% yield. Next,
we investigated the reaction scope with o-fluoro-,
m-chloro- and p-phenyl substituted 3-phenyl-2H-
benzo[1,2,4]thiadiazine1,1-dioxide and benzyl
alcohol to furnish the corresponding products 3q,
3r and 3u in 48%, 50% and 52% yields
respectively.
Scheme 5. CDC/annulation of 1a with toluene
To realise the reaction mechanism, we have
carried out radical trapping experiments using
2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO)
and 2,6-di-tert-butyl-4-methyl-phenol (BHT)
(Scheme 6). It was observed that the reaction was
considerably inhibited by radical scavengers under
stranded conditions. Indeed, the benzoyl radical
was trapped with TEMPO to afford the product 7
in 40% yield, which clearly suggests that the
reaction proceeds through a radical mechanism.
Furthermore, the reaction did not proceed with -
NCH3 derivative (8). It reveals that free -NH
group is essential for the success of the reaction
(Scheme 6). To support the reaction mechanism,
the compound 918 was prepared and treated with 5
mol% Pd(OAc)2 in DMSO at 130 C. To our
delight, the desired product 3a was observed in
45% yield. On the other hand, the compound 9
failed to give the expected product 3a in the
absence of Pd(II) catalyst. It clearly suggests that
Pd(II) catalyst is required for the cyclisation.
In order to expand the substrate scope of our
strategy, we performed the reaction with toluene
instead of aryl aldehyde and benzyl alcohol.
However, the desired product 3a was obtained
only in 25% yield. By increasing the quantity of
TBHP to 8 equiv, the product 3a was isolated in
50% yield (Scheme 5). Subsequently, we carried
out the reactions with substituted toluene. The
substrate bearing electronegative groups such as
o-chloro- and p-fluoro- on the aromatic ring gave
the products 3w and 3y in 32% and 34% yields
respectively. Whereas electron-rich toluene
derivatives like ortho- para- and meta-methoxy
afforded the products 3f, 3g and 3z in 38%, 43%
and 45% yields respectively. A sterically hindered
4-tert-butyltoluene gave the product 3aa in 46%
yield.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901509
European Journal of Organic Chemistry
FULL PAPER
Scheme 6. Control experiment
Scheme 7. A plausible reaction pathway
Based on previous reports19 and control
experiments, we proposed a possible reaction
mechanism as shown in Scheme 6. Initially,
Pd(OAc)2 undergoes cyclometalation with 3-
phenyl-4H-benzo[1,2,4]thiadiazine-1,1-dioxide
(1a) to generate a five-membered cyclopalladated
complex A, which can undergo tautomerization to
give the complex B. Up on oxidation of
palladacycle B with benzoyl radical, formed in
situ by hydrogen abstraction generates the
complex C.2 A migratory inserion of benzoyl
radical with a concomitant reductive elimination
of palladium(II) forms the intermediate D. A
subsequent nucleophilic attack on carbonyl group
generates the palladium alkoxide E. Reductive
elimination of E would give the desired product
3a (Scheme 7).
The structure of compound 3f was established by
a single crystal X-ray analysis (Figure 2).19
To know the role of AgOAc, we carried out the
reaction of compound 9 using AgOAc, but the
reaction did not proceed. However, the reaction of
compound 9 in the presence of both Pd(OAc)2 and
AgOAc afforded the product 3a in 67% yield. It
clearly indicates that AgOAc act as a co-oxidant
to regenerate the Pd(II).
Figure 2. ORTEP diagram of 3f
Conclusion
In conclusion, we have developed a direct
palladium
catalyzed
cross-dehydrogenative
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901509
European Journal of Organic Chemistry
FULL PAPER
coupling and intramolecular cyclization of
benzothiadiazine-dioxide with aldehyde to A mixture of benzothiadiazine-1,1-dioxide (1.0
produce hydroxyisoindolo[1,2- equiv), benzyl alchol (1.2 equiv), Pd(OAc)2 (5
b]benzothiadiazinedioxide derivatives in good mol%), AgOAc (1.2 equiv), TBHP (6 equiv) in
yields. This method is extended to benzylalcohol DMSO was heated in a sealed tube at 130 °C for
and toluene using TBHP as a sole oxidant.
12h. After completion, the mixture was cooled to
room temperature and then quenched with water
(5 mL) and extracted with EtOAc (3 × 10 mL).
The combined organic layers were further washed
Experimental
Melting points (mp) were obtained on Buchi B- with brine solution, dried over Na2SO4 and
1
13
540. H and C NMR (proton-decoupled) spectra purified by chromatography on silica gel using
were recorded in DMSO, CDCl3 solvents on 100, ethyl acetate/hexane (v/v=1:4) to afford the
300, 400 or 500 MHz NMR spectrometer. desired product. The products were characterized
Chemical shifts (δ) were reported in parts per by their spectral data.
million (ppm) with respect to TMS as an internal
standard. Coupling constants (J) are quoted in
hertz (Hz). Mass spectra and HRMS were
recorded on mass spectrometer by Electrospray
ionization (ESI) or Atmospheric pressure
chemical ionization (APCI) technique.
Experimental
hydroxylisoindole[1,2-b]quinazosulfone from
toluene (c)
procedure
for
the
A mixture of benzothiadiazine-1,1-dioxide (1.0
equiv), toluene (1.2 equiv), Pd(OAc)2 (5 mol%),
AgOAc (1.2 equiv), TBHP (8 equiv) in DMSO
was heated in a sealed tube at 130 °C for 12h.
After completion, the mixture was cooled to room
temperature and then quenched with water (5 mL)
and extracted with EtOAc (3 × 10 mL). The
combined organic layers were further washed with
brine solution, dried over Na2SO4 and purified by
chromatography on silica gel using ethyl
acetate/hexane (v/v=1:4) to afford the desired
product. The products were characterized by their
spectral data.
Experimental
procedure
for
the
hydroxylisoindole[1,2-b]quinazosulfone (a)
A mixture of benzothiadiazine-1,1-dioxide (1.0
equiv), aldehyde (1.2 equiv), Pd(OAc)2 (5 mol %),
AgOAc (1.2 equiv), TBHP (4 equiv) in DMSO
was heated in a sealed tube at 130 °C for 12h.
After completion, the mixture was cooled to room
temperature and then quenched with water (5 mL)
and extracted with EtOAc (3 × 10 mL). The
combined organic layers were further washed with
brine solution, dried over Na2SO4 and purified by
chromatography on silica gel using ethyl
acetate/hexane (v/v=1:4) to afford the desired
product. The products were characterized by their
spectral data.
11-Hydroxy-11-phenyl-11H-benzo[5,6][1,2,4]
thiadiazino[3,4-a]isoindole-5,5-dioxide (3a).
(0.105 g, 75% yield) White solid. mp: 260-262 oC.
IR (neat)  3338.3, 3035.6, 2960.5, 2865.7,
1605.1, 1471.1, 1396.7, 1295.9, 1163.6, 1073.1,
941.8, 850.1, 753.5, 674.8, 555.4 cm-1. 1H NMR
(400 MHz, DMSO) δ 8.52 (s, 1H), 8.01 (d, J = 7.5
Hz, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.73 (t, J = 7.4
Experimental
procedure
for
the
hydroxylisoindole[1,2-b]quinazosulfone from
benzyl alcohol (b)
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901509
European Journal of Organic Chemistry
FULL PAPER
Hz, 1H), 7.67 (t, J = 7.3 Hz, 1H), 7.54 (t, J = 7.3 (m, 2H), 7.40 (t, J = 7.9 Hz, 1H), 7.29 (d, J = 8.4
13
Hz, 1H), 7.47-7.40 (m, 6H), 7.37-7.31 (m, 2H). Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H). C NMR (100
13C NMR (100 MHz, DMSO) δ 154.9, 148.6, MHz, DMSO) δ 154.9, 148.0, 141.3, 135.3, 134.5,
138.6, 134.7, 132.9, 132.6, 130.5, 129.5, 129.2, 133.3, 132.6, 131.9, 131.2, 129.6, 128.6, 126.8,
128.7, 126.2, 125.2, 124.6, 123.6, 123.3, 122.7, 125.4, 125.0, 124.0, 124.0, 123.6, 122.6, 117.9,
118.1, 97.2. HRMS (Orbitrap ESI): Exact mass 96.4. HRMS (Orbitrap ESI): Exact mass calcd for
calcd for C20H14N2O3S[M+H]+: 363.0798. found: C20H13ClN2O3S[M+H]+: 397.0414.
found:
363.0811.
397.0426.
11-(2-Fluorophenyl)-11-hydroxy-11H-benzo
[5,6][1,2,4]thiadiazino[3,4-a]isoindole-5,5-
dioxide (3b).
11-(4-Bromophenyl)-11-hydroxy-11H-benzo
[5,6][1,2,4]thiadiazino[3,4-a]isoindole-5,5-
dioxide (3d).
(0.088 g, 60% yield) White solid mp: 264-266 oC. (0.126 g, 70% yield) White solid. mp: 239-241 oC.
IR (neat)  3401.8, 3022.8, 2963.7, 2854.6, IR (neat)  3411.7, 3025.1, 2964.7, 2853.1,
1610.5, 1469.3, 1393.8, 1291.7, 1162.6, 1074.1, 1612.4, 1470.0, 1391.9, 1230.4, 1166.3, 1071.5,
955.1, 853.6, 755.7, 675.1, 549.8 cm-1. H NMR 954.6, 851.9, 746.3, 679.0, 550.1 cm-1. H NMR
(400 MHz, DMSO) δ 8.76 (s, 1H), 8.32-8.25 (m, (300 MHz, DMSO) δ 8.63 (s, 1H), 8.02 (d, J = 7.3
1H), 8.03 (d, J = 7.2 Hz, 1H), 7.95 (dd, J = 7.8, Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.80-7.66 (m,
0.9 Hz, 1H), 7.75 (td, J = 7.5, 0.98 Hz, 1H), 7.73 3H), 7.66-7.54 (m, 4H), 7.51-7.34 (m, 5H), 7.28
1
1
(td, J = 7.5, 0.98 Hz, 1H), 7.59-7.52 (m, 1H). C (d, J = 7.7 Hz, 1H). 13C NMR (75 MHz,
13
NMR (100 MHz, DMSO) δ 159.8, 157.4, 154.7, CDCl3+DMSO) δ 159.6, 152.8, 142.7, 139.5,
146.7, 135.1, 133.2, 132.8, 132.3, 132.3, 131.2, 137.4, 137.2, 135.4, 133.5, 132.2, 131.0, 129.4,
129.7, 129.1, 126.7, 125.9, 125.8, 125.1, 123.5, 128.5, 128.0, 127.7, 127.4, 122.7. HRMS
123.3, 122.4, 117.1, 116.8, 116.7, 94.2. HRMS (Orbitrap ESI): Exact mass calcd for
(Orbitrap ESI): Exact mass calcd for C21H17O4N2BrSNa[M+Na]+: 472.0086. found:
C20H13O3N2FSNa[M+Na]+: 403.0523. found: 472.0073.
403.0543.
11-Hydroxy-11-(4-isopropylphenyl)-11H-benzo
[5,6][1,2,4]thiadiazino[3,4-a]isoindole-5,5-
dioxide (3e).
11-(3-Chlorophenyl)-11-hydroxy-11H-benzo
[5,6][1,2,4]thiadiazino[3,4-a]isoindole-5,5-
dioxide (3c).
(0.121 g, 78% yield) White solid. mp: 209-211 oC.
(0.098 g, 65% yield) White solid. mp: 259-261 oC.
IR (neat)  3338.3, 3035.6, 2960.5, 2865.7,
IR (neat)  3340.1, 3025.8, 2964.1, 2856.2,
1609.3, 1472.0, 1394.6, 1299.0, 1164.1, 1070.6,
945.7, 854.2, 756.4, 671.9, 554.3 cm-1. H NMR
(400 MHz, DMSO) δ 8.69 (s, 1H), 8.03 (d, J = 7.3
Hz, 1H), 7.97 (dd, J = 7.9, 1.2 Hz, 1H), 7.75 (td, J
= 7.5, 1.2 Hz, 1H), 7.71-7.66 (m, 2H), 7.58 (dd, J
= 8.6, 1.3 Hz, 1H), 7.52-7.49 (m, 1H), 7.47-7.44
1605.13, 1471.1, 1396.7, 1295.9, 1163.6, 1073.1,
1
941.8, 850.1, 753.5, 674.8, 555.4 cm-1. H NMR
1
(400 MHz, DMSO) δ 8.46 (s, 1H), 8.01 (d, J = 7.4
Hz, 1H), 7.95 (d, J = 7.4 Hz, 1H), 7.72 (t, J = 7.1
Hz, 1H), 7.66 (t, J = 7.3 Hz, 1H), 7.56 (t, J = 7.4
Hz, 1H), 7.44 (t, J = 7.3 Hz, 2H), 7.39 (d, J = 8.5
Hz, 1H), 7.31 (m, 4H), 2.85 (sept, J = 6.8 Hz, 1H).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901509
European Journal of Organic Chemistry
FULL PAPER
1.14 (d, J = 6.9 Hz, 7H). 13C NMR (100 MHz, 148.5, 140.4, 135.2, 133.2, 132.8, 131.1, 131.0,
DMSO) δ 154.9, 149.5, 148.8, 136.1, 135.2, 133.1, 128.5, 126.7, 124.8, 123.8, 123.5, 122.6, 118.1,
132.9, 130.9, 128.5, 127.7, 126.6, 125.3, 124.8, 117.1, 114.3, 111.5, 97.0, 55.6. HRMS (Orbitrap
123.8, 123.5, 122.6, 118.1, 9.3, 3.4, 24.0. HRMS ESI): Exact mass calcd for C21H17O4N2S[M+H]+:
(Orbitrap ESI): Exact mass calcd for 393.0903. found: 393.0925.
C23H21O3N2S[M+H]+: 405.1267. found: 405.1270.
11-Hydroxy-11-(2,3,4-trimethoxyphenyl)-11H-
11-Hydroxy-11-(2-methoxyphenyl)-11H-benzo
[5,6][1,2,4]thiadiazino[3,4-a]isoindole-5,5-
dioxide (3f).
benzo[5,6][1,2,4]thiadiazino[3,4-a]isoindole-5,5-
dioxide (3h).
(0.096 g, 55% yield) White solid. mp: 261-263 oC.
(0.098 g, 65% yield) White solid. mp: 246-248 oC.
IR (neat)  3345.6, 2945.6, 2834.2, 1644.1,
IR (neat)  3413.6, 3017.5, 2973.8, 1624.5,
1464.2, 1391.4, 1299.2, 1161.6, 991.4, 826.2,
1499.7, 1470.3, 1333.3, 1266.2, 1166.0, 971.1, 766.3, 628.7, 555.8 cm-1. H NMR (400 MHz,
770.9, 609.2 cm-1. 1H NMR (400 MHz, DMSO) δ DMSO) δ 8.34 (s, 1H), 7.99 (d, J = 7.2 Hz, 1H),
8.42 (s, 1H), 8.22 (dd, J = 7.8, 1.6 Hz, 1H), 7.99- 7.94-7.88 (m, 2H), 7.73-7.63 (m, 3H), 7.56-7.49
7.96 (m, 1H), 7.89 (dd, J = 7.8, 1.2 Hz, 1H), 7.70- (m, 1H), 7.46-7.36 (m, 3H), 7.31 (d, J = 7.3 Hz,
7.60 (m, 2H), 7.50-7.30 (m, 6H), 7.22-7.16 (m, 1H), 7.02 (d, J = 8.9 Hz, 1H), 3.84 (s, 3H), 3.50
1H), 6.78 (d, J = 7.9 Hz, 1H), 3.19 (s, 3H). 13C (s, 3H), 2.95 (s, 3H). 13C NMR (100 MHz,
NMR (100 MHz, DMSO) δ 155.8, 155.5, 147.0, DMSO) δ 155.1, 154.9, 150.3, 148.0, 142.0,
134.4, 133.3, 132.8, 131.3, 130.7, 130.5, 128.4, 134.4, 133.2, 132.9, 130.6, 130.4, 126.2, 124.9,
126.1, 125.9, 124.8, 122.9, 122.3, 121.5, 116.8, 123.2, 123.0, 123.0, 122.7, 122.3, 116.8, 107.9,
112.8, 95.0, 56.1. HRMS (Orbitrap ESI): Exact 95.0, 60.6, 60.3, 56.2 HRMS (Orbitrap ESI):
mass calcd for C21H17O4N2S[M+H]+: 393.0903. Exact mass calcd for C23H21O6N2S[M+H]+:
1
found: 393.0925.
453.1124. found: 453.1114.
11-(6-Bromobenzo[d][1,3]dioxol-5-yl)-11-
hydroxy-11H-benzo[5,6][1,2,4]thiadiazino[3,4-
a]isoindole-5,5-dioxide (3i).
11-Hydroxy-11-(3-methoxyphenyl)-11H-benzo
[5,6][1,2,4]thiadiazino[3,4-a]isoindole-5,5-
dioxide (3g).
(0.093 g, 50% yield) White solid. mp: 240-242 oC.
IR (neat)  3416.8, 2956.1, 2895.6, 1647.9,
1465.2, 1392.6, 1290.5, 1162.3, 995.8, 823.8,
(0.105 g, 70% yield) White solid. mp: 251-253 oC.
IR (neat)  3412.5, 2953.4, 2842.7, 1644.1,
1464.2, 1391.4, 1299.2, 1161.6, 991.4, 826.2,
1
763.6, 625.9, 545.4 cm-1. H NMR (400 MHz,
1
766.3, 628.7, 555.8 cm-1. H NMR (300 MHz,
DMSO) δ 8.54 (s, 1H), 8.00 (s, 1H), 7.98-7.91 (m,
2H), 7.73 (td, J = 7.5, 1.1 Hz, 1H), 7.68 (td, J =
7.4, 1.0 Hz, 1H), 7.60-7.54 (m, 1H), 7.45 (t, J =
7.3 Hz, 1H), 7.35 (d, J = 7.3 Hz, 1H), 7.28 (d, J =
8.4 Hz, 1H), 7.08 (s, 1H), 6.23 (s, 1H), 6.19 (s,
1H). 13C NMR (100 MHz, DMSO) δ 155.8, 149.5,
DMSO) δ 8.53 (s, 1H), 8.01 (d, J = 7.3 Hz, 1H),
7.95 (d, J = 7.6 Hz, 1H), 7.77-7.63 (m, 3H), 7.61-
7.53 (m, 2H), 7.52-7.41 (m, 3H), 7.36 (d, J = 8.5
Hz, 1H), 7.28 (t, J = 7.9 Hz, 1H), 7.13 (s, 1H),
6.93 (d, J = 7.9 Hz, 1H), 6.77 (d, J = 7.4 Hz, 1H).
13C NMR (100 MHz, DMSO) δ 160.3, 155.0,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901509
European Journal of Organic Chemistry
FULL PAPER
148.5, 145.8, 135.0, 133.2, 132.8, 131.1, 129.3, 116.5, 107.9, 93.6, 56.6. HRMS (Orbitrap ESI):
126.6, 125.1, 123.2, 123.2, 122.5, 122.4, 117.6, Exact mass calcd for C21H16O4N2FS[M+H]+:
116.7, 114.8, 110.2, 109.7, 103.2, 95.3. HRMS 411.0809. found: 411.0825.
(Orbitrap ESI): Exact mass calcd for
C21H14O5N2BrS[M+H]+:
484.9825.
484.9801.
found:
11-Hydroxy-9-methoxy-11-(o-tolyl)-11H-benzo
[5,6][1,2,4]thiadiazino[3,4-a]isoindole-5,5-
dioxide (3l).
11-Hydroxy-9-methoxy-11-phenyl-11H-benzo
[5,6][1,2,4]thiadiazino[3,4-a]isoindole-5,5-
dioxide (3j)
(0.099 g, 71% yield) White solid. mp: 216-218 oC.
IR (neat)  3317.8, 3084.9, 2959.4, 2843.8,
1600.6, 1461.9, 1394.2, 1292.4, 1166.2, , 954.7,
848.0, 753.4, 545.7 cm-1. 1H NMR (400 MHz,
DMSO) δ 8.37 (s, 1H), 8.35 (s,1H), 7.96 (d, J =
8.5 Hz, 1H), 7.91 (dd, J = 7.8, 1.3 Hz, 1H), 7.55-
7.45 (m, 2H), 7.45-7.38 (m, 1H), 7.32 (t, J = 7.9
Hz, 2H), 7.24 (dd, J = 8.5, 2.1 Hz, 1H), 7.04 (d, J
= 7.0 Hz, 1H), 6.71 (s, 2H), 3.81 (s, 3H), 1.53 (s,
3H). 13C NMR (100 MHz, DMSO) δ 165.2, 155.2,
149.1, 136.2, 134.3, 133.0, 129.9, 127.9, 127.5,
126.4, 125.3, 124.8, 122.4, 122.2, 117.7, 116.8,
108.0, 95.5, 79.6, 56.6, 19.2. HRMS (Orbitrap
ESI): Exact mass calcd for C22H19O4N2S[M+H]+:
407.1060. found: 407.1064.
(0.097 g, 72% yield) White solid. mp: 256-258 oC.
IR (neat)  3456.5, 2982.2, 2838.3, 1684.7,
1603.8, 1424.0, 1299.5, 1257.6, 1166.8, 927.1,
770.7, 616.8, 546.1 cm-1. H NMR (400 MHz,
1
DMSO) δ 8.52 (s, 1H), 7.96-7.89 (m, 2H), 7.54-
7.47 (m, 1H), 7.45-7.33 (m, 7H), 7.30 (d, J = 8.5
Hz, 1H), 7.20 (dd, J = 8.6, 2.3 Hz, 1H), 6.90 (d, J
13
= 2.2 Hz, 1H), 3.82 (s, 3H). C NMR (100 MHz,
DMSO) δ 164.0, 153.7, 150.2, 137.6, 131.9, 128.7,
128.3, 125.2, 124.6, 124.2, 123.7, 121.3, 119.4,
116.7, 116.5, 107.0, 95.5, 55.5. HRMS (Orbitrap
ESI): Exact mass calcd for C21H17O4N2[M+H]+:
393.0903. found: 393.0925.
11-(4-Ethylphenyl)-11-hydroxy-9-methoxy-
11H-benzo[5,6][1,2,4]thiadiazino[3,4-a]
isoindole-5,5-dioxide (3m).
11-(2-Fluorophenyl)-11-hydroxy-9-methoxy-
11H-benzo[5,6][1,2,4]thiadiazino[3,4-a]
isoindole-5,5-dioxide (3k).
(0.113 g, 78% yield) White solid. mp: 210-212 oC.
IR (neat)  3348.6, 2980.5, 1643.6, 1453.1,
1340.0, 1300.8, 1166.9, 989.6, 767.4, 627.5, 548.6
cm-1. 1H NMR (400 MHz, DMSO) δ 8.49 (s, 1H),
7.97-7.88 (m, 2H), 7.57-7.50 (m, 1H), 7.44-7.36
(m, 1H), 7.33 (d, J = 8.3 Hz, 3H), 7.24 (d, J = 8.4
Hz, 2H), 7.22-7.16 (m, 1H), 6.90 (d, J = 2.1 Hz,
1H), 3.82 (s, 3H), 2.57 (q, J = 7.6 Hz, 2H), 1.13 (t,
(0.092 g, 65% yield) White solid. mp: 236-238 oC.
IR (neat)  3399.3, 3012.7, 2978.6, 1632.5,
1475.1, 1325.6, 1286.4, 1169.5, 985.4, 782.6,
1
611.6 cm-1. H NMR (400 MHz, DMSO) δ 8.32-
8.22 (m, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.91-7.88
(m, 1H), 7.54-7.44 (m, 3H), 7.42-7.33 (m, 2H),
7.23 (dd, J = 8.6, 2.2 Hz, 1H), 7.07-6.96 (m, 1H),
13
J = 7.6 Hz, 3H). C NMR (100 MHz, DMSO) δ
13
6.88 (d, J = 2.1 Hz, 1H). 3.82 (s, 3H). C NMR
164.0, 153.7, 150.4, 143.8, 135.0, 132.0, 131.9,
128.0, 125.1, 124.6, 124.2, 123.7, 121.3, 119.4,
116.8, 116.4, 107.0, 95.6, 78.5, 55.5, 27.0, 14.4.
(100 MHz, DMSO) δ 165.0, 159.9, 154.6, 149.3,
133.1, 132.3, 132.2, 129.2, 126.2, 125.8, 125.8,
125.4, 125.0, 122.2, 121.7, 117.7, 117.0, 116.8,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901509
European Journal of Organic Chemistry
FULL PAPER
HRMS (Orbitrap ESI): Exact mass calcd for Exact mass calcd for C22H16O4N2F3SNa[M+Na]+:
C23H21O4N2S[M+H]+: 421.1216. found: 421.1236. 461.0777. found: 461.0794.
11-(4-(tert-Butyl)phenyl)-11-hydroxy-9-
methoxy-11H-benzo[5,6][1,2,4]thiadiazino[3,4-
a]isoindole-5,5-dioxide (3n).
11-Hydroxy-9-methoxy-11-(thiophen-2-yl)-
11H-benzo[5,6][1,2,4]thiadiazino[3,4-a]
isoindole-5,5-dioxide (3p).
(0.080 g, 58% yield) White solid. mp: 210-212 oC.
IR (neat)  3421.2, 2965.2, 2890.9, 1647.8,
1459.1, 1389.0, 1284.6, 1167.4, 996.0, 824.2,
(0.117 g, 76% yield) White solid. mp: 206-208 oC.
IR (neat)  3418.9, 2976.8, 1651.3, 1455.8.,
1379.6, 1285.7, 1165.9, 988.4, 767.3, 629.7, 546.3
cm-1. 1H NMR (400 MHz, DMSO) δ 8.48 (s, 1H),
7.95-7.88 (m, 2H), 7.56-7.51 (m, 1H), 7.45-7.39
(m, 3H), 7.39-7.31 (m, 3H), 7.20 (dd, J = 8.6, 2.2
Hz, 1H), 6.90 (d, J = 2.1 Hz, 1H), 3.82 (s, 3H),
1.22 (s, 9H). 13C NMR (100 MHz, DMSO) δ
165.1, 154.8, 151.8, 151.4, 135.8, 133.1, 133.0,
126.6, 126.2, 125.7, 125.1, 124.7, 122.4, 120.5,
117.8, 117.3, 108.3, 96.7, 56.6, 34.8, 31.4. HRMS
(Orbitrap ESI): Exact mass calcd for
C25H25O4N2S[M+H]+: 449.1529. found: 449.1538.
1
764.1, 630.0, 555.1 cm-1. H NMR (400 MHz,
DMSO) δ 8.76 (s, 1H), 7.93 (d, J = 8.5 Hz, 2H),
7.62-7.52 (m, 3H), 7.47-7.42 (m, 2H), 7.23 (d, J =
13
8.6 Hz, 1H), 7.01 (s, 3H), 3.86 (s, 3H). C NMR
(100 MHz, DMSO) δ 165.2, 154.2, 150.8, 142.7,
136.4, 133.0, 131.8, 128.4, 128.1, 126.4, 125.9,
124.8, 122.4, 120.0, 117.8, 117.7, 107.9, 95.2,
56.6. HRMS (Orbitrap ESI): Exact mass calcd for
C19H16O4N2S2[M+H]+:
399.0474.
399.0467.
found:
8-Chloro-11-hydroxy-11-phenyl-11H-benzo
[5,6][1,2,4]thiadiazino[3,4-a]isoindole-5,5-
dioxide (3q).
11-Hydroxy-9-methoxy-11-(4-(trifluoromethyl)
phenyl)-11H-benzo[5,6][1,2,4]thiadiazino[3,4-a]
isoindole-5,5-dioxide (3o).
(0.074 g, 54% yield) White solid. mp: 260-262 oC.
IR (neat)  3423.5, 3002.7, 3023.6, 1644.8,
1465.2, 1391.5, 1295.4, 1170.1, 991.0, 822.8,
(0.073 g, 63% yield) White solid. mp: 208-210 oC.
IR (neat)  3416.3, 2992.8, 2875.4, 1649.4,
1449.7, 1341.9, 1281.1, 1168.2, 997.3, 820.8,
1
766.1, 626.8, 550.8 cm-1. H NMR (400 MHz,
1
759.9, 627.4, 548.7 cm-1. H NMR (300 MHz,
DMSO) δ 8.59 (s, 1H), 7.95 (dd, J = 7.9, 1.4 Hz,
1H), 7.80-7.73 (m, 1H), 7.57-7.51 (m, 1H), 7.50-
7.43 (m, 5H), 7.38 (m, 2H), 7.31 (d, J = 8.1 Hz,
1H), 7.27 (d, J = 7.5 Hz, 1H).13C NMR (100
MHz, DMSO) δ 153.7, 147.2, 138.2, 135.7, 135.1,
133.2, 132.6, 130.6, 129.9, 129.6, 127.0, 125.4,
124.9, 123.5, 122.6, 118.1, 97.1. HRMS (Orbitrap
DMSO) δ 8.78 (s, 1H), 8.15 (d, J = 8.0 Hz, 1H),
7.96 (t, J = 7.5 Hz, 2H), 7.89 (d, J = 8.2 Hz, 1H),
7.81 (d, J = 8.3 Hz, 2H), 7.69 (d, J = 8.0 Hz, 2H),
7.54 (t, J = 7.3 Hz, 1H), 7.43 (t, J = 7.4 Hz, 1H),
7.24 (d, J = 8.5 Hz, 2H), 6.97 (s, 1H), 3.83 (s, 3H).
13C NMR (100 MHz, DMSO) δ 166.6, 165.3,
154.7, 150.5, 143.3, 135.0, 133.2, 133.1, 132.7,
130.6, 130.0, 129.7, 126.8, 126.5, 126.4, 126.1,
125.9, 125.7, 125.0, 123.0, 122.4, 120.5, 117.9,
117.5, 108.2, 96.0, 56.7. HRMS (Orbitrap ESI):
ESI):
Exact
mass
calcd
397.0408.
for
C20H14O3N2ClS[M+H]+:
397.0415.
found:
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901509
European Journal of Organic Chemistry
FULL PAPER
(0.105g, 56% yield) White solid. mp: 246-248 oC.
IR (neat)  3448.2, 3095.6, 3032.1, 1584.8,
1479.0, 1353.0, 1259.0, 1072.8, 858.9, 726.3,
694.6 cm-1. 1H NMR (300 MHz, DMSO) δ 8.66 (s,
1H), 8.10 (dd, J = 8.3, 4.7 Hz, 1H), 7.96 (d, J =
7.8 Hz, 1H), 7.61 - 7.49 (m, 2H), 7.49 - 7.35 (m,
11-(4-Bromophenyl)-8-chloro-11-hydroxy-11H-
benzo[5,6][1,2,4]thiadiazino[3,4-a]isoindole-5,5-
dioxide (3r).
(0.106 g, 65% yield) White solid. mp: 265-267 oC.
IR (neat)  3424.0, 2948.5, 2848.7, 1646.3,
1463.2, 1390.1, 1292.5, 1165.4, 999.0, 825.4, 7H), 7.30 (d, J = 8.4 Hz, 1H). 13C NMR (100 MHz,
761.2, 626.4, 549.2 cm-1. H NMR (400 MHz, DMSO) δ 167.7, 165.2, 154.0, 151.3, 138.1, 133.1,
1
DMSO) δ 8.68 (s, 1H), 8.07 (s, 1H), 7.97 (d, J = 132.7, 129.9, 129.7, 126.7, 125.4, 124.9, 124.8,
6.9 Hz, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.61 (t, J = 122.4, 119.0, 118.8, 118.0, 111.2, 110.9, 96.6.
8.5 Hz, 3H), 7.53-7.37 (m, 5H), 7.27 (d, J = 8.2 HRMS (Orbitrap ESI): Exact mass calcd for
13
Hz, 1H). C NMR (100 MHz, DMSO) δ 153.6, C20H14O3N2FS[M+H]+:
146.6, 137.7, 135.8, 135.2, 133.4, 132.8, 132.5, 381.0735.
130.7, 127.8, 127.0, 125.4, 125.0, 123.6, 123.1,
381.0735.
found:
122.6, 117.9, 96.7. HRMS (Orbitrap ESI): Exact
mass calcd for C20H13O3N2BrClS[M+H]+:
474.9513. found: 474.9524.
7-Fluoro-11-hydroxy-11-phenyl-11H-benzo
[5,6][1,2,4]thiadiazino[3,4-a]isoindole-5,5-
dioxide (3u).
(0.100 g, 65% yield) White solid. mp: 248-250 oC.
IR (neat)  3423.1, 3032.6, 2985.4, 11648.0,
1462.8, 1385.2, 1289.1, 1165.0, 996.0, 824.2,
11-Hydroxy-9,11-diphenyl-11H-benzo[5,6]
[1,2,4]thiadiazino[3,4-a]isoindole-5,5-dioxide
(3s).
1
764.2, 629.8, 544.6 cm-1. H NMR (400 MHz,
(0.106 g, 70% yield) White solid. mp: 270-272 oC.
DMSO) δ 8.63 (s, 1H), 8.09 (d, J = 8.1 Hz, 1H),
7.97 (t, J = 7.3 Hz, 3H), 7.72-7.66 (m, 3H), 7.55
IR (neat)  3411.6, 3014.7, 2976.2, 1627.1,
1490.7, 1373.8, 1279.4, 1166.4, 980.6, 770.4, (t, J = 7.5 Hz, 1H), 7.49 (t, J = 7.4 Hz, 4H), 7.46 -
1
13
659.4 cm-1. H NMR (400 MHz, DMSO) δ 8.63 7.38 (m, 4H), 7.36 (t, J = 6.4 Hz, 2H). C NMR
(s, 1H), 8.09 (d, J = 8.1 Hz, 1H), 7.97 (t, J = 7.3 (100 MHz, DMSO) δ 159.3, 156.7, 152.4, 152.4,
Hz, 2H), 7.73-7.64 (m, 3H), 7.55 (t, J = 7.5 Hz, 150.9, 138.3, 137.7, 137.6, 133.2, 132.6, 130.2,
1H), 7.49 (t, J = 7.4 Hz, 4H), 7.43 (dd, J = 13.7, 129.9, 129.6, 126.9, 125.4, 124.9, 122.1, 119.9,
13
7.3 Hz, 4H), 7.36 (t, J = 6.4 Hz, 2H). C NMR 119.9, 118.2, 118.1, 118.0, 115.9, 115.8, 96.8.
(100 MHz, CDCl3+DMSO) δ 159.4, 154.4, 151.6, HRMS (Orbitrap ESI): Exact mass calcd for
143.5, 143.4, 137.8, 137.6, 134.6, 134.4, 134.2, C20H14O3N2FS[M+H]+:
134.0, 132.4, 131.4, 130.2, 129.6, 129.3, 127.4, 381.0715.
122.9, 102.1. HRMS (Orbitrap ESI): Exact mass
381.0703.
found:
calcd for C26H19O3N2S[M+H]+: 439.1110. found:
11-Hydroxy-11-(4-isopropylphenyl)-11H-benzo
[5,6][1,2,4]thiadiazino[3,4-a]isoindole-9-
carbonitrile 5,5-dioxide (3v).
439.1122.
9-Fluoro-11-hydroxy-11-phenyl-11H-benzo
[5,6][1,2,4]thiadiazino[3,4-a]isoindole-5,5-
dioxide (3t).
(0.075 g, 51% yield) White solid. mp: 202-204 oC.
IR (neat)  3450.2, 2983.7, 2829.4, 1679.2,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901509
European Journal of Organic Chemistry
FULL PAPER
1611.5, 1429.2, 1300.4, 1255.8, 1165.4, 955.3, 1472.4, 1340.6, 1266.7, 1168.4, 974.3, 769.4,
1
771.8, 612.6, 555.7 cm-1. H NMR (400 MHz, 629.7, 555.4 cm-1. 1H NMR (300 MHz, DMSO) δ
DMSO) δ 8.62 (s, 1H), 8.20 (d, J = 7.9 Hz, 1H), 8.48 (s, 1H), 8.06 - 7.89 (m, 2H), 7.76 -7.60 (m,
8.12 (d, J = 8.0 Hz, 1H), 8.08 (s, 1H), 7.98 (d, J = 2H), 7.60 -7.51 (m, 1H), 7.49 - 7.39 (m, 2H), 7.38
7.7 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.49 (t, J = - 7.26 (m, 3H), 7.21 (d, J = 8.0 Hz, 2H), 2.26 (s,
7.5 Hz, 1H), 7.37 (t, J = 7.1 Hz, 3H), 7.30 (d, J = 3H). 13C NMR (100 MHz, DMSO) δ 154.9, 148.8,
8.3 Hz, 2H), 2.85-2.87 (m, 1H), 1.15 (d, J = 6.9 138.9, 135.8, 135.2, 133.1, 132.8, 130.9, 130.4,
Hz, 6H). 13C NMR (100 MHz, DMSO) δ 153.4, 128.5, 126.6, 125.2, 124.8, 123.8, 123.5, 122.6,
149.9, 149.0, 135.0, 133.4, 132.5, 127.8, 127.7, 118.1, 97.3, 21.1. HRMS (Orbitrap ESI): Exact
127.3, 125.5, 124.9, 122.6, 118.3, 118.0, 117.0, mass calcd for C21H17O3N2S[M+H]+: 377.0975.
97.3, 79.6, 33.4, 24.0. HRMS (Orbitrap ESI): found: 377.0986.
Exact mass calcd for C24H20O3N3S[M+H]+:
430.1219. found: 430.1229.
11-(4-Fluorophenyl)-11-hydroxy-11H-benzo
[5,6][1,2,4]thiadiazino[3,4-a]isoindole-5,5-
dioxide (3y).
11-(2-Chlorophenyl)-11-hydroxy-11H-
(0.055 g, 34% yield) White solid. mp:262-264 oC.
benzo[5,6][1,2,4]thiadiazino[3,4-a]isoindole-5,5-
IR (neat)  3425.4, 2978.5, 1655.1, 1460.6,
1383.5, 1290.3, 1166.3, 997.4, 825.6, 768.7, 630.4,
545.3 cm-1.1H NMR (400 MHz, DMSO) δ 8.57 (s,
dioxide (3w).
(0.072 g, 47% yield) White solid. mp: 259-261 oC.
1H), 8.01 (d, J = 7.5 Hz, 1H), 7.95 (d, J = 7.3 Hz,
1H), 7.74 (t, J = 7.4 Hz, 1H), 7.67 (t, J = 7.4 Hz,
1H), 7.56 (t, J = 7.6 Hz, 1H), 7.49 - 7.43 (m, 4H),
7.31 (d, J = 8.6 Hz, 1H), 7.24 (t, J = 8.8 Hz, 2H).
13C NMR (75 MHz, DMSO) δ 159.2, 154.4, 147.9,
134.7, 132.6, 130.5, 127.4, 127.3, 126.3, 126.2,
124.4, 123.4, 123.0, 122.1, 120.9, 118.6, 117.6,
117.5, 116.4, 115.9. HRMS (Orbitrap ESI): Exact
mass calcd for C20H14O3N2FS[M+H]+: 381.0712.
found: 381.0706.
IR (neat)  3299.8, 3073.9, 2926.0, 1601.1,
1467.3, 1331.6, 1259.3, 1159.2, 978.4, 776.3
630.2, 549.5 cm-1. 1H NMR (400 MHz, DMSO) δ
8.53 (d, J = 7.8 Hz, 1H), 8.49 (s, 1H), 8.10 (d, J =
3.9 Hz, 1H), 7.99 (d, J = 7.2 Hz, 1H), 7.92 - 7.90
(m, 1H), 7.73 -7.65 (m, 2H), 7.61 (t, J = 7.6 Hz,
1H), 7.41 (t, J = 6.2 Hz, 3H), 7.29 (d, J = 6.4 Hz,
13
1H), 7.21 (d, J = 7.9 Hz, 1H). C NMR (100
MHz, CDCl3+DMSO) δ 155.5, 145.7, 134.7,
134.5, 132.9, 132.6, 131.7, 131.3, 131.1, 130.7,
130.5, 129.9, 128.2, 126.1, 124.8, 123.1, 123.0,
122.4, 116.6. HRMS (Orbitrap ESI): Exact mass
calcd for C20H14O3N2ClS[M+H]+: 397.0427.
found: 397.0439.
11-Hydroxy-11-(4-methoxyphenyl)-11H-benzo
[5,6][1,2,4]thiadiazino[3,4-a]isoindole-5,5-
dioxide (3z).
(0.068 g, 45% yield) White solid. mp:259-261 oC.
IR (neat)  3423.1, 2987.3, 1648.0, 1462.8,
1385.2, 1289.1, 1165.0, 996.0, 824.2, 764.2, 629.8,
544.6 cm-1.1H NMR (400 MHz, DMSO) δ 8.43 (s,
1H), 8.00 (d, J = 7.5 Hz, 1H), 7.94 (d, J = 7.8 Hz,
1H), 7.73 (t, J = 7.1 Hz, 1H), 7.65 (t, J = 7.4 Hz,
1H), 7.56 (t, J = 7.4 Hz, 1H), 7.47 - 7.37 (m, 3H),
11-Hydroxy-11-(p-tolyl)-11H-benzo[5,6][1,2,4]
thiadiazino[3,4-a]isoindole 5,5-dioxide (3x).
(0.098 g, 68% yield) White solid. mp: 239-241 oC.
IR (neat)  IR (neat)  3341.3, 2976.8, 1607.3,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901509
European Journal of Organic Chemistry
FULL PAPER
7.33 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), (0.045 g, 45% yield) White solid. mp: 238-240 oC.
3.72 (s, 3H). 13C NMR (100 MHz, DMSO) δ 1H NMR (400 MHz, DMSO) δ 9.33 (s, 1H), 8.47
160.0, 154.9, 148.9, 135.3, 135.2, 133.2, 133.1, (d, J = 7.9 Hz, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.82
131.0, 130.8, 130.5, 128.5, 127.9, 127.8, 126.8, - 7.76 (m, 2H), 7.75 - 7.68 (m, 2H), 7.60 (dt, J =
126.6, 124.9, 124.8, 123.9, 123.8, 123.5, 122.6, 6.4, 3.4 Hz, 3H), 7.43 - 7.38 (m, 1H), 7.32 - 7.23
13
118.2, 118.0, 116.8, 116.6, 115.1, 55.6. HRMS (m, 3H). C NMR (100 MHz, DMSO) δ 165.7,
(Orbitrap ESI): Exact mass calcd for 147.0, 136.7, 135.0, 134.6, 133.8, 133.5, 132.9,
C21H17O3N2S[M+H]+: 393.0909. found: 393.0907. 130.7, 129.2, 129.0, 128.7, 127.9, 127.2, 127.0,
126.1, 125.0, 124.6, 123.7, 123.2, 81.7. HRMS
(Orbitrap ESI): Exact mass calcd for
C20H15N2O3S[M+H]+: 363.0802 found: 363.0811.
11-(4-(tert-Butyl)phenyl)-11-hydroxy-11H-
benzo[5,6][1,2,4]thiadiazino[3,4-a]isoindole 5,5-
dioxide (3aa).
Acknowledgements
(0.067 g, 46% yield) White solid. mp:210-212 oC.
IR (neat)  3420.3, 2982.7, 1655.1, 1476.2,
1380.6, 1276.9, 1165.4, 989.6, 770.8, 632.0, 548.4.
cm-1. 1H NMR (400 MHz, DMSO) δ 8.47 (s, 1H),
8.00 (d, J = 7.5 Hz, 1H), 7.96 - 7.92 (m, 1H), 7.7 -
7.75 (m, 1H), 7.66 (t, J = 7.2 Hz, 1H), 7.59 - 7.54
(m, 1H), 7.47 - 7.38 (m, 5H), 7.34 (d, J = 8.4 Hz,
2H), 1.22 (s, 9H). 13C NMR (75 MHz, DMSO) δ
154.4, 151.3, 148.3, 135.2, 134.7, 132.6, 132.4,
130.4, 128.0, 126.1, 124.5, 124.3, 123.3, 123.0,
122.1, 117.6, 96.8, 34.3, 30.9. HRMS (Orbitrap
ESI): Exact mass calcd for C24H23O3N2S[M+H]+:
419.1436. found: 419.1429.
G.R and B.R, thanks UGC, New Delhi for the
award of fellowships, S.B thanks DST and AcSIR,
IICT/Pubs./2019/362.
Keywords: C–H activation · Palladium ·
Acylation ·Benzo[e][1,2,4]thiadiazine-1,1-dioxide.
Annulation · Aldehydes . Benzyl alcohol
References and Notes
[1] a) S. Khelili, N. Kihal, M. Yekhlef, P. d.
Tullio, P. Lebrun and B. Pirotte, Eur. J. Med.
Chem. 2012, 54, 873-878; b) P. de Tullio, A.
C. Servais, M. Fillet, F. Gillotin, F. Somers, P.
Chiap, P. Lebrun and B. Pirotte, J. Med.
Chem. 2011, 54, 8353-8361; c) P. Francotte,
E. Goffin, P. Fraikin, P. Lestage, J. C. van
Heugen, F. Gillotin, L. Danober, J. Y.
Thomas, P. Chiap, D. H. Caignard, B. Pirotte
and P. de Tullio, J. Med. Chem. 2010, 53,
1700-1711; d) B. Pirotte, P. d. Tullio, Q. A.
Nguyen, F. Somers, P. Fraikin, X. Florence, P.
Wahl, J. B. Hansen and P. Lebrun, J. Med.
Chem. 2010, 53, 147-154.
2,2,6,6-Tetramethylpiperidin-1-yl benzoate (7)
(0.098 g, 40% yield) White solid. mp: 86-88
oC.1H NMR (400 MHz, CDCl3) δ 8.10 - 8.06 (m,
2H), 7.60 - 7.54 (m, 1H), 7.49 - 7.44 (m, 2H), 1.84
- 1.72 (m, 2H), 1.72 - 1.62 (m, 2H), 1.62 - 1.59
(m, 1H), 1.49 - 1.44 (m, 1H), 1.28 (s, 6H), 1.12 (s,
6H). 13C NMR (125 MHz, CDCl3) δ 166.4, 132.8,
129.7, 129.6, 128.4, 60.4, 41.7, 39.1, 32.0, 20.9,
17.0.
[2] a) A. Tait, A. Luppi, S. Franchini, E. Preziosi,
C. Parenti, M. Buccioni, G. Marucci, A.
Leonardi, E. Poggessi and L. Brasili, Bioorg.
Med. Chem. Lett. 2005, 15, 1185-1188; b) J.
G. Topiliss and M. D. Yudis, J. Med. Chem.
(2-(1,1-Dioxido-2H-benzo[e][1,2,4]thiadiazin-3-
yl)phenyl)(phenyl)methanone. (9)
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901509
European Journal of Organic Chemistry
FULL PAPER
1972, 15, 391-394; M. Dibella, M. Rinaldi, U.
Fabio and G. Manicard, Farmaco, 1973, 28,
777-783.
Wu and P. L. Wu, J. Nat. Prod. 2008, 71,
1275-1279.
[9] a) S. Vaidya and N. Argade, Indian J. Chem. -
Section B, 2017, 56, 527-530; b) M. Ahire, M.
D. Pol, D. S. Kavale, R. G. Gonnade and S. B.
Mhaske, Org. Biomol. Chem. 2019, 17, 7135-
7139; c) S. K. Ghosh and R. Nagarajan, RSC
Adv. 2014, 4, 63147-63149; d) U. A.
Kshirsagar, Org. Biomol. Chem. 2015, 13,
9336-9352; e) M. Ramanathan and S. T. Liu,
J. Org. Chem. 2018, 83, 14138-14145.
[3] P. Zhan, X. Y. Liu and E. De Clercq, Curr.
Med. Chem., 2008, 15, 1529.
[4] a) R. Mannhold, Med. Res. Rev. 2004, 24, 213-
266; b) P. Tullio, B. Becker, S. Boverie, M.
Dabrowski, P. Wahl, M. H. Antoine, F.
Somers, S. Sebille, R. Ouedraogo, J. B.
Hansen, P. Lebrun and B. Pirotte, J. Med.
Chem. 2003, 46, 3342-3353; c) S. Boverie, M.
H. Antoine, F. Somers, B. Becker, S. Sebille,
R. Ouedraogo, S. Counerotte, B. Pirotte, P.
Lebrun and P. d. Tullio, J. Med. Chem. 2005,
48, 3492-3503; d) P. d. Tullio, S. Boverie, B.
Becker, M. H. Antoine, Q. A. Nguyen, P.
Francotte, S. Counerotte, S. Sebille, B. Pirotte
and P. Lebrun, J. Med. Chem. 2005, 48, 4990-
5000; e) S. Lachenicht, A. Fischer, C.
Schmidt, M. Winkler, A. Rood, H. Lemoine
and M. Braun, ChemMedChem. 2009, 4, 1850-
1858.
[10] a) J. W. Delord, T. Drçge, F. Liu, F. Glorius,
Chem. Soc. Rev. 2011, 40, 4740-4761; b) C.
Pan, X. Jia, J. Cheng, Synthesis. 2012, 44,
677-685; c) T. S. Mei, L. Kou, S. Ma, K. M.
Engle, J. Q. Yu, Synthesis. 2012, 44, 1778-
1791; d) S. Messaoudi, J. D. Brion, M. Alami,
Eur. J. Org. Chem. 2010, 34, 6495-6516; e) C.
Liu, H. Zhang, W. Shi, A. Lei, Chem. Rev.
2011, 111, 1780-1824; f) T. W. Lyons, M. S.
Sanford, Chem. Rev. 2010, 110, 1147-1169; g)
O. Daugulis, H. Q. Do, D. Shabashov, Acc.
Chem. Res. 2009, 42, 1074-1086; h) X. Chen,
K. M. Engle, D. H. Wang, J. Q. Yu, Angew.
Chem. Int. Ed. 2009, 121, 5196-5217; i) M.
Catellani, E. Motti, N. D. Ca, Acc. Chem. Res.
2008, 41, 1512-1522; j) T. S. Mei, L. Kou, S.
MA, K. M. Engle, J. Q. Yu, Synthesis 2012,
44, 1778-1791; g) S. R. Neufeldt, M. S.
Sanford, Acc. Chem. Res. 2012, 45, 936-946.
[11] a) R. H. Crabtree, Chem. Rev. 1985, 85, 245-
269; b) A. D. Ryabov, Chem. Rev. 1990, 90,
403-424; c) A. E. Shilov, G. B. Shulpin,
Chem. Rev. 1997, 97, 2879-2932; d) S. V. Ley,
A. W. Thomas, Angew. Chem. Int. Ed. 2003,
42, 5400-5449; e) D. Ma, Q. Cai, Acc. Chem.
Res. 2008, 41, 1450-1460; f) A. R Muci, S. L.
Buchwald, Top. Curr. Chem. 2002, 219, 131-
209; g) J. F. Hartwig, Acc. Chem. Res. 2008,
41, 1534-1544; h) J. P. Wolfe, S. Wagaw, J.
Marcoux, S. L. Buchwald, Acc. Chem. Res.
1998, 31, 805-818; i) D. S. Surry, S. L.
Buchwald, Angew. Chem. Int. Ed. 2008, 47,
[5] T. V. P. Bliss and G. L. Collingridge, Nature.
1993, 31, 36-39.
[6] G. Wang, Y. He, J. Sun, D. Das, M. Hu, J.
Huang, D. Ruhrmund, L. Hooi, S. Misialek, P.
T. R. Rajagopalan, A. Stoycheva, B. O.
Buckman, K. Kossen, S. D. Seiwert and L.
Beigelman, Bioorg. Med. Chem. Lett. 2009,
19, 4476-4479.
[7] a) J. Drews, Science. 2000, 287, 1960-1964; b)
A. Scozzafava, T. Owa, A. Mastrolorenzo, C.
T. Supuran, Curr. Med. Chem. 2003, 10, 925-
953; c) A. Kalgutkar, R. Jones, A. Sawant, In
Metabolism Pharmacokinetics and Toxicity of
Functional groups; RSC Drug Discovery; D.
A. Smith, Ed.; RSC: Cambridge, U.K. 2010;
[8] a) A. Kamal, B. V. S. Reddy, B. Sridevi, A.
Ravikumar, A. Venkateswarlu, G. Sravanthi, J.
P. Sridevi, P. Yogeeswari and D. Sriram,
Bioorganic Med. Chem. Lett. 2015, 25, 3867-
3872; (b) R. Kaur, S. K. Manjal, R. K. Rawal
and K. Kumar, Bioorganic Med. Chem., 2017,
25, 4533-4552; c) C. W. Jao, W. C. Lin, Y. T.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901509
European Journal of Organic Chemistry
FULL PAPER
6338-6361; j) D. S. Surry, S. L. Buchwald,
Chem. Sci. 2011, 2, 27-50.
[18] F. Szabó, J. Daru, D. Simkó, T. Z. Nagy, A.
Stirling, Z. Novák, Adv. Synth. Catal. 2013,
355, 685-691.
[12] a) X. Jia, S. Zhang, W. Wang, F. Luo, J.
Cheng, Org. Lett. 2009, 11, 3120-3123; b) O.
Basle, J. Bidange, Q. Shuai, C. J. Li, Adv.
Synth. Catal. 2010, 352, 1145-1149; c) F.
Xiao, Q. Shuai, F. Zhao, O. Basle, G. Deng, C.
J. Li, Org. Lett. 2011, 13, 1614-1647; d) Y.
Wu, B. Li, F. Mao, X. Li, F. Y. Kwong, Org.
Lett. 2011, 13, 3258-3261.
[19] CCDC 1954833 contains supplementary
Crystallographic data for the structure 3f.
These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or
from the Cambridge Crystallographic Data
Centre (CCDC), 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44(0) 1223 336 033;
email: deposit@ccdc.cam.ac.uk].
[13] a)
G.
Dyker,
Handbook
of
CH
Transformations: Application in Organic
Synthesis; Wiley-VCH: Weinheim, 2005. b) J.
Q. Yu, Z. J. Shi. CH Activation; Springer:
Berlin, Germany, 2010.
[14] a) B. V. S. Reddy, C. R. Reddy, M. R. Reddy,
S. Yarlagadda, B. Sridhar, Org. Lett. 2015, 17,
3730-3733; b) B. V. S. Reddy, G.
Narasimhulu, N. Umadevi, J. S. Yadav,
Synlett. 2012, 23, 1364-1370; c) B. V. S.
Reddy, G. Revathi, A. S. Reddy, J. S. Yadav,
Tetrahedron Lett. 2011, 52, 5926-5929; d) B.
V. S. Reddy, N. Umadevi, G. Narasimhulu, J.
S. Yadav, Tetrahedron Lett. 2012, 53, 6091-
6093; e) B. V. S. Reddy, G. Revathi, A. S.
Reddy, J. S. Yadav, Synlett. 2011, 16, 2374-
2378.
[15] a) S. A. Girard, T. Knauber and C. J. Li,
Angew. Chem. Int. Ed. 2014, 53, 74-100;
b) C. Li, Acc Chem Res 2009, 42, 335-344.
[16] a) M. Dabiri, N. F. Lehi, S. K. Movahed, and
H. R. Khavasi, Eur. J. Org. Chem. 2019,
2933-2940; b) P. Duan, Y. Yang, R. Ben, Y.
Yan, L. Dai, M. Hong, Y. D. Wu, D. Wang, X.
Zhang, J. Zhao, Chem. Sci. 2014, 5, 1574-
1578; c) C. W. Chan, Z. Zhou, A. S. C. Chan,
W. Y. Yu, Org. Lett. 2010, 12, 3926-3929.
[17] a) X. Wang, J. Li, N. Zhao and X. Wan, Org.
Lett. 2011, 13, 709-711; b) L. Long, Y. H.
Wang, J. X. Zhuo, Z. C. Tu, R. Wu, M. Yan,
Q. Liu and G. Lu, Eur. J. Med. Chem. 2018,
157, 1361-1375.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901509
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
Layout 1:
((Key Topic: palladium catalyzed cross-
dehydrogenative coupling))
G. Ravi Kumar,a Swarnayu Banik,a
Boora Ramesh,a B Sridhar,b B. V.
Subba Reddya
A novel strategy has been developed for the
synthesis
benzothiadiazinedioxide
through a sequential cross-dehydrogenative
coupling (CDC) and intramolecular
of
hydroxyisoindolo[1,2-b]
derivatives
…….. Page No. – Page No.
annulation. This method works not only
with aryl aldehydes and alcohols but also
with toluene to produce annulated products.
Oxidative Annulation of 3-Aryl-2H-
benzo[e][1,2,4]thiadiazine-1,1-dioxides with
Aryl Aldehydes: An Easy Access to
Hydroxyisoindolo[1,2-b]
benzothiadiazinedioxide Scaffolds
Keywords: C–H activation · Palladium ·
Acylation
·Benzo[e][1,2,4]thiadiazine-1,1-
.
dioxide. Annulation · Aldehydes Benzyl
alcohol
This article is protected by copyright. All rights reserved.