Synthesis of Dibenzosultams by "transition-Metal-Free" Photoinduced Intramolecular Arylation of N-Aryl-2-halobenzenesulfonamides

Article abstract of DOI:10.1021/acs.joc.6b00330

A new and general synthetic route to prepare dibenzosultams is here reported. This approach involves the synthesis of N-aryl-2-halobenzenesulfonamides (3), followed by intramolecular C-C photoinduced arylation under soft conditions without the use of "Tra

Full text of DOI:10.1021/acs.joc.6b00330

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Article
Synthesis of Dibenzosultams by “Transition-Metal Free” Photoinduced
Intramolecular Arylation of N-aryl-2-halobenzenesulfonamides
Walter Damian Guerra, Roberto Arturo Rossi, Adriana Beatriz Pierini, and Silvia Maricel Barolo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00330 • Publication Date (Web): 11 May 2016
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Synthesis of Dibenzosultams by “Transition-Metal Free” Photoinduced
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Intramolecular Arylation of N-aryl-2-halobenzenesulfonamides
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Walter D. Guerra, Roberto A. Rossi, Adriana B. Pierini* and Silvia M. Barolo*
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INFIQC, Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad
Nacional de Córdoba, Ciudad Universitaria, 5000 Córdoba, Argentina.
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
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CORRESPONDING AUTHOR FOOTNOTE (Phone number: (+54) 351-5353867, e-mail:
adriana@fcq.unc.edu.ar and sbarolo@fcq.unc.edu.ar
TITLE RUNNING HEAD: Synthesis of Dibenzosultams by Photoinduced Arylation
X
O
O
O
O
S
S
NH
NH
R1
R1
hν (LED)
t-BuOK
- X-
R2
R2
X= Cl, Br
17 Examples
up to 98% yield
ABSTRACT: A new and general synthetic route to prepare dibenzosultams is here reported. This
approach involves the synthesis of N-aryl-2-halobenzenesulfonamides (3) followed by
intramolecular C-C photoinduced arylation under soft conditions without the use of “Transition-
Metal”. The photostimulated reactions exhibit very good tolerance to different substituent groups
with good to excellent isolated yields (42 – 98%) of products. Moreover, it is shown that LED
(λ=395 nm) is an efficient light energy source to initiate efficiently the reactions. Theoretical
inspection about the mechanism was made to probe the involvement of the radical-anion SRN1
process.
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Introduction
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Sulfonamides and their derivatives are known as “sulfa drugs” and are widely used in
medicine.1 This group is an important organic structure within the drug discovery field.
Compounds with benzothiazine dioxide or benzosultam core exhibit versatile inhibitory properties
against a diverse array of enzymes such as COX-2,2 HIV integrase3 or Calpain-1.4 Also,
benzothiazine dioxide derivatives have been found to play an active role in nuclear factor-κappaB
(NFκB) down regulation.5
Due to the remarkable importance of benzosultams across medicinal chemistry many
synthetic approaches have been developed. 6 For dibenzosultams the synthetic approaches are less
known and are represented in Scheme 1. These protocols include intramolecular radical
cyclization7 or palladium-catalyzed intramolecular arylation8 of 2-bromo-N-alkyl-N-
arylbenzenesulfonamides (A), intramolecular oxidative amination of 2-arylbenzenesulfonamides
under “Transition-Metal Free” condition (B),9 double C(sp2)-H palladium-catalyzed intramolecular
oxidative coupling of N-arylbenzenesulfonamides (C)10 or 1,6 radical addition of N-(2-iodophenyl)
-N-methyl-benzenesulfonamide (D)11 (Scheme 1).
R
NH
O
O
Br
S
S
N
R
O
O
Pd or Radical
cyclization
A
B
O
O
PhI(OAc)2
S
R
N
Radical
1,6 addition
D
C
O
O
O
O
S
Pd - Double
C-H activation
S
N
N
R
I
H
R
Scheme 1. Strategies to synthesize dibenzosultams
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Radical nucleophilic substitution involving electron-transfer (ET) steps (SRN1)12 is a cyclic
process with radicals and radical anions as intermediates. In the SRN1 reactions carbanions and
anions derived from heteroatoms can be used as nucleophiles to form new C-C or C-heteroatom
bonds. This mechanism has proven to be an important synthetic strategy in heterocycle chemistry.
The intramolecular SRN1 has been successfully developed to obtain different annulated
systems bearing between 5 to 9 members with broad substitution tolerance.13 In this context, the
reaction of 2-iodobenzensulfonamide with aliphatic ketone enolates to afford 3-subtituted
benzothiazines has been reported.14 However, the reactivity of N-aryl-2-halobenzenesulfonamides
under SRN1 conditions to obtain dibenzosultamas has not been studied yet.
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It is important to notice that despite useful synthetic protocols have been investigated to
prepare dibenzosultams, still several limitations remain like the use of “Transition-Metal” (Pd),
activated substrates like iodide or bromide aromatic precursors, harsh conditions or time-
consuming reactions which need to be overcome.
In this context, we developed a novel protocol to synthesize dibenzosultams by
intramolecular C-C photoinduced arylation of 2-halo-arylsulfonamides. This protocol involves
chloride precursors easily prepared from commercial sources. Besides, the heterocycle could be
obtained with a free N-H group that is easily functionalized. Furthermore, the utility of this method
is fully demonstrated by exploring the scope toward a broad family of dibenzosultams and greener
methodologies. This is a new contribution within our efforts devoted to the synthesis of
heterocyclic compounds by “Transition-Metal-free” intramolecular photoinduced arylation
reactions.13a
Results and Discussion
Initially, we investigated different alternative to obtain N-aryl-2-halobenzenesulfonamides 3
(Scheme 2). The first strategy involves
copper-catalyzed N-arylation of 2-
chlorobenzenesulfonamide (1) with aryl halides 215 (Method A). Under our optimized conditions,16
the reaction of 1 with iodobenzene (2a) gave the coupling product N-phenyl-2-
chlorobenzenesulfonamide (3a, Ar=Ph, X=Cl) in 78% isolated yield. This protocol was extended to
different aryl halides obtaining good to very good isolated yields (50-84%) of the corresponding N-
aryl-2-chloroarylsulfonamides (3b-f, m-n X=Cl) (Scheme 2).
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O O
S
Method A
R
´
X
ArX´ (2) =
NH2
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9
Z
Cl
X´=I, Br
R=H, 4-CH3, 4-OCH3,
3,5-di-OCH3, 4-Ph, 4-CF3
Z=CH, N
1
CuI/DMEDA
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O O
S
NH
Ar
R1
X
3
O O
Pyridine, DCM
S
NH2
Cl
Z
ArNH2 (5) =
R1
X
R2
4
Method B
Z=CH, N
X=Br, Cl
R2=H, 4-CO2Et, 4-F,
4-CN, 4-CH3 ,2-Ph, 2-
(1-pyrrolyl)
R1=H, F, CF3
3a, R=H
3b, R=4-CH3
3c, R=4-OCH3
3d, R=3,5-(OCH3)2 (35%)
3e, R=4-Ph
3f, R=4-CF3
3g,R=4-C(O)OC2H5 (89%)
3h,R=4-CN
3i, R=4-F
3j, R=2-Ph
3k, R=2-(1-pyrrolyl) (51%)
(78%)
(62%)
(50%)
O O
R
S
N
(59%)
(51%)
H
Cl
(57%)
(93%)
(75%)
O O
Z
S
NH
Cl
3l, Z=CH, 1-naphtyl (77%)
3m, Z=CH, 2-naphtyl (78%)
3n, Z=N, 3-quinolyl
R2
O O
S
(61%)
N
Z
H
R1
X
3o, X=Cl, Z=CH, R1=F, R2=H
3p, X=Cl, Z=CH, R1=F, R2=CH3 (91%)
3q, X=Br, Z=CH, R1=CF3, R2=CH3 (85%)
(97%)
3r, X=Cl, Z=N, R1=H, R2=H
(30%)
Scheme 2. Synthesis of N-aryl-2-haloarylsulfonamides
The other strategy to afford the corresponding sulfonamides 3 involves a known reaction
between substituted benzenesulfonyl chlorides 4 and different arylamines 5 with pyridine in DCM
at room temperature (Method B).17 With this methodology we synthesized sulfonamides 3g-l, o-r
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with a range of isolated yields from moderate to excellent depending on the corresponding amine
(30 – 97%) (Scheme 2).18
6
N-phenyl-2-chlorobenzenesulfonamide (3a) was chosen as model substrate to attempt the
intramolecular arylation using t-BuOK in DMSO. In this basic medium the initially neutral 3a
(λmax=279 and 281 nm) undergoes an acid-base reaction to give the corresponding anion 3a-
(continuum absorption spectrum until 370 nm, see SI).19
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After 3 hours of irradiation (HPI-T metal iodide lamps (400 W)), the reaction of 3a in
DMSO with 2 equiv of t-BuOK afforded the desired product, 6H-dibenzo[c,e][1,2]thiazine 5,5-
dioxide (6a) in 27% yield, together with 45% of the starting material (entry 1, Table 1).
Encouraged by this result, various combinations of irradiation times and equivalents of base were
screened (entries 2-5) finding that 3 equivalents of t-BuOK and 3 hours of irradiation gave the best
result (97% (86% isolated yield)).20
The other solvents tested were NH3(liq), CH3CN and THF. Similar results were obtained in
liquid ammonia (-33 ºC) (entry 6, Table 1), in CH3CN the reaction gave a very good yield (72 %)
and THF proved to be ineffective for the reaction (entries 7-8, respectively, Table 1).
Table 1. Optimization of the Reaction Conditions a
O
O
O O
S
S
NH
N
H
Base,
Solvent, hν, t
Cl
3a
6a
Conditions
Solvent/ Base
(Equiv)/ hυ, t (h)
Yields (%)b
Entry
3ac
6a
DMSO/ t-BuOK (2)/
hυ, 3h
1
2
3
4
5
45
27
DMSO/ t-BuOK (2)/
hυ, 4h
27
23
13
0
53
57
75
DMSO/ t-BuOK (2)/
hυ, 6h
DMSO/ t-BuOK (3)/
hυ, 2h
DMSO/ t-BuOK (3)/
hυ, 3h
97
(86)
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NH3/ t-BuOK (3)/
95
(84)
6d
7e
4
hυ, 3h
THF/ t-BuOK (3)/
75
15
72
75
64
92
0
hυ, 3 h
CH3CN/ t-BuOK (3)/
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8 e
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hυ, 3 h
DMSO/ NaH (3)/
9
0
hυ, 3 h
DMSO/ t-BuOK (3)/
10
11 f
12
13 g
14 h
21
hυ, 1.5 h
DMSO/ t-BuOK (3)/
0
hυ, 1.5 h
DMSO/ t-BuOK (3)/
91
dark, 3h
DMSO/ t-BuOK (3)/
97
0
hυ, 1.5 h
DMSO/ t-BuOK (3)/
79
13
hυ, 1.5 h
aThe reactions were run in 5 mL of solvent with 0.03 M of 3a and 0.09M of t-BuOK and irradiated for the specific
time. Irradiation was conducted in a photochemical reactor equipped with two Philips metal iodide HPI-T 400 W lamps
of (air and water refrigerated). bYields were determined by CG (internal standard method). Isolated yields are given in
parentheses. cSubstrate 3a recovered. The reaction of liquid ammonia (NH3(liq)) was run in 200 ml (-33ºC), with 0.75
d
e
f
mM of 3a and 2.25 mM of t-BuOK. The reactions in THF or CH3CN were run in 5 mL. 1 equiv of pinacolone was
added with respect to the substrate. g0.3 equiv of m-DNB was added with respect to the substrate. h1 equiv of TEMPO
was added with respect to the substrate.
When the reaction was carried out without t-BuOK (NaH as base) it proceeded completely
which indicates that anion 3a- could initiate the reaction (entry 9, Table 1). Also, the reaction time
could be shortened under entrainment conditions such as in the presence of pinacolone enolate ions
(entry 11 versus entry 10, Table 1).
Mechanistically it is important to notice that there was no reaction under dark conditions
(entry 12, Table 1), the photostimulated reaction was completely inhibited by m-dinitrobenzene (m-
DNB) (entry 13 versus entry 10, Table 1)12c and equimolecular quantities of TEMPO could
partially inhibit the reaction (entry 14 versus entry 10, Table 1). These results exclude a benzyne
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and other polar mechanisms and evidence an Electron Transfer (ET) process with formation of
radicals. We propose a radical-anion type mechanism (SRN1) to be in play.
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To extend the scope of the cyclization reaction, sulfonamides previously synthesized were
submitted to the t-BuOK/DMSO/hν system, the results being shown in Scheme 3. Modifying the
R-substituent in the NH-phenyl moiety of the sulfonamides, with EWG or EDG, 3b-k, led to full
conversion of the substrate after 5h of irradiation providing products 6b-k in good to excellent
isolated yields (54 – 98%). This reveals broad substitution tolerance (CH3, OCH3, di-OCH3, CF3, F,
CN, C(O)OC2H5, Ph) and low steric hindrance (tolerate o-substitution, 6j-k).
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The strategy was extended successfully to obtain fused dibensultams after longer irradiation
times. 5H-Benzo[e]naphtho[1,2-c][1,2]thiazine 6,6-dioxide (6n) and 6H-benzo[5,6][1,2]thiazino-
[3,4-c]quinoline 5,5-dioxide (6l) were obtained after 6h with 97% and 69% yields, respectively.
6H-Benzo[e]naphtho[2,1-c][1,2]thiazine 5,5-dioxide (6m) was obtained in good yield (51%) after 8
h of irradiation without full conversion of the substrate.
The effect of modifying the R-substituent in the sulfonyl-phenyl system was also examined.
Substrates with a EWG like F or CF3 (3o-q) were prepared. In these cases the reaction underwent
partially without full conversion after 8h to afford the corresponding dibenzosultams 6o-q with
moderate yields (∼45%).
Finally, we attempted the reaction of 2-chloro-N-(pyridin-2-yl)benzenesulfonamide (3r) as
substrate, with a pyridine system, but it was unreactive under our experimental conditions.
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O
O
O O
S
S
R2
NH
t-BuOK, DMSO
N
H
hν , -Cl-
R1
R1
Cl
R2
3
6
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O
O
O
O
O
O
S
S
S
NH
NH
NH
6c
6b
H3CO
OCH3
98% (A)
77% (A)
65% (B)
CH3
6d
OCH3
O
65% (A)
O
O
O
O
O
S
S
S
NH
NH
NH
6g
6e
6f
79% (A)
94% (B)
54% (A)
Ph
79% (A)
CF3
O
OC2H5
O
O
S
O
O
O
O
S
S
NH
NH
NH
Ph
6h
6i
6j
91% (B)
81% (A)
83% (A)
CN
F
O
O
O
S
O
O
S
O
S
NH
NH
NH
N
6m
6k
6l
51%b (A)
69%a (B)
78% (A)
O
O
O
O
S
S
NH
NH
F
6n
97%c
6o
44%b(A)
N
O
O
O
O
S
S
NH
NH
F3C
F
6q
6p
43%b (A)
X=Br
42%b (A)
CH3
CH3
A=Conventional “work-up” and purification. B= Direct filtration and recrystallization.
aReaction time=6h. Reaction time= 8h. cAcid extraction as “work-up” without further purification.
b
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Scheme 3. Scope of the Intramolecular Photoinduced Arylation to synthesize 6H-
dibenzothiazines 5,5-dioxide 6.
6
7
8
9
In order to accomplish the goal of sustainable chemistry we changed the conventional
“workup” and purification processes to direct filtration and recrystallization which leaded to a
reduction in wastes and in the use of solvents. With this methodology we synthesized
dibenzosultams 6c,e,h,l, with a range of isolated yields from moderate to excellent (Scheme 3).
To extend our study, the irradiation source was changed to LED light. Chemical
transformations via visible-LED light is one of the emerging strategies to achieve the increasing
demand for more sustainable chemical processes due to their ultra-efficient lighting and low-cost.21
The results under visible LED light are summarized in Table 2. Employing a Violet LED light
(λmax=395 nm) the reaction undergo full conversion obtaining 82% yields of 6a (entry 1, Table
2).22 For other studied substrates 3b,i,j,l,m (entries 2-6, Table 2) the yields obtained were
comparable to the classical irradiation source under the same irradiation time. It is interesting to
notice that employing this source of irradiation, substrates like 3m,o,p achieved full conversion
with very good yields of dibenzosultams 6m,o,p (76-94 %), showing the efficiency of LED lights
(compare Scheme 3 with entries 6-8, Table 2).
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Table 2. Use of Visible-LED lights in the Intramolecular photoinduced arylationa
O
O
O
S
O
NH
S
t-BuOK, DMSO
HN
R1
hν
(LED(λ=395 nm)), t
R1
X
R2
R2
3
6
Products
Yields
(%)c
Entry 3 (%) b t (h)
6
1
2
3
4
5
6
3a (---)
3b (---)
3i (23)
3j (15)
3l (12)
3m (8)
3h 6a
5h 6b
5h 6i
5h 6j
6h 6l
8h 6m
82
84
71
80
84
76
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3o (---)
3p (10)
5h 6o
8h 6p
94
87
7
8
9
aThe reactions were run in 5 mL of DMSO with 3 (0.03 M) and 0.09M of t-BuOK. Irradiation was performed for the
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b
c
specific time with Violet LED (LEDs (λ = 395 ± 15 nm), 3 W, 700 mA). Substrate 3 recovered. Yields were
determined by CG (internal standard method).
To support our experimental evidences of a radical-anion type mechanism (SRN1), we
performed a computational study of key mechanistic intermediates and reactive pathways with
anion 3a- as model. The results are summarized in Scheme 4. The computational data were
obtained with M06-2X DFT functional,23 the 6-311+G* basis set and the PCM continuum solvent
model.24
Initially, we propose that anion 3a- is formed in presence of excess t-BuO-. The most stable
conformer of 3a-, presented in Scheme 4, could form radical dianion (3a-)•- by an ET process. This
ET could be achieved from different sources (for example t-BuO-).25 In our case the ET from the
base to the excited anion [3a-]* (S1 state of 3a- evaluated with TD-DFT) is exothermic and could be
responsible for the initiation pathway. 26
The (3a-)•- formed bears the unpaired spin density at the π system of the aryl-Cl moiety
(Scheme 4). This intermediate could dissociate with a very low activation energy (0.4 kcal/mol) to
afford the distonic radical anion 3a•- through a transition state characterized by a C-Cl bending
transition vector. As known, a σ(C-Cl)-π overlap is required for this π-σ intramolecular
dissociative ET to take place.27
After C-Cl fragmentation, the distonic radical anion intermediate 3a•-, represented in
•-
Scheme 4, could afford the cyclic radical anion 6a1 . In this pathway the C-C coupling is achieved
with an activation energy (Ea) of 9.15 kcal/mol. Also, it is important to emphasize that cyclic
radical anion 6a1•- is 24 kcal/mol more stable than the distonic radical anion 3a•- and this difference
could be the driving force of the reaction.
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•-
Finally, 6a1 and (3a-)•- could be formed after an ET from 6a1 to 3a-. The latter ET
propagates the reaction cycle. Under the basic media 6a1 generate 6a- and upon reaction work up,
product 6a was formed.
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Scheme 4. Proposed Mechanism. The spin density is shown for (3a-)-. and 3a-. (isodensity =
0.004).
Conclusions
To conclude, we described an efficient route to synthesize dibenzosultams under “Transition-
Metal-Free” conditions starting from N-aryl-2-halobenzenesulfonamides easily prepared by two
different procedures. The cyclization reactions are promoted by t-BuOK and occur in DMSO at
room temperature. Many functional groups are tolerated, giving access to a wide range of
synthetically relevant heterocycles. Other solvents such as NH3 and CH3CN seem promising to
perform the reactions. We also explored the use of visible LED light improving some yields of
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challenging substrates. Finally, DFT calculations were performed to inspect the energetic and thus
confirm our proposal of the radical-anion type SRN1 mechanism.
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Experimental Section
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Computational Procedure. All calculations were performed with the Gaussian09 program. The
conformers obtained were refined with complete geometry optimization within the M06-2X DFT
functional and the 6-311+G* basis set. The geometries thus found were used as starting points for
the evaluation of the reaction profiles by using the distinguished reaction coordinate scan. The
effect of DMSO as solvent was evaluated through the Tomasi’s Polarized Continuum Model
(PCM) as implemented in Gaussian09. The inclusion of the solvent in the calculations is a requisite
to evaluate valence radical anions. The characterization of stationary points was done by Hessian
matrix calculations. The energy informed for TSs, anions and radical anions includes zero-point
corrections. The vertical excited singlet stated (S1) of anion 3a was calculated with TD-DTF the
M06-2X functional and the 6-311+G* basis set. The energy of S1 was calculated including the
PCM contribution under the StateSpecific approach.
General Considerations. Column chromatography was carried out on silica gel. Melting points
were determined using a standard melting point instrument and are uncorrected. Gas
chromatographic analyses were performed with a flame-ionization detector, on 30 m capillary
column of a 0.32 mm x 0.25 μm film thickness, with a 5% phenylpolysiloxane phase. GC-MS
analyses were performed employing a 25 m x 0.2 mm x 0.33 μm with a 5% phenylpolysiloxane
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phase column. H NMR spectra and C NMR spectra were recorded on a 400.16 MHz in CDCl3,
Dimethyl sulfoxide-d6 (CD3SOCD3) or acetone-d6 (CD3COCD3) as solvent with TMS as internal
standard. Coupling constants are given in Hz and chemical shifts are reported in δ values in ppm.
Data are reported as followed: chemical shift, multiplicity (s = singlet, s br = broad singlet, d =
doublet, t = triplet, dd = double doublet, dt = double triplet, ddd = double double doublet, m =
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multiplet), coupling constants (Hz), and integration. Copies of H NMR and C NMR spectra are
provided.
All new products were further characterized by HRMS. HRMS analyses were carried out
using a TOF-MS instrument with an ESI source.
Irradiation was conducted in a reactor equipped with two Philips HPI-T 400 W lamps of
metallic iodide (cooled with water) or with LED lights performing at 3W of potency and 700 mV
of current.
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DMSO as solvent was stored under molecular sieves (4 Å). Anhydrous ethyl ether was stored
over Na wire. All solvents were analytical grade. Silica gel (0.063−0.200 mm) was used in column
chromatography. Unless otherwise stated, all reagents were purchased from commercial suppliers
and used without further purification.
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Representative Procedure for synthesis of 2-halo-N-phenylbenzenesulfonamides
Method A: The Cross-coupling copper-catalyzed of 2-chlorobenzenesulfonamide (1) with aryl
halides was the procedure to synthesize sulfonamides 3a-f/m-n. A Schlenk tube equipped with a
nitrogen inlet and magnetic stirred was charged with 1 (115.0 mg, 0.6 mmol), copper (I) iodide
(11.4 mg, 0.06 mmol), aryl halide (iodobenzene, 2a) (244.4 mg, 1.2 mmol), K2CO3 (381.3 mg, 1.8
mmol), acetonitrile (CH3CN) (4 mL), and N,N-dimethylethane-1,2-diamine (DMEDA) (21.6 mg,
0.3 mmol). The tube was then heated to 90ºC for 18 h. The reaction mixture was then cooled to
room temperature, 2M HCl (10 mL) was added slowly, followed by EtOAc extraction (15 mL x 3).
The organic layers were combined, dried over Na2SO4, and filtered. After removal of volatile
components from the filtrate, the resulting crude product was purified by column chromatography
on silica gel eluting with pentane/EtOAc (100:0 → 80:20 %). White solid of 2-Chloro-N-
phenylbenzenesulfonamide (3a) was isolated in 78% yield (125.9 mg, 0.468 mmol), m.p. 145-
147°C. 1H NMR (400.16 MHz, CDCl3) δH: 8.00 (dd, J = 7.8, 1.4, 1H), 7.49 (dd, J = 8.0, 1.6, 1H),
7.45 (td, J = 7.6, 1.6, 1H), 7.34-7.30 (m, 1H), 7.23-7.19 (m, 2H), 7.13-7.06 (m, 4H). 13C NMR
(100.62 MHz, CDCl3) δC: 136.1, 135.7, 134.1, 132.0, 131.5, 131.3, 129.3, 127.2, 125.7, 121.6. GC-
MS (EI) m/z 267 (M+, 21), 168 (48), 167 (11), 111 (22), 93 (10), 92 (100), 75 (24), 65 (56), 64
(8).28
2-Chloro-N-(p-tolyl)benzenesulfonamide (3b). The product was purified by column
chromatography on silica gel eluting with pentane/ EtOAc (100:0 → 85:15 %). White solid was
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isolated in 62% yield (104.8 mg, 0.372 mmol), m.p. 151-152 °C. H NMR (400.16 MHz, CDCl3)
δH: 7.96 (dd, J = 7.8, 1.4, 1H), 7.49 (dd, J = 7.8, 1.4, 1H), 7.44 (td, J = 7.7, 1.6, 1H), 7.30 (td, J =
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7.6, 1.2, 1H), 7.02 (br.s, 1H), 7.00 (br.s, 4H), 2.22 (s, 3H); C NMR (100.62 MHz, CDCl3) δC:
136.2, 135.8, 133.9, 132.9, 132.0, 131.5, 131.3, 129.9, 127.2, 122.3, 20.8. GC-MS (EI) m/z 281
(M+, 9), 111 (15), 107 (8), 106 (100), 79 (30), 78 (12), 77 (35), 75 (18), 51 (9). HRMS (TOF,
ESI+): calcd for C13H12ClNNaO2S (M+Na)+: 304.0170; Found: 304.0169.
2-Chloro-N-(4-methoxyphenyl)benzenesulfonamide (3c). The product was purified by column
chromatography on silica gel eluting with pentane/ EtOAc (100:0 → 85:15 %). Colorless crystal
was isolated in 50% yield (89.1 mg, 0.3 mmol), m.p. 134-135 °C. 1H NMR (400.16 MHz, CDCl3)
δH: 7.89 (dd, J = 7.8, 1.6, 1H), 7.52 (dd, J = 8.0, 1.2, 1H), 7.45 (td, J = 7.6, 1.6, 1H), 7.29 (td, J =
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7.6, 1.2, 1H), 7.06-7.02 (m, 2H), 6.95 (br.s, 1H), 6.74-6.7 (m, 2H), 3.71 (s, 3H). 13C NMR (100.62
MHz, CDCl3) δC: 158.1, 136.2, 133.9, 132.0, 131.4, 131.2, 128.1, 127.0, 125.2, 114.4, 55.3. GC-
MS (EI) m/z 327 (M+, 10), 263 (10), 229 (16), 228 (96), 213 (20), 197 (11), 152 (10), 126 (9), 125
(10), 111 (17). HRMS (TOF, ESI+): calcd for C13H12ClNNaO3S (M+Na)+: 320.0119; Found:
320.0106.
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2-Chloro-N-(3,5-di-methoxyphenyl)benzenesulfonamide (3d). The product was purified by column
chromatography on silica gel eluting with pentane/ EtOAc (100:0 → 70:30 %). Colorless crystal
was isolated in 35% yield (68.7 mg, 0.21 mmol), m.p. 164-165 °C. 1H NMR (400.16 MHz, CDCl3)
δH: 8.05 (dd, J = 7.8, 1, 1H), 7.51-7.44 (m, 2H), 7.37-7.33 (m, 1H), 7.01 (s, 1H), 6.29 (d, J = 2.4,
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2H), 6.16 (t, J = 2, 1H), 3.69 (s, 6H). C NMR (100.62 MHz, CDCl3) δC: 161.2, 136.1, 134.2,
132.1, 131.6, 131.4, 129.1, 127.2, 99.4, 97.6, 55.4. GC-MS (EI) m/z 327 (M+, 10), 263 (10), 229
(16), 228 (96), 213 (20), 197 (11), 152 (10), 126 (9), 125 (100), 111 (17). HRMS (TOF, ESI+):
calcd for C14H14ClNNaO4S (M+Na)+: 350.0224; Found: 350.0227.
N-([1,1'-Biphenyl]-4-yl)-2-chlorobenzenesulfonamide (3e). The product was purified by column
chromatography on silica gel eluting with pentane/ EtOAc (100:0 → 80:20 %). White solid was
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isolated in 59% yield (60.9 mg, 0.177 mmol), m.p. 139-141 °C. H NMR (400.16 MHz,
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CD3COCD3) δH: 9.42 (br.s, 1H), 8.14 (d, J = 8.0, 1H), 7.60-7.48 (m, 7H), 7.47-7.28 (m, 5H). C
NMR (100.62 MHz, CD3COCD3) δC: 139.8, 137.0, 136.9, 136.4, 134.3, 131.9, 131.7, 131.3, 128.7,
127.4, 127.3, 127.1, 126.4, 120.4. GC-MS (EI) m/z 343 (M+, 16), 169 (14), 168 (100), 166 (4), 141
(24), 139 (5), 115 (17), 111 (4), 75 (4). HRMS (TOF, ESI+): calcd for C18H14ClNNaO2S (M+Na)+:
366.0326; Found: 366.0329.
2-Chloro-N-(4-(trifluoromethyl)phenyl)benzenesulfonamide (3f). The product was purified by
column chromatography on silica gel eluting with pentane/ EtOAc (100:0 → 80:20 %). White solid
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was isolated in 51% yield (102.8 mg, 0.306 mmol), m.p. 209-211°C. H NMR (400.16 MHz,
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CDCl3) δH: 8.10-8.08 (m, 1H), 7.53-7.36 (m, 6H), 7.22 (d, J = 8.4, 2H). C NMR (100.62 MHz,
CDCl3) δC: 139.1, 135.8, 134.5, 132.0, 131.8, 131.4, 127.4, 127.2 (q, J = 33, 1C), 126.7 (q, J = 4.0,
1C), 123.8 (q, J = 273, 1C), 119.9. GC-MS (EI) m/z 335 (M+, 16), 236 (41), 177 (16), 175 (43),
160 (21), 140 (27), 114 (14), 113 (51), 111 (100), 75 (48), 63 (14), 50 (14). HRMS (TOF, ESI+):
calcd for C13H9ClF3NNaO2S (M+Na)+: 357.9887; Found: 357.9896.
2-Chloro-N-(naphthalen-2-yl)benzenesulfonamide (3m). The product was purified by column
chromatography on silica gel eluting with pentane/ EtOAc (100:0 → 70:30 %). White solid was
isolated in 78% yield (74.4 mg, 0.234 mmol), m.p. 187-189°C. 1H NMR (400.16 MHz, CDCl3) δH:
8.02 (dd, J = 8.0, 1.6, 1H), 7.73-7.68 (m, 3H), 7.57 (d, J = 2.0, 1H), 7.45-4.36 (m, 3H), 7.30-7.24
(m, 3H). 13C NMR (100.62 MHz, CDCl3) δC: 136.1, 134.1, 133.5, 133.2, 132.0, 131.5, 131.3,
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131.2, 129.4, 127.6, 127.5, 127.2, 126.7, 125.7, 120.9, 118.7. GC-MS (EI) m/z 319 (M++2, 5), 317
(M+, 13), 218 (25), 143 (7), 142 (64), 140 (5), 116 (10), 115 (100), 89 (6), 75 (6). HRMS (TOF,
ESI+): calcd for C16H12ClNNaO2S (M+Na)+: 340.0170; Found: 340.0164.
2-Chloro-N-(quinolin-3-yl)benzenesulfonamide (3n). The product was purified by column
chromatography on silica gel eluting with pentane/ EtOAc (100:0 → 50:50 %). Light yellow solid
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was isolated in 61% yield (116.6 mg, 0.366 mmol), m.p. 166-167 °C. H NMR (400.16 MHz,
CDCl3) δH: 8.68 (d, J = 2.8, 1H), 8.04-8.00 (3H, m), 7.94 (br.s, 1H), 7.73 (d, J = 8.4, 1.2, 1H), 7.64
(ddd, J = 8.3, 7.1, 1.2, 1H), 7.54-7.49 (m, 2H), 7.44 (td, J = 7.8, 1.6, 1H), 7.29 (td, J = 7.6, 1.6, 1H).
13C NMR (100.62 MHz, CDCl3) δC: 145.9, 145.3, 135.9, 134.5, 132.0, 131.8, 131.3, 129.5, 129.2,
129.1, 127.8, 127.6, 127.5, 127.4, 126.7. GC-MS (EI) m/z 320 (M++2, 10), 318 (M+, 25), 144 (11),
143 (100), 116 (94), 115 (10), 111 (20), 89 (53), 75 (22), 63 (18). HRMS (TOF, ESI+): calcd for
C15H12ClN2O2S (M+H)+: 319.0302; Found: 319.0303.
Method B: Sulfonamides 3g-l/o-r were synthesized by sulfonylation of the corresponding aniline.
The aniline (0.72 mmol) was dissolved in dry CH2Cl2 (1.2 mL), and the solution was treated with
the corresponding 2-halobenzene-1-sulfonyl chloride (0.6 mmol) and pyridine (0.142 g, 1.8 mmol).
The mixture was stirred at room temperature for 18 h, diluted with H2O (15 mL) and extracted with
CH2Cl2 (3 x 25 mL). The combined organic layers were washed with 1M HCl, brine, dried over
Na2SO4, and concentrated in vacuum. After removal of volatile components from the filtrate, the
resulting crude product was purified by column chromatography on silica gel. Ethyl 4-(2-
chlorophenylsulfonamido)benzoate (3g) was synthesized from 2-chlorobenzene-1-sulfonyl chloride
(4a) and ethyl 4-aminobenzoate and purified eluting with pentane/ EtOAc (100:0 → 70:30 %).
Light yellow solid was isolated in 89% yield (181.4 mg, 0.534 mmol), m.p. 191-193 °C. 1H NMR
(400.16 MHz, CD3SOCD3) δH: 11.22 (br.s, 1H), 8.13 (d, J = 7.6, 1H), 7.81 (d, J = 8.8, 2H), 7.67-
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7.63 (m, 2H), 7.57-7.53 (m, 1H), 7.20 (d, J = 8.4, 2H), 4.25-4.20 (m, 2H), 1.27-1.23 (m, 3H). C
NMR (100.62 MHz, CD3SOCD3) δC: 165.1, 141.6, 136.0, 135.0, 132.0, 131.7, 130.7, 130.5, 127.8,
124.6, 117.6, 60.5, 14.1. GC-MS (EI) m/z 339 (M+, 60), 294 (41), 240 (30), 212 (21), 175 (21), 168
(25), 164 (67), 136 (25), 119 (48), 113 (22), 111 (66), 108 (100), 92 (55), 91 (47), 90 (18), 65 (22),
64 (33), 63 (26). HRMS (TOF, ESI+): calcd for C15H14ClNNaO4S (M+Na)+: 362.0224; Found:
362.0228.
2-Chloro-N-(4-cyanophenyl)benzenesulfonamide (3h). The product was purified by column
chromatography on silica gel eluting with pentane/ EtOAc (100:0 → 70:30 %). Light yellow solid
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was isolated in 57% yield (100.2 mg, 0.342 mmol), m.p. 199-201 °C. H NMR (400.16 MHz,
CD3SOCD3) δH: 11.41 (br.s, 1H), 8.16-8.14 (m, 1H), 7.70-7.55 (m, 5H), 7.21 (d, J = 8.8, 2H). 13C
NMR (100.62 MHz, CD3SOCD3) δC: 141.6, 135.9, 135.2, 133.7, 132.1, 131.7, 130.7, 128.0, 118.6,
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117.9, 105.3. GC-MS (EI) m/z 294 (M+ +1, 14), 292 (M+, 33), 277 (19), 193 (22), 177 (27), 175
(69), 117 (17), 113 (32), 111 (100), 90 (29), 75 (40), 64 (12), 63 (13). HRMS (TOF, ESI+): calcd
for C13H9ClN2NaO2S (M+Na)+: 314.9966; Found: 314.9966.
2-Chloro-N-(4-fluorophenyl)benzenesulfonamide (3i). The product was purified by column
chromatography on silica gel eluting with pentane/ EtOAc (100:0 → 80:20 %). White solid was
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isolated in 93% yield (159.4 mg, 0.558 mmol), m.p. 214-215 °C. H NMR (400.16 MHz,
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CD3SOCD3) δH: 10.59 (br.s, 1H), 8.00-7.98 (m, 1H), 7.64-7.47 (m, 3H), 7.13-7.04 (m, 4H). C
NMR (100.62 MHz, CD3SOCD3) δC: 158.9 (d, J = 240, 1C), 136.3, 134.7, 133.2 (d, J = 3, 1C),
131.8, 131.6, 130.7, 127.7, 121.9 (d, J = 8, 1C), 115.9 ( d, J = 23, 1C). GC-MS (EI) m/z 287
(M++2, 7), 285 (M+, 18), 186 (9), 111 (15), 110 (100), 83 (34), 75 (10), 57 (7). HRMS (TOF,
ESI+): calcd for C12H9ClFNNaO2S (M+Na)+: 307.9909; Found: 307.9919.
N-([1,1'-Biphenyl]-2-yl)-2-chlorobenzenesulfonamide (3j). The product was purified by column
chromatography on silica gel eluting with pentane/ EtOAc (100:0 → 80:20 %). White solid was
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isolated in 75% yield (154.8 mg, 0.45 mmol), m.p. 159-161 °C. H NMR (400.16 MHz,
CD3SOCD3) δH: 9.72 ( br.s, 1H), 7.67 (dd, J = 7.9, 1.5, 1H), 7.59-7.54 (m, 1H), 7.51 (dd, J = 8.0,
1.3, 1H), 7.41-7.23 (m, 9H), 7.01 ( dd, J = 7.6, 1.3, 1H). 13C NMR (100.62 MHz, CD3SOCD3) δC:
139.7, 138.4, 138.2, 133.9, 132.8, 131.8, 130.9, 130.7, 130.2, 129.0, 128.2, 128.0, 128.0, 127.4,
127.4, 127.0. GC-MS (EI) m/z 343 (M+, 8), 169 (12), 168 (100), 167 (72), 140 (5), 139 (8), 115
(5), 111 (4), 75 (4). HRMS (TOF, ESI+): calcd for C18H14ClNNaO2S (M+Na)+: 366.0326; Found:
366.0322.
N-(2-(1H-Pyrrol-1-yl)phenyl)-2-chlorobenzenesulfonamide (3k). The product was purified by
column chromatography on silica gel eluting with pentane/ EtOAc (100:0 → 90:10 %). Amber
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crystal was isolated in 51% yield (100.2 mg, 0.306 mmol), m.p. 122-124 °C. H NMR (400.16
MHz, CDCl3) δH: 8.10 (dd, J = 8.0, 1.6, 1H), 7.56 (dd, J = 8.4, 1.2, 1H), 7.48 (ddd, J = 8.0, 7.2, 1.6,
1H), 7.43 (dd, J = 7.8, 1.4, 1H), 7.24 (1H, ddd, J = 8.3, 7.3, 1.6, 1H), 7.20-7.17 (m, 2H), 7.08 (td, J
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= 7.6, 1.2, 1H), 6.66 (t, J = 2.2, 2H), 6.37 (t, J = 2.2, 2H). C NMR (100.62 MHz, CDCl3) δC:
136.2, 134.2, 132.2, 131.1, 131.8, 131.8, 131.1, 128.7, 127.7, 127.0, 124.5, 121.9, 119.0, 110.9.
HRMS (TOF, ESI+): calcd for C16H13ClN2NaO2S (M+Na)+: 355.0278; Found: 355.0266.
2-Chloro-N-(naphthalen-1-yl)benzenesulfonamide (3l). The product was purified by column
chromatography on silica gel eluting with pentane/ EtOAc (100:0 → 80:20 %). Brown crystal was
isolated in 77% yield (146.8 mg, 0.462 mmol), m.p. 166-167 °C.1H NMR (400.16 MHz, CDCl3)
δH: 8.16 (d, J = 8.4, 1H), 7.91 (dd, J = 8.0, 1.6, 1H), 7.81 (d, J = 7.6, 1H), 7.69 (d, J = 8.4, 1H),
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7.56-7.44 (m, 4H), 7.30-7.21 (m, 4H). C NMR (100.62 MHz, CDCl3) δC: 136.9, 134.3, 134.0,
131.8, 131.7, 131.5, 131.0, 129.3, 128.3, 127.5, 127.2, 126.8, 126.5, 125.2, 122.0, 121.9. GC-MS
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(EI) m/z 317 (M+, 14), 218 (8), 143 (12), 142 (100), 140 (6), 116 (9), 115 (87), 89 (6), 75 (7).
HRMS (TOF, ESI+): calcd for C16H12ClNNaO2S (M+Na)+: 340.0170; Found: 340.0161.
2-Chloro-4-fluoro-N-phenylbenzenesulfonamide (3o). The product was purified by column
chromatography on silica gel eluting with pentane/ EtOAc (100:0 → 80:20 %). White solid was
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isolated in 97% yield (166.2 mg, 0.582 mmol), m.p. 109-110 °C. H NMR (400.16 MHz, CDCl3)
δH: 8.01 (dd, J = 8.8, 6.0, 1H), 7.26-7.20 (m, 3H), 7.12-7.09 (m, 3H), 7.06 (br.s, 1H), 7.02 (ddd, J =
8.8, 7.6, 2.4, 1H). 13C NMR (100.62 MHz, CDCl3) δC: 164.7 (d, J = 257, 1C), 135.5, 134.1 (d, J =
10, 1C), 133.1 ( d, J = 11, 1C), 132.4 (d, J = 4, 1C), 129.4, 125.9, 121.6, 119.2 (d, J = 25, 1C),
114.5 (d, J = 21, 1C). GC-MS (EI) m/z 287 (M++2, 6), 285 (M+, 18), 186 (26), 185 (6), 131 (5),
129 (17), 109 (7), 94 (6), 93 (14), 92 (100), 65 (49), 64 (8), 63 (8). HRMS (TOF, ESI+): calcd for
C12H9ClFNNaO2S (M+Na)+: 307.9919; Found: 307.9919.
2-Chloro-4-fluoro-N-(p-tolyl)benzenesulfonamide (3p). The product was purified by column
chromatography on silica gel eluting with pentane/ EtOAc (100:0 → 80:20 %). Light yellow solid
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was isolated in 91% yield (163.6 mg, 0.546 mmol), m.p. 110-112 °C. H NMR (400.16 MHz,
CDCl3) δH: 7.97 (dd, J = 9.0, 5.8, 1H), 7.24 (dd, J = 8, 2.4, 1H), 7.03-7.00 (6H, m), 2.24 (s, 3H).
13C NMR (100.62 MHz, CDCl3) δC: 164.7 (d, J = 257, 1C), 136.1, 134.1 (d, J = 8, 1C), 133.1 (d, J
= 11, 1C), 132.8, 132.5, 130.0, 122.3, 119.2 (d, J = 26, 1C), 114.5 (d, J = 22, 1C), 20.8. GC-MS
(EI) m/z 301 (M++2, 7), 299 (M+, 19), 129 (7), 107 (9), 106 (100), 79 (25), 78 (8), 77 (24), 52 (4),
51 (4). HRMS (TOF, ESI+): calcd for C13H11ClFNNaO2S (M+Na)+: 322.0075; Found: 322.0069.
2-Bromo-N-(p-tolyl)-4-(trifluoromethyl)benzenesulfonamide (3q). The product was purified by
column chromatography on silica gel eluting with pentane/ EtOAc (100:0 → 80:20 %). Colorless
solid was isolated in 85% yield (200.1 mg, 0.51 mmol), m.p. 129-130 °C. 1H NMR (400.16 MHz,
CD3SOCD3) δH: 10.70 (br.s, 1H), 8.23 (d, J = 0.8, 1H), 8.19 (d, J = 8.0, 1H), 7.94 (dt, J = 8.2, 0.8,
1H), 7.04 ( d, J = 8.4, 2H), 7.00-6.98 (2H, m), 2.16 (s, 3H). 13C NMR (100.62 MHz, CD3SOCD3)
δC: 142.4, 133.9, 133.7 (q, J = 33, 1C), 133.7, 132.5, 132.2 (q, J = 4, 1C), 129.7, 125.3 (q, J = 4,
1C), 122.4 (q, J = 272, 1C), 120.2, 118.3, 20.2. GC-MS (EI) m/z 395 (M++2, 11), 393 (M+, 11),
223 (4), 144 (12), 125 (4), 107 (8), 106 (100), 79 (25), 78 (10), 77 (27), 52 (4). HRMS (TOF,
ESI+): calcd for C14H11BrF3NNaO2S (M+Na)+: 415.9538; Found: 415.9531.
2-Chloro-N-(pyridin-2-yl)benzenesulfonamide (3r). The product was purified by column
chromatography on silica gel eluting with pentane/ EtOAc (100:0 → 70:30 %). White solid was
isolated in 30% yield (24.2 mg, 0.09 mmol), m.p. 212-213 °C. 1H NMR (400.16 MHz, CDCl3) δH:
14.5 (br.s, 1H), 8.37-8.28 (m, 2H), 7.65 (ddd, J = 9.1, 7.1, 2.0, 1H), 7.45-7.40 (m, 3H), 7.31 (d, J =
8.8, 1H), 6.77 (t, J = 6.4, 1H). 13C NMR (100.62 MHz, CDCl3) δC: 155.5, 142.9, 139.4, 139.2,
132.9, 132.1, 131.9, 131.1, 126.7, 115.5, 113.2. GC-MS (EI) m/z 270 (M++2, 2), 268 (M+, 47), 266
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(100), 264 (74), 172 (22), 168 (16), 133 (22), 124 (30), 121 (24), 118 (15), 109 (32), 98 (17), 79
(16), 78 (16), 62 (14). HRMS (TOF, ESI+): calcd for C11H9ClN2NaO2S (M+Na)+: 290.9966;
Found: 290.9965.
Representative Procedure for Photostimulated Reactions. Reactions in DMSO (THF or
CH3CN). The following procedure is representative of all these reactions. The reaction was carried
out in a Schlenk tube equipped with a nitrogen inlet and magnetic stirred at r.t. DMSO (5 ml) was
dried and deoxygenated, then t-BuOK (3.0 equiv, 50.5 mg, 0.45 mmol) was added and after 5 min
the corresponding 2-halo-N-phenylbenzenesulfonamide (1 equiv, 0.15 mmol) was added and the
reaction mixture was irradiated for the corresponding time. In case the 2-halo-N-
phenylbenzenesulfonamide was an oil, it was added dissolved in anhydrous ethyl ether. The
reaction was quenched with ammonium nitrate in excess. The “work-up” of the reaction could have
two processes. “Work-up A” the residue was extracted with ethyl acetate (EtOAc) (3 x 30 ml) and
the organic extracted was washed with water and dried with anhydrous Na2SO4. The solvent was
removed under reduced pressure to give the crude products. The products were purified by
chromatography on silica gel or quantified by GC using the internal standard method. Or “Work-
up B” the residue was filtrate over a bed of silica gel with 300 ml of pentane/ EtOAc 70:30 %. The
solvent was removed under reduced pressure and the crude obtained was then recrystallized.
Reaction in Liquid Ammonia. Liquid ammonia (150 ml), previously dried over Na metal, was
distilled into a 250 mL three-necked, round-bottomed flask equipped with a cold-finger condenser
and a magnetic stirrer under a nitrogen atmosphere. The base t-BuOK (3.0 equiv, 50.5 mg, 0.45
mmol) and then the corresponding 2-halo-N-phenylbenzenesulfonamides (1 equiv, 0.15 mmol)
were added to the liquid ammonia. After 180 min of irradiation the reaction was quenched by
addition of NH4NO3 in excess, and the ammonia was allowed to evaporate. Water (50 mL) was
added to the residue and the mixture was extracted with ethyl acetate (3 x 30 mL). The organic
extract was dried over Na2SO4, and filtered. The solvent was removed under reduced pressure to
leave the crude products. The products were purified by chromatography on silica gel or quantified
by GC using the internal standard method.
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Isolation and Identification of Products. 6H-Dibenzo[c,e][1,2]thiazine 5,5-dioxide (6a). The
product was purified by column chromatography on silica gel eluting with pentane/ EtOAc (100:0
→ 75:25 %). White solid was isolated in 86% yield (29.6 mg, 0.128 mmol), m.p. 195-197°C (lit.10
194-195ºC ).1H NMR (400.16 MHz, CD3COCD3) δH: 9.89 (br.s, 1H), 8.24-8.19 (m, 2H), 7.89 (dd,
J = 7.8, 1.0, 1H), 7.84-7.80 (m, 1H), 7.68 (td, J = 7.6, 0.8, 1H), 7.49 (td, J = 7.6, 1.2, 1H), 7.36-7.31
(m, 2H). 13C NMR (100.62 MHz, CD3COCD3) δC: 136.8, 135.5, 132.4, 132.3, 130.2, 128.2, 125.4,
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125.2, 124.1, 122.4, 121.3, 119.9. GC-MS (EI) m/z 232 (M++1, 13), 231 (M+, 91), 168 (14), 167
(100), 166 (56), 140 (29), 139 (39), 115 (9), 113 (10), 89 (8), 84 (10), 70 (11), 69 (10), 63 (14).
9-Methyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (6b). The product was purified by column
chromatography on silica gel eluting with pentane/ EtOAc (100:0 → 70:30 %). White solid was
isolated in 98% yield (36.1 mg, 0.147 mmol). This solid was recrystallized from acetone/pentane as
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white crystal, m.p. 217-219 °C. H NMR (400.16 MHz, CD3SOCD3) δH: 11.19 (br.s, 1H), 8.23 (d,
J = 8.0, 1H), 8.02 (s, 1H), 7.96 (dd, J = 7.8, 1.0, 1H), 7.82-7.78 (m, 1H), 7.65 (t, J = 7.4, 1H), 7.28
(dd, J = 8.2, 1.0, 1H), 7.11 (d, J = 8.0, 1H), 2.369 (s, 3H). 13C NMR (100.62 MHz, CD3SOCD3) δC:
134.6, 134.1, 133.2, 132.4, 131.8, 131.1, 128.4, 125.5, 125.4, 121.4, 121.1, 119.8, 20.6. GC-MS
(EI) m/z 246 (M++1, 9), 245 (M+, 69), 181 (21), 180 (100), 178 (9), 153 (6), 152 (17), 151 (7), 127
(5), 90 (9), 89 (5), 77 (11), 76 (7), 75 (5), 63 (6), 51 (5). HRMS (TOF, ESI+): calcd for
C13H11NNaO2S (M+Na)+: 268.0403; Found: 268.0400.
9-Methoxy-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (6c). The product was purified by column
chromatography on silica gel eluting with pentane/ EtOAc (100:0 → 60:40 %). White solid was
isolated in 77% yield (30.2 mg, 0.115 mmol). This solid was recrystallized from acetone/pentane as
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light yellow crystal, m.p. 209-210 °C. H NMR (400.16 MHz, CD3SOCD3) δH: 11.0 (br.s, 1H),
8.29 (d, J = 8.0, 1H), 7.92 (dd, J = 7.8, 1.0, 1H), 7.82-7.78 (m, 1H), 7.70 (d, J = 2.8, 1H), 7.67 (td, J
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= 7.6, 0.8, 1H), 7.16 (d, J = 8.8, 1H), 7.09 (dd, J = 8.8, 2.8, 1H), 3.86 (s, 3H). C NMR (100.62
MHz, CD3SOCD3) δC: 156.1, 134.8, 132.4, 131.7, 129.7, 128.7, 126.0, 123.1, 121.8, 121.2, 117.1,
109.5, 55.6. GC-MS (EI) m/z 262 (M++1,11), 261 (M+, 69), 183 (14), 182 (100), 155 (8), 154 (70),
153 (14), 128 (23), 127 (30), 126 (12), 77 (10), 75 (8), 51 (8). HRMS (TOF, ESI+): calcd for
C13H11NNaO3S (M+Na)+: 284.0352; Found: 284.0357.
8,10-Di-methoxy-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (6d). The product was purified by
column chromatography on silica gel eluting with pentane/ EtOAc (100:0 → 60:40 %). Light
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yellow solid m.p. 229-231 °C was isolated in 65% yield (28.4 mg, 0.0975 mmol).. H NMR
(400.16 MHz, CD3COCD3) δH: 9.70 (br.s, 1H), 8.59 (d, J = 8.4, 1H), 7.90 (dd, J = 7.8, 1.0, 1H),
7.66 (td, J = 7.8, 1.2, 1H), 7.52 (td, J = 7.6, 0.8, 1H), 6.56 (d, J = 2.4, 1H), 6.49 (d, J = 2.4, 1H),
4.00 (s, 3H), 3.87 (s, 3H). 13C NMR (100.62 MHz, CD3COCD) δC: 161.5, 159.6, 139.4, 134.7,
131.4, 131.3, 128.7, 126.4, 120.8, 105.5, 96.5, 95.0, 55.5, 55.0. GC-MS (EI) m/z 292 (M++1, 29),
291 (M+, 100), 290 (12), 227 (17), 226 (9), 212 (11), 185 (9), 136 (9), 127 (14), 114 (9), 113 (9).
HRMS (TOF, ESI+): calcd for C14H13NNaO4S (M+Na)+: 314.0457; Found: 314.0469.
9-Phenyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (6e). The product was purified by column
chromatography on silica gel eluting with pentane/ EtOAc (70:30 %). White solid was isolated in
94% yield (43.3 mg, 0.141 mmol). This solid was recrystallized from EtOAc /pentane as colorless
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flakes, m.p. 235-236 °C. 1H NMR (400.16 MHz, CD3SOCD3) δH: 11.50 (br.s, 1H), 8.47 (d, J = 8.4,
1H), 8.45 (d, J = 2.0, 1H), 7.96 (d, J = 7.2, 1H), 7.85-7.77 (m, 4H), 7.70 (t, J = 7.6, 1H), 7.50 (t, J =
7.6, 2H), 7.39 (t, J = 7.6, 1H), 7.30 (d, J = 8.4, 1H). 13C NMR (100.62 MHz, CD3SOCD3) δC:
139.4, 136.0, 135.9, 134.5, 132.6, 131.7, 128.9, 128.8, 128.7, 127.5, 126.8, 126.1, 123.5, 121.8,
121.1, 120.2. HRMS (TOF, ESI+): calcd for C18H13NNaO2S (M+Na)+: 330.0559; Found: 330.0551.
9-(Trifluoromethyl)-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (6f). The product was purified by
column chromatography on silica gel eluting with pentane/ EtOAc (100:0 → 60:40 %). White solid
was isolated in 79% yield (35.5 mg, 0.118 mmol). This solid was recrystallized from ethyl
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eter/pentane as white crystal, m.p. 234-236 °C. H NMR (400.16 MHz, CD3COCD3) δH: 10.48
(br.s, 1H), 8.56 (s, 1H), 8.42-8.40 (m, 1H), 8.04 (dd, J = 7.8, 1.0, 1H), 7.89 ( ddd, J = 8.0, 7.6, 1.2,
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1H), 7.84-7.81 (m, 1H), 7.77 (1H, td, J = 7.6, 1.2, 1H), 7.52 (d, J = 8.4, 1H). C NMR (100.62
MHz, CD3COCD) δC: 140.0, 135.4, 132.7, 131.1, 129.3, 126.8 (q, J = 4, 1C), 126.1, 125.5 (q, J =
33, 1C), 124.3 (q, J = 270, 1C), 122.7 (q, J = 4, 1C), 122.3, 121.5, 120.2. GC-MS (EI) m/z 300
(M++1, 26), 299 (M+, 100), 281 (22), 236 (15), 235 (61), 234 (17), 216 (29), 207 (53), 204 (13),
185 (28), 166 (23), 140 (14), 139 (17), 93 (15), 69 (16), 58 (74), 57 (18). (26). HRMS (TOF, ESI+):
calcd for C13H8F3NNaO2S (M+Na)+: 322.0120; Found: 322.0120.
Ethyl 6H-dibenzo[c,e][1,2]thiazine-9-carboxylate 5,5-dioxide (6g). The product was purified by
column chromatography on silica gel eluting with pentane/ EtOAc (100:0 → 50:50 %). Light
yellow solid was isolated in 54% yield (24.6 mg, 0.081 mmol). This solid was recrystallized from
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acetone/pentane as small white solid, m.p. 263-264 °C. H NMR (400.16 MHz, CD3SOCD3) δH:
12.0 (br.s, 1H), 8.71 (s, 1H), 8.30 (d, J = 8.1, 1H), 8.03 (d, J = 8.4, 1H), 7.97 (d, J = 7.8, 1H), 7.87-
7.83 (m, 1H), 7.72 (t, J = 7.6, 1H), 7.29 (d, J = 8.3, 1H), 4.36 (q, J = 7.1, 2H), 1.36 (t, J = 7.1, 3H).
13C NMR (100.62 MHz, CD3SOCD3) δC: 165.2, 142.2, 134.0, 132.5, 131.0, 130.7, 128.9, 126.2,
125.4, 124.0, 121.4, 120.3, 119.8, 60.7, 14.2. GC-MS (EI) m/z 304 (M++1, 13), 303 (M+, 70), 275
(35), 259 (18), 258 (100), 211 (9), 194 (17), 167 (10), 166 (36), 165 (9), 164 (13), 140 (21), 139
(46), 138 (9). HRMS (TOF, ESI+): calcd for C15H13NNaO4S (M+Na)+: 326.0458; Found:
326.0454.
6H-Dibenzo[c,e][1,2]thiazine-9-carbonitrile 5,5-dioxide (6h). The product was filtrate over a bed
of silica gel with 300 ml of pentane/ EtOAc 70:30 %. The solvent was removed under reduced
pressure and then was recrystallized from acetone/pentane. Light yellow solid was isolated in 91%
yield (35.0 mg, 0.136 mmol), m.p. decomposed over 213°C. 1H NMR (400.16 MHz, CD3SOCD3)
δH: 12.16 (br.s, 1H), 8.80 (d, J = 1.6, 1H), 8.40 (d, J = 8.0, 1H), 7.99 (dd, J = 7.8, 1.0, 1H), 7.91-
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7.85 (m, 2H), 7.77-7.73 (m, 1H), 7.33 (d, J = 8.4, 1H). C NMR (100.62 MHz, CD3SOCD3) δC:
140.4, 134.0, 133.6, 132.9, 130.2, 130.1, 129.6, 126.2, 121.4, 121.2, 120.0, 118.6, 106.0. GC-MS
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(EI) m/z 257 (M++1, 20), 256 (M+, 85), 193 (17), 192 (100), 191 (39), 165 (36), 164 (49), 144 (15),
139 (11), 138 (19), 89 (9), 83 (10), 75 (12), 63 (13), 50 (9). HRMS (TOF, ESI+): calcd for
C13H8N2NaO2S (M+Na)+: 279.0199 ; Found: 279.0190.
9-Fluoro-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (6i). The product was purified by column
chromatography on silica gel eluting with pentane/ EtOAc (100:0 → 60:40 %). White solid was
isolated in 81% yield (30.0 mg, 0.121 mmol). This solid was recrystallized from EtOAc/pentane as
white crystal, m.p. 214-215 °C. 1H NMR (400.16 MHz, CD3SOCD3) δH: 11.41 (br.s, 1H), 8.28 (d,
J = 7.9, 1H), 8.13 (dd, J = 10.2, 2.8, 1H), 7.95 (dd, J = 7.8, 1.1, 1H), 7.85-7.81 (m, 1H), 7.71 (td, J
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= 7.6, 1.0, 1H), 7.36 (td, J = 8.6, 2.8, 1H), 7.24 (dd, J = 8.8, 5.2, 1H). C NMR (100.62 MHz,
CD3SOCD3) δC: 158.7 (d, J = 238, 1C), 134.5, 132.9, 132.6, 130.9, 129.3, 126.1, 123.3 (d, J = 9,
1C), 121.8 (d, J = 8, 1C), 121.2, 117.5 (d, J = 23, 1C), 111.8 (d, J = 24, 1C). HRMS (TOF, ESI+):
calcd for C12H8FNNaO2S (M+Na)+: 272.0152; Found: 272.0153
7-Phenyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (6j). The product was purified by column
chromatography on silica gel eluting with pentane/ EtOAc (100:0 → 70:30 %). White solid was
isolated in 83% yield (38.3 mg, 0.124 mmol). This solid was recrystallized from EtOAc/pentane as
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small white needles, m.p. 221-222 °C. H NMR (400.16 MHz, CD3SOCD3) δH: 10.2 (br.s, 1H),
8.27 (d, J = 8.0, 1H), 8.23 (dd, J = 7.8, 1.4, 1H), 7.91 (dd, J = 7.6, 0.8, 1H), 7.85-7.80 (m, 1H),
7.70-7.67 (m, 1H), 7.58-7.41 (m, 7H). 13C NMR (100.62 MHz, CD3SOCD3) δC: 138.0, 137.0,
135.7, 133.1, 132.6, 132.4, 131.6, 129.5, 128.9, 128.4, 127.6, 126.5, 126.2, 125.0, 121.6. HRMS
(TOF, ESI+): calcd for C18H13NNaO2S (M+Na)+: 330.0559; Found: 330.0554.
7-(1H-Pyrrol-1-yl)-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (6k). The product was purified by
column chromatography on silica gel eluting with pentane/ EtOAc (100:0 → 70:30 %). White solid
was isolated in 78% yield (34.7 mg, 0.117 mmol). This solid was recrystallized from
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EtOAc/pentane as light yellow crystal, m.p. 196-197 °C. H NMR (400.16 MHz, CD3SOCD3)
δH:10.4 (br.s, 1H), 8.28 (d, J = 8.0, 1H), 8.21 (dd, J = 7.8, 1.4, 1H), 7.94 (dd, J = 7.8, 1.0, 1H),
7.87-7.82 (m, 1H), 7.73-7.70 (m, 1H), 7.55-7.51 (m, 1H), 7.49 (dd, J = 8.0, 1.6, 1H), 7.14 (t, J =
2.0, 2H), 6.31 (t, J = 2.2, 2H). 13C NMR (100.62 MHz, CD3SOCD3) δC: 135.7, 135.6, 132.7, 132.0,
129.8, 129.3, 127.3, 127.0, 126.7, 124.1, 122.1, 121.8, 109.5. GC-MS (EI) m/z 297 (M++1, 12),
296 (M+, 75), 233 (14), 232 (94), 231 (71), 229 (12), 205 (29), 204 (100), 164 (14), 151 (11), 139
(16), 115 (16), 102 (18). HRMS (TOF, ESI+): calcd for C16H12N2NaO2S (M+Na)+: 319.0512;
Found: 319.0513.
5H-Benzo[e]naphtho[1,2-c][1,2]thiazine 6,6-dioxide (6l). The product was purified by column
chromatography on silica gel eluting with pentane/ EtOAc (70:30 %). Red solid was isolated in
69% yield (29.1 mg, 0.103 mmol). This solid was recrystallized from Acetone/pentane as brown
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crystal, m.p. 281-283°C. H NMR (400.16 MHz, CD3SOCD3) δH: 11.36 (br.s, 1H), 8.41-8.40 (m,
1H), 8.35 (d, J = 8.0, 1H), 8.30 (d, J = 8.8, 1H), 8.04-8.02 (m, 1H), 8.00 (dd, J = 7.6, 1.2, 1H), 7.93
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(d, J = 8.8, 1H), 7.88-7.84 (m, 1H), 7.74-7.66 (m, 3H). C NMR (100.62 MHz, CD3SOCD3) δC:
134.9, 133.6, 132.6, 132.4, 132.2, 128.6, 128.1, 127.6, 127.0, 126.7, 126.5, 125.1, 123.0, 122.3,
121.4, 119.7. GC-MS (EI) m/z 282 (M++1, 16), 281 (M+, 82), 218 (14), 217 (100), 216 (49), 189
(16), 187 (10), 108 (29), 95 (17), 94 (13)..HRMS (TOF, ESI+): calcd for C16H11NNaO2S (M+Na)+:
304.0403; Found: 304.0392.
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6H-Benzo[e]naphtho[2,1-c][1,2]thiazine 5,5-dioxide (6m). After evaporation of the solvent the
organic phase was purified by column chromatography on silica gel eluting with pentane/ EtOAc
(100:0 → 80:20 %) obtaining a mixture of products. After recrystallization of the mixture from
acetone/pentane 6m was afforded as a colorless solid, m.p. decomposed over 223 °C (51 % isolated
yield, 21.5 mg, 0.075 mmol). 1H NMR (400.16 MHz, CDCl3) δH: 8.54 (d, J = 8.4, 1H), 8.27 (d, J =
8, 1H), 8.09 (d, J = 7.2, 1H), 7.92-7.87 (m, 2H), 7.72 (d, J = 7.2, 1H), 7.63-7.59 (m, 2H), 7.52 (d, J
= 7.6, 1H), 7.23 (d, J = 8.4, 1H). GC-MS (EI) m/z 282 (M++1, 18), 281 (M+, 100), 218 (13), 217
(80), 216 (43), 214 (14), 190 (19), 189 (39), 187 (11), 109 (22), 96 (11), 95 (25), 94 (43), 82 (13).
HRMS (TOF, ESI+): calcd for C16H11NNaO2S (M+Na)+: 304.0403; Found: 304.0392.
6H-Benzo[5,6][1,2]thiazino[3,4-c]quinoline 5,5-dioxide (6n). An especial procedure was followed
to purify this compound. The crude was obtained by extraction from acid media (pH=1, H2SO4),
with EtOAc (3 x 30 ml), the combined organic layers were washed with H2O (20 mL) and dried
over anhydrous MgSO4; the solvent was evaporated under vacuum. Without further purification a
yellow solid was obtained in 97% yield (41.1 mg, 0.145 mmol), m.p. decomposed over 185 °C. 1H
NMR (400.16 MHz, CD3SOCD3) δH: 8.94 (s, 1H), 8.63 (d, J = 7.6, 1H), 8.46 (d, J = 7.6, 1H), 8.22-
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8.14 (m, 2H), 8.00-7.83 (m, 4H). C NMR (100.62 MHz, CD3SOCD3) δC: 143.8, 143.7, 136.9,
132.4, 130.6, 130.5, 129.9, 129.2, 128.9, 128.8, 128.6, 125.3, 124.2, 123.4, 121.7. HRMS (TOF,
ESI+): calcd for C15H11N2O 2S (M+H)+: 283.0536; Found: 283.0530.
2-Fluoro-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (6o). The product was purified by column
chromatography on silica gel eluting with pentane/ EtOAc (100:0 → 70:30 %). White solid was
isolated in 44% yield (16.5 mg, 0.066 mmol). This solid was recrystallized from EtOAc/pentane as
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colorless crystal, m.p. 214-216 °C. H NMR (400.16 MHz, CD3SOCD3) δH: 11.5 (br.s, 1H), 8.23
(d, J = 7.2, 1H), 8.15 (dd, J = 10.8, 2.4, 1H), 8.00 (dd, J = 8.8, 5.6, 1H), 7.53-7.48 (m, 2H), 7.31-
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7.27 (m, 1H), 7.21 (d, J = 8.0, 1H). C NMR (100.62 MHz, CD3SOCD3) δC: 165.4 (d, J = 248,
1C), 137.1, 134.9 (d, J = 9, 1C), 130.9 (d, J = 2, 1C), 124.4 (d, J = 10, 1C), 120.6 ( d, J = 4, 1C),
115.9 (d, J = 23, 1C), 112.3 (d, J = 20, 1C). HRMS (TOF, ESI+): calcd for C12H8FNNaO2S
(M+Na)+: 272.0152; Found: 272.0164.
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2-Fluoro-9-methyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (6p). The product was purified by
column chromatography on silica gel eluting with pentane/ EtOAc (100:0 → 80:20 %). White solid
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was isolated in 43% yield (17.0 mg, 0.065 mmol), m.p. 244-245 °C. H NMR (400.16 MHz,
CD3COCD3) δH: 8.03-7.98 (m, 3H), 7.44 (td, J = 8.5, 2.4, 1H), 7.34 (d, J = 8.4, 1H), 7.21 (d, J =
8.0, 1H), 2.43 (s, 3H). 13C NMR (100.62 MHz, CD3COCD3) δC: 164.7 (d, J = 248, 1C), 135.7 (d, J
= 9, 1C), 134.8, 134.1, 132.1 (d, J = 3, 1C), 131.8, 125.9, 124.6 (d, J = 10, 1C), 121.7, 120.2, 115.4
(d, J = 23, 1C), 112.1 (d, J = 25, 1C), 20.0. GC-MS (EI) m/z 264 (M++1, 2), 263 (M+, 75), 199
(22), 198 (100), 196 (6), 170 (13), 151 (6), 99 (9), 89 (6), 86 (7). HRMS (TOF, ESI+): calcd for
C13H10FNNaO2S (M+Na)+: 286.0308; Found: 286.0304.
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9-Methyl-2-(trifluoromethyl)-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (6q). The product was
purified by column chromatography on silica gel eluting with pentane/ EtOAc (100:0 → 80:20 %).
White solid was isolated in 42% yield (19.7 mg, 0.063 mmol), m.p. 244-245 °C. 1H NMR (400.16
MHz, CDCl3) δH: 8.21 (s, 1H), 8.11 (d, J = 8, 1H), 7.82-7.79 (m, 2H), 7.30 (d, J = 8, 1H), 7.09 (d, J
= 8, 1H), 7.07 (br. s, 1H) 2.48 (s, 3H). 13C NMR (100.62 MHz, CDCl3) δC: 137.7, 135.7, 134.4 (q,
J = 33, 1C), 133.5, 133.0, 132.2, 125.8, 124.8 (q, J = 4, 1C), 123.3 (q, J = 271, 1C), 123.2, 122.6
(q, J = 4, 1C), 122.4, 121.2 21.2. GC-MS (EI) m/z 314 (M++1, 13), 313 (M+, 98), 249 (23), 248
(100), 229 (8), 228 (14), 180 (26), 179 (15), 178 (15), 152 (10), 151 (7), 114 (9), 69 (9). HRMS
(TOF, ESI+): calcd for C14H10F3NNaO2S (M+Na)+: 336.0276; Found: 336.0264.
Acknowledgments. We thank Licentiate student Andres G. Teobaldi for conducting some
of the reactions. This work was supported in part by the Agencia Córdoba Ciencia, the Consejo
Nacional de Investigaciones Científicas y Técnicas (CONICET), Secretaría de Ciencia y
Tecnología, Universidad Nacional de Córdoba (SECyT), and the Agencia Nacional de Promoción
Científica y Técnica (ANPCyT). W.D.G. gratefully acknowledges the receipt of a fellowship from
CONICET.
Supporting Information Available. The screening of optimal conditions for N-arylation Copper-
catalyzed for the synthesis of N-phenyl-2-halobenzenesulfonamides and the Uv-vis spectra for 3a
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and anion derivative are presented in Supporting Information. Copies of H NMR and C NMR
spectra for all substrates and products and theoretical section (xyz of stationary points) are available
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in Supporting Information. This material is available free of charge via the Internet at
http://pubs.acs.org.
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Guastavino, J. F., Budén, M. E., The SRN1 Reaction, in “Arene Chemistry: Reaction
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(16) Reactions carried out under N2 with 0.6 mmol of 2-chlorobenzenesulfonamide (1), 1.2 mmol
of aryl halide (2), 0.06 mmol of CuI, 0.3 mmol of DMEDA, 1.8 mmol of K2CO3 in 2 mL of
CH3CN. For more details see Supporting Information, Screening of Optimal Conditions for N-
arylation Copper-catalyzed.
(17) Ryan, S. J.; Francis C. L.; Savage, J. P. Aust. J. Chem. 2013, 66, 874-881.
(18) Reaction carried out under N2 with 0.6 mmol of sulfonyl chloride (4a-c), 0.72 mmol of
corresponding aniline (5), 1.8 mmol of pyridine in 1.2 mL of CH2Cl2 at room temperature for 18h.
(19) Uv-vis spectra for compounds 3a (7.4 x 10-5 M) and anion derivative 3a- are presented in
supporting information.
(20) The reaction was tested with 4 equivalents of t-BuOK with the same results.
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shown to proceed without full conversion even after 6h.
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(26) The first excited state of 3a- can be achieved with an energy of 101 kcal/mol (λ= 282 nm).
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(27) Vera, M. A.; Pierini A. B. J. Org. Chem. 2003, 68, 9191-9199.
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