Synthesis of benzothiazine sulfonamides via heteroatomic Diels-Alder reaction of para-fluoro-N-sulfinylaniline with bicyclo[2.2.1]heptenes

Article abstract of DOI:10.1134/S1070363216020158

Reaction of 4-fluoro-N-sulfinylaniline with norbornene and norbornadiene has afforded the Diels-Alder adducts of benzothiazine structure that have been oxidized into the corresponding benzothiazine sulfonamides. Structure of the obtained compounds and ste

Full text of DOI:10.1134/S1070363216020158

ISSN 1070-3632, Russian Journal of General Chemistry, 2016, Vol. 86, No. 2, pp. 296–299. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © Ya.V. Veremeichik, D.N. Shurpik, O.A. Lodochnikova, V.V. Plemenkov, 2016, published in Zhurnal Obshchei Khimii, 2016, Vol. 86,
No. 2, pp. 268–271.
Synthesis of Benzothiazine Sulfonamides
via Heteroatomic Diels–Alder Reaction
of para-Fluoro-N-sulfinylaniline with Bicyclo[2.2.1]heptenes
a
b
c
a
Ya. V. Veremeichik , D. N. Shurpik , O. A. Lodochnikova , and V. V. Plemenkov
a
Immanuel Kant Baltic Federal University, Kaliningrad, Russia
b
Kazan (Volga) Federal University, Kazan, Tatarstan, Russia
c
Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences,
ul. Akademika Arbuzova 8, Kazan, Tatarstan, 420088 Russia
e-mail: olga@iopc.ru
Received July 9, 2015
Abstract—Reaction of 4-fluoro-N-sulfinylaniline with norbornene and norbornadiene has afforded the Diels–
Alder adducts of benzothiazine structure that have been oxidized into the corresponding benzothiazine
sulfonamides. Structure of the obtained compounds and stereochemistry of the diene addition and epoxidation
of norbornene olefin bonds have established by means of X-ray diffraction method.
Keywords: Diels–Alder reaction, fluoro-N-sulfinylaniline, sulfonamides, bicyclo[2.2.1]heptene
DOI: 10.1134/S1070363216020158
Sulfonamide fragment is probably the most
important of the known pharmacophore groups [1],
whereas the fluorine-containing drugs such as fludro-
cortisone [2] and fluorouracil [3] were discovered and
put into practice only in the second half of the XXth
century. However, by the beginning of this century,
various fluorine-containing compounds have taken
firmly the niche in the pharmaceutical chemistry [4],
since the fluoroaliphatic or fluoroaromatic fragments
in combination with other pharmacophore groups
substantially improve the medical and biological
properties of key drugs. For example, introduction of
the fluorine-containing substituent at the indole
heterocycle of antitumor drug vinblastine molecule has
increased the activity by 30 times [5].
The Diels–Alder reaction was conducted by heating
the reactants at the diene : dienophile ratio of 1 : 1.5 in
a sealed ampoule at 90–95°C during 8–10 hours. The
target reaction products were o-benzothiazine
sulfinamides 4 and 5 (70–80%). Oxidation of the
adducts 4 and 5 with excess of hydrogen peroxide in
an acetic acid medium at room temperature during
1 day resulted in the formation of sulfonamides 6 and 7
with yield of 50–60% (Scheme 1).
The structure of the prepared compounds was
confirmed by means of IR and NMR spectroscopy. For
example, IR spectra of benzo-ortho-thiazine sulfin-
amides 4 and 5 contained strong absorption bands due
–1
to stretching of S=O (1050–1060 cm ) and NH (3230–
–1
3
260 cm ) groups. IR spectra of benzo-ortho-thiazine
sulfonamides 6 and 7 contained a pair of strong
In the present study, we attempted the synthesis of
fluorinated sulfonamides according to the earlier
developed method [6, 7] based on the heteroatomic
Diels–Alder reaction of 4-fluoro-N-sulfinylaniline 1
with bicyclo[2.2.1]heptenes such as norbornene 2 and
norbornadiene 3. A special feature of this Diels–Alder
reaction is the use of N-sulfinylaniline as the diene,
reacting only with the strained cycloolefine dieno-
philes.
absorption bands characteristic of sulfone group
–
1
(
1130–1135 and 1310–1320 cm ) and a broadened
absorption band of the amide N–H bond (3200–
–
1
3
260 cm ). The spectra of all the resulting compounds
contained absorption bands due to C –F stretching in
Ar
–
1
the range of 1500–1505 cm .
1
H NMR spectra of adducts 4 and 5 contained the
signals of aromatic ring protons at 6.80–7.20 ppm with
2
96

SYNTHESIS OF BENZOTHIAZINE SULFONAMIDES
297
Scheme 1.
O
:
O
O
S
S
HN
HN
2
SO
N
F
F
4
6
H O
2
2
O
O
O
:
CH COOH
S
3
O
S
HN
HN
3
F
1
F
F
5
7
3
the corresponding spin-spin coupling constants J ,
Structure of sulfinamide 4 was additionally con-
firmed by X-ray diffraction data (Fig. 1); the addition
of 4-fluoro-N-sulfinylaniline occurs from the side of
endo-methylene bridge of the bicyclic system.
HH
4
3
4
4а
10b
J , J , and J . The signals of Н and Н atoms
were observed as the AB system with J = 8.7 Hz.
Н and Н atoms were assigned to the broadened
singlets at 2.20 and 2.35 ppm (4) or 2.85 and 3.07 ppm
5). The signals of methylene bridge protons at C
atom were observed as the AB system with J = 10.0
4) and 8.8 Hz (5). Multiplets at 1.60 (4) and 6.35 ppm
5) corresponded to the protons of C –C bridge. The
HH
HF
HF
3
HH
1
4
1
H NMR spectrum of the sulfonamide 6 was
1
1
(
essentially similar to the spectrum of the correspond-
ing sulfinamide 4, the only difference being that the
signals of the protons of the bicyclic moiety were
shifted downfield to 0.2–0.3 ppm, and the downfield
shift of the NH proton signal was of 0.8 ppm.
2
HH
(
(
2
3
NH protons resonated as singlets at 8.9–9.2 ppm.
1
9
1
F NMR spectra of the adducts 4 and 5 contained
the signals of fluorine atom at –121.28 (4) and
The positions of the aromatic ring signals in the H
NMR spectrum of sulfonamide 7 were similar to those
for starting sulfinylamide 5, whereas the signals of Н
and Н were shifted downfield by 0.7 and 0.5 ppm,
respectively. The H and H signals were shifted
4
а
–
(
121.19 ppm (5) with the corresponding constants
JFH = and J ) of spin-spin coupling with aromatic
protons.
3
4
10b
FH
1
4
Fig. 1. Crystal structure of compound 4.
Fig. 2. Crystal structure of compound 7.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 2 2016

2
98
VEREMEICHIK et al.
towards strong-field region by 0.2 ppm. In addition,
the signals of the protons of the methylene bridge at
ferential Fourier series and refined in isotropic ap-
proximation in the both structures. All the calculations
were performed using WinGX [10] and AREX2 [11]
software packages.
1
1
the C atom were shifted downfield (by 0.1 and
.4 ppm). Noteworthily, the spectrum of compound 7
0
as compared to that of compound 5 revealed the
disappearance of the signals of the olefin protons, and
the signals of the epoxide moiety appeared as the AB
system at 3.38–3.44 ppm with spin-spin coupling
constants of 3.1–3.2 Hz. The given signal assignment
was made basing on the similar oxidation pathway
observed earlier [7].
The crystals of compound 4 were rhombic,
C H FNOS; unit cell parameters at 20°C: a = 5.581(5),
13
14
3
b = 8.218(7), c = 25.56 (2) Å, V = 1172(2) Å , Z = 4,
–3
–1
dcalc = 1.424 g cm , space group P2 2 2 , μ = 2.71 cm .
1
1 1
Intensity of 10467 reflections were measured (2337
with I ≥ 2σ). The final values of the divergence factors:
R = 0.0425, R = 0.0938.
W
The fluorine atoms of sulfonamides 6 and 7
resonated as multiplet signals at –119.07 and –118.64 ppm,
respectively.
The crystals of compound 7 were monoclinic,
C H FNO S; unit cell parameters at 20°C: a = 13.338(8),
13
12
3
b = 10.473(6), c = 8.887(5) Å, β = 105.638(7)°, V =
3
–3
The structure of sulfonamide 7 was additionally
confirmed by X-ray diffraction method (Fig. 2). Both
the Diels–Alder addition and the formation of epoxide
ring took place on the side of endo-methylene bridge
of the bicyclo[2.2.1]heptene fragment.
1195(2) Å , Z = 4, d = 1.563 g cm , space group
calc
–
1
P2 /c, μ = 2.87 cm . Intensity of 9233 reflections were
1
measured (1940 with I ≥ 2σ). The final values of
divergence factors: R = 0.0501, R = 0.1332.
W
Coordinates, refinement details, and structure factors
were deposited at the Cambridge Crystallographic
Data Centre (CCDC 1406833 and 1406834).
In summary, the possibility of preparation of
fluorinated benzothiazine sulfonamides via the
heteroatomic Diels–Alder reaction of N-sulfinylanilines
with bicyclo[2.2.1]heptenes followed by oxidation of
the resulting adducts. According to X-ray diffraction
data, both the Diels–Alder reaction and the formation
of the epoxide ring occurred on the side of endo-
methylene bridge of bicyclo[2.2.1]heptene moiety.
4
-Fluoro-N-sulfinylaniline 1 was prepared via
reaction of 4-fluoroaniline with the equimolar amount
of SOCl in refluxing benzene according to [7]; bp 95–
2
9
6°C (12 mmHg).
9-Fluoro-1,2,3,4,4а,10b-hexahydro-1,4-methano-
Н-dibenzo[c,e]-5,6-thiazine-5-oxide (4). A mixture
6
EXPERIMENTAL
of 15.7 g (0.1 mol) of aniline 1 and 14.1 g (0.15 mol)
of norbornene 2 was heated in a sealed tube at 90–95°C
during 8 h. After cooling, the reaction mixture was
diluted with petroleum ether (100 mL) and filtered.
The crystalline precipitate was washed with petroleum
ether and recrystallized from ethanol. Yield 20.1 g
Elemental analysis was performed using a EuroEA
000 CHNS-analyzer. IR spectra were recorded using
3
a Bruker Vertex 70 IR Fourier spectrometer (KBr
1
19
pellets). H (400.0 MHz) and F (376.5 MHz) NMR
–
1
spectra of the DMSO-d solutions were registered
(80%), mp 217–219°С. IR spectrum, ν, cm : 1055 vs
6
1
using a Bruker Avance-400 spectrometer. Melting
points were measured using a Digital Mel-Temp 3.0
analyzer.
(S=O), 1502 s (C–F), 3258 s (N–H). Н NMR spec-
1
1
2
trum, δ, ppm: 0.98 d (1Н , J 10.0 Hz), 1.47 d
НН
1
1
2
2,3
1(4)
(1Н , J = 10.0 Hz), 1.60 m (4Н ), 2.21 s [1Н ],
HH
4
(1)
4a(10b)
3
2
.32 s [1Н ], 2.98 d [1Н
, J = 8.6 Hz], 3.25 d
HH
X-Ray diffraction analysis was performed using a
Bruker SMART Apex II diffractometer (graphite
1
0b(4a)
3
7
3
[1Н
, J = 8.6 Hz], 6.82 d.d (1Н , J = 8.6,
HH HH
4
8
3
3
JHF = 5.2 Hz), 6.96 t.d (1Н , J = 8.6, J = 8.6,
JHH = 2.8 Hz), 7.08 d.d (1Н , J = 9.6, J
HH
HF
monochromator, MoK irradiation, λ = 0.71073 Å) at
α
4
10
3
4
=
HF
HH
2
93 K. The semi-empirical absorption accounting was
made using SADABS software [8]. The structure was
solved by the direct method using SHELXS software
1
9
2
–
.8 Hz), 8.80 s (1Н, NH). F NMR spectrum, δ , ppm:
F
3
3
4
121.28 t.d (1F, J = 9.6, J = 8.6, J = 5.2 Hz).
FH
FH
FH
Found, %: С 62.02, 62.10; Н 5.63, 5.66; N 5.43, 5.60;
[
9]. Non-hydrogen atoms were refined in isotropic and
S 12.68, 12.80. C H FNOS. Calculated, %: C 62.13;
1
3
14
then anisotropic approximation for SHELXL-97
software [9]. The hydrogen atoms were placed into the
calculated positions and refined in the rider model.
Amino hydrogen atom was detected from the dif-
H 5.61; N 5.57; S 12.76.
9-Fluoro-1,4,4а,10b-tetrahydro-1,4-methano-6Н-
dibenzo[c,e]-5,6-thiazine-5-oxide (5) was prepared
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 2 2016

SYNTHESIS OF BENZOTHIAZINE SULFONAMIDES
299
=
1
1
2
11
2
similarly from 15.7 g (0.1 mol) of aniline 1 and 13 g
0.15 mol) of norbornadiene 3; the reaction duration
1.09 d (1Н , J = 10.7 Hz), 1.37 d (1Н , J
HH
HH
1
(4)
4(1)
2(3)
(
10.7 Hz), 2.65 s [1Н ), 2.90 s (1Н ], 3.38 d [1Н
,
3
3(2) 3
was 10 h. After cooling, the reaction mixture was
diluted with hexane (100 mL) and filtered. The
crystalline precipitate was washed with cold hexane
and recrystallized from ethanol. Yield 19.2 g (77%),
JHH = 3.2 Hz], 3.44 d [1Н , J = 3.2 Hz], 3.49 d
HH
4
a(10b)
3
10b(4a)
3
[1Н
, J = 9.2 Hz], 3.57 d [1Н
, J
=
HH
HH
7
3
4
9.2 Hz], 6.87 d.d (1Н , J = 8.6, J = 5.2 Hz), 7.04
HH
HF
8
3
3
4
t.d (1Н , J = J = 8.6, J = 2.8 Hz), 7.23 d.d
HH
HF
HH
–
1
10
3
4
19
mp 213–214°C. IR spectrum, ν, cm : 1057 vs (S=O),
(1Н , J = 9.7, J = 2.8 Hz), 10.00 (1Н, NH). F
HF HH
1
3
1
504 s (C–F), 3232 s (N–H). Н NMR spectrum, δ,
NMR spectrum, δ , ppm: –118.64 d. t (1F, J = 9.7,
F FH
1
1
2
11
2
3
4
ppm: 1.17 d (1Н , J = 8.8 Hz), 1.78 d (1Н , J
=
HH
1(4)
JFH = 8.6, J = 5.2 Hz). Found, %: С 5.46, 5.53; Н
HH
a(10b)
FH
4
3
8
3
(
.8 Hz), 2.76 d [1Н
.07 s [1Н ], 3.10 d [1Н
, J = 8.7 Hz], 2.83 s [1Н ],
, J = 8.7 Hz], 6.36 m
2Н ), 6.87 d.d (1Н , J = 8.7, J = 5.2 Hz), 6.98
4.26, 4.28; N 5.05, 5.08; S 11.32, 11.36. C H FNO S.
13 12 3
Calculated, % : С 55.51; Н 4.30; N 4.98; S 11.40.
HH
10b(4a)
4
(1)
3
HH
4
2
,3
7
3
HH
HF
8
3
3
4
t.d (1Н , J = J = 8.5, J = 2.8 Hz), 7.16 d.d
REFERENCES
HH
HF
HH
1
0
3
4
19
(
1Н , J = 9.6, J = 2.8 Hz), 9.15 s (1Н, NH). F
HF HH
3
1
2
3
. Mashkovskii, M.D., Lekarstvennye sredstva (Drugs),
Moscow: Novaya Volna, 2005, vol. 2, p. 323.
. Fried, J. and Sabo, E.F., J. Am. Chem. Soc., 1953,
vol. 75, no. 9, p. 2273. DOI: 10.1021/ja01105a527.
. Heidelberg, C., Chaudhuri, N. K., Danneberg, P.,
Mooren, D., Griesbach, L., Duschinsky, R., Schnitzer, R.J.,
Pleven, E., and Scheiner, J., Nature, 1957, vol. 179,
no. 4561, p. 663. DOI: 10.1038/179663a0.
NMR spectrum, δ , ppm: –121.20 t.d (1F, J = 9.5,
F
FH
3
4
JFH = 8.5, J = 5.2 Hz). Found, %: С 62.58, 62.70; Н
FH
4
.73, 4.78; N 5.50, 5.58; S 12.80, 12.92. C H FNOS.
13 12
Calculated, %: С 62.63; H 4.85; N 5.62; S 12.86.
-Fluoro-1,2,3,4,4а,10b-hexahydro-1,4-methano-
Н-dibenzo[c,e]-5,6-thiazine-5,5-dioxide (6). 5.0 g
0.02 mol) of compound 4 was dissolved in a
9
6
(
minimum amount of warm (≈50°C) glacial acetic acid
upon stirring. After dissolution, the heating was
stopped and 15 mL of 30% H O was added to the
mixture. The reaction mixture was incubated at room
temperature during 1 day. The precipitate was separated
by decantation and recrystallized from ethanol. Yield
4. Wang, J., Sancher-Roselo, M., Acena, J.L., Pozo, C.,
Sorochinsky, A.E., Fustero, S., Soloshonok, V.A., and
Liu, H., Chem. Rev., 2014, vol. 114, no. 4, p. 2432.
DOI: 10.1021/cr4002879.
2
2
5. Sears, J.E. and Boger, D.L., Acc. Chem. Res., 2015,
vol. 48, no. 3, p. 653. DOI: 10.1021/ar500400w.
–
1
3
.4 g (64%), mp 159°C. IR spectrum, ν, cm : 1134 vs
6. Veremeichik, Ya.V., Merabov, P.V., Lodochnikova, O.A.,
Krivolapov, D.B., Litvinov, I.A., Spirikhin, L.V.,
Lobov, A.N., and Plemenkov, V.V., Russ. J. Gen.
Chem., 2012, vol. 82, no. 8, p. 1416. DOI: 10.1134/
S1070363212080130.
1
and 1318 s (SO ), 1502 s (C–F), 3199 vs (NH). Н
NMR spectrum, δ, ppm: 1.16 d (1Н , J = 10.3 Hz),
2
1
1 2
HH
2
,3
11
2
1
2
.40–1.55 m (4Н ), 1.78 d (1Н , J = 10.3 Hz),
HH
1
(4)
4(1)
4a(10b)
.35 s [1Н )], 2.79 s [1Н ], 3.34 s [1Н
], 3.45 s
1
0b(4a)
7
3
4
7. Veremeichik, Ya.V., Merabov, P.V., Chuiko, A.V.,
Lodochnikova, O.A., and Plemenkov, V.V., Russ. J.
Org. Chem., 2013, vol. 49, no. 11, p. 1605. DOI:
[1Н
], 6.82 d.d (1Н , J = 8.7, J = 5.3 Hz),
.98 t.d (1Н , J = J = 8.7, J = 2.8 Hz), 7.17
HH
HF
8
3
3
4
6
HH HF HH
1
0
3
4
d.d (1Н , J = 9.7, J = 2.8 Hz), 9.85 s (1Н, NH).
HF
HH
1
0.1134/S1070428013110079.
1
3
9
3
F NMR spectrum, δ , ppm: –119 t.d (1F, J = 9.7,
F
FH
4
8. Sheldrick, G.M., SADABS, University of Göttingen,
JFH = 8.7, J = 5.3 Hz). Found, %: С 58.38, 58.50; Н
FH
Germany, 2004.
5
.12, 5.18; N 5.29, 5.32; S 12.03, 12.06. C H FNO S.
13 14 2
9
. Sheldrick, G.M., Acta Crystallogr. (A), 2008, vol. 64,
Calculated, %: С 58.41; H 5.28; N 5.24; S 12.00.
-Fluoro-1,2,3,4,4а,10b-hexahydro-2,3-epoxy-1,4-
methano-6Н-dibenzo[c,e]-5,6-thiazine-5,5-dioxide
7) was prepared similarly from 5.0 g (0.02 mol) of
adduct 5. Yield 3.5 g (62%), mp 228–229°С. IR
p. 112. DOI: 10.1107/S0108767307043930.
9
1
1
0. Farrugia, L.J., J. Appl. Crystallogr., 1999, vol. 32,
p. 837. DOI: 10.1107/S0021889899006020.
(
1. APEX (Version 2.1), SAINTPlus, Data Reduction and
Correction Program Version 7.31A. Bruker Advanced
X-Ray Solutions, Bruker XS Inc. Madison, Wisconsin,
USA, 2006.
–
1
spectrum, ν, cm : 1135 vs and 1311 s (SO ), 1503 s
(
2
1
C–F), 3263 vs (N–H). Н NMR spectrum, δ, ppm:
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 2 2016