Synthesis of cyclic sulfonamides by reaction of N-Sulfinyl-3-(trifluoromethyl)aniline with Norbornenes

Article abstract of DOI:10.1134/S1070428016010176

N-Sulfinyl-3-(trifluoromethyl)aniline reacted with bicyclo[2.2.1]hept-2-ene and bicyclo[2.2.1]hepta-2,5-diene to give the corresponding Diels?Alder adducts which were oxidized to 8-trifluoromethyl2,3,4,4a,6,10b-hexahydro-5λ⁶-1,4-methanodibenzo[

Full text of DOI:10.1134/S1070428016010176

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 1, pp. 92–95. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © Ya.V. Veremeichik, D.N. Shurpik, O.A. Lodochnikova, V.V. Plemenkov, 2016, published in Zhurnal Organicheskoi Khimii, 2016,
Vol. 52, No. 1, pp. 99–102.
Synthesis of Cyclic Sulfonamides by Reaction
of N-Sulfinyl-3-(trifluoromethyl)aniline with Norbornenes
Ya. V. Veremeichika, D. N. Shurpikb, O. A. Lodochnikovac, and V. V. Plemenkova
a Immanuel Kant Baltic Federal University, ul. Universitetskaya 2, Kaliningrad, 236040 Russia
e-mail: plem-kant@yandex.ru
b Butlerov Institute of Chemistry, Kazan (Volga Region) Federal University,
Kremlevskaya ul. 18, Kazan, 420008 Tatarstan, Russia
c Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences,
ul. Arbuzova 8, Kazan, 420088 Tatarstan, Russia
Received September 23, 2015
Abstract—N-Sulfinyl-3-(trifluoromethyl)aniline reacted with bicyclo[2.2.1]hept-2-ene and bicyclo[2.2.1]-
hepta-2,5-diene to give the corresponding Diels‒Alder adducts which were oxidized to 8-trifluoromethyl-
2,3,4,4a,6,10b-hexahydro-5λ6-1,4-methanodibenzo[c,e][1,2]thiazine-5,5(1H)-diones. The cycloaddition
occurred predominantly with participation of the S=N–C1=C6 fragment of N-sulfinyl-3-(trifluoromethyl)aniline
and exclusively at the endo side of bicyclo[2.2.1]heptenes.
DOI: 10.1134/S1070428016010176
Among all known pharmacophoric groups, sulfon-
amido group has been studied most thoroughly, and
sulfonamides occupy a leading position in pharma-
ceutics [1], whereas fluorinated medicines have been
introduced into pharmacological practice relatively
recently. However, by the beginning of the XXI cen-
tury various fluorinated derivatives have firmly occu-
pied their pharmaceutical niche. Fluoroaromatic and
fluoroaliphatic molecular fragments in combination
with other pharmacophoric moieties are often present
in efficient drugs with a broad spectrum of action [2].
For example, trifluoromethyl group is present in the
antitumor drugs sorafenib [3] and nilotinib [4], drugs
acting on the central nervous system (aprepitant [5],
ezogabine [6]) and urogenital system (dutasteride [7],
silodosin [8]), and antidiabetic drug sitagliptin [9]. The
anti-HIV drug tipranavir possesses both trifluoro-
methyl and sulfonamide functionalities [10].
We endeavored to synthesize sulfonamides posses-
sing a trifluoromethyl group according to the protocol
developed by us previously [11, 12], namely by hetero-
Diels–Alder reaction of N-sulfinyl-3-(trifluoromethyl)-
aniline (1) with bicyclo[2.2.1]heptenes, norbornene (2)
and norbornadiene (3). In this reaction, N-sulfinyl-
aniline acts as diene toward strained cycloolefins as
dienophiles, and meta position of the CF3 group with
respect to the N=S=O group provides the possibility of
formation in each case of structural isomers differing
by the position of the trifluoromethyl group relative to
the newly formed heterocyclic fragment.
The reactions were carried out by heating the reac-
tants at a diene-to-dienophile ratio of 1:1.5 without
a solvent in a sealed ampule on a boiling water bath for
8‒10 h, and the yields exceeded 80%. In the reaction
of N-sulfinylaniline 1 with norbornene (2) (Scheme 1)
we isolated a crystalline product which characteristi-
Scheme 1.
11
O
5S
O
O
4
6
HN
S
4a
3
HN
H2O2, AcOH
O
+
6a
1
2
S
10b
7
8
10a
10
F3C
N
F3C
F3C
9
1
2
4
5
92

SYNTHESIS OF CYCLIC SULFONAMIDES
93
Scheme 2.
O
O
O
S
S
O
HN
HN
H2O2, AcOH
O
+
S
F3C
N
F3C
F3C
1
3
6
7
cally displayed in the IR spectrum absorption bands
due to stretching vibrations of S=O (1055 cm–1), C‒F
(1121, 1172, 1327 cm–1), and N‒H bonds (3142 cm–1).
similar to the spectra of 6, but some proton signals of 7
were located in a weaker field; the largest downfield
shift was observed for the NH signal (Δδ = 1.0 ppm).
1
1
Its H NMR spectrum contained signals at δ 9.12 and
Furthermore, the H NMR spectrum of 7 lacked
9.22 (NH), 7.0‒7.5 (Harom), and 1.0‒3.5 ppm (bicyclic
fragment). The 19F NMR spectrum showed signals at
δF ‒61.5 and ‒57.5 ppm. These findings, in combina-
tion with the elemental analysis data, indicated forma-
olefinic proton signals, but signals from two oxirane
protons appeared in the region δ 3.40‒3.50 ppm (3J =
3.0–3.2 Hz).
The proposed structure of adduct 7 was confirmed
by X-ray analysis (Fig. 2). Both Diels–Alder reaction
and subsequent epoxidation were characterized by
endo selectivity.
1
tion of a 1:1 adduct, and the H NMR spectral pattern
in the aromatic region (one-proton singlet and two one-
proton AB doublets) proved the position of the tri-
fluoromethyl group on C8. Figure 1 shows the structure
of 8-trifluoromethyl-2,3,4,4a,6,10b-hexahydro-5λ4-
1,4-methanodibenzo[c,e][1,2]thiazin-5(1H)-one (4)
determined by X-ray analysis. It is seen that diene 1
approached the dienophile 2 molecule at the endo side.
EXPERIMENTAL
The elemental analyses were obtained on a EuroEA
3000 CHNS analyzer. The IR spectra were recorded in
KBr on a Bruker Vertex 70 spectrometer with Fourier
The oxidation of adduct 4 with hydrogen peroxide
in acetic acid at room temperature (24 h) afforded
compound 5 whose IR spectrum displayed absorption
bands at 1144, 1334 cm–1 (SO2), 1121, 1317 cm–1
1
transform. The H and 19F NMR spectra were
measured on a Bruker Avance 400 spectrometer at
1
400.0 and 376.5 MHz, respectively. The H chemical
1
(CF3), and 3172 cm–1 (N‒H). The H and 19F NMR
shifts were determined relative to the residual proton
signal of the deuterated solvent (DMSO-d6). The
melting points were measured with an Electrothermal
Digital Mel-Temp 3.0 melting point apparatus.
spectra of 5 were analogous to the spectra of 4 with the
difference that some signals were displaced downfield,
the largest downfield shift being observed for the NH
proton signal (Δδ = 1.0 ppm).
The X-ray analyses of single crystals of 4 and 7
were performed on a Bruker SMART Apex II diffrac-
tometer (graphite monochromator, λMoKα 0.71073 Å)
The reaction of 1 with norbornadiene (3) under
similar conditions gave adduct 6 (Scheme 2). It
showed in the IR spectrum absorption bands typical of
stretching vibrations of S=O (1057 cm–1), CF3 (1126,
1171, 1332 cm–1), and N‒H bonds (3180 cm–1). The
1H and 19F NMR spectra of 6 resembled those of 4, but
F2
C11
C2
C3
C1
C4
F1
C9
C10
C8
C16
1
the H NMR spectrum of the former lacked signals
C15
C14
assignable to the CH2CH2 fragment (multiplet at
δ 1.45–1.65 ppm in the spectrum of 4); instead,
a multiplet signal was observed at δ 6.30‒6.40 ppm
due to olefinic protons.
C13 C7
N6
S5
O5
F3
C12
Adduct 6 was oxidized with hydrogen peroxide in
acetic acid at room temperature (24 h). The IR spec-
trum of the product (compound 7) contained absorp-
tion bands corresponding to SO2 (1141, 1325 cm–1),
CF3 (1175, 1330 cm–1), and N‒H stretching modes
Fig. 1. Structure of the molecule of 8-trifluoromethyl-
2,3,4,4a,6,10b-hexahydro-5λ4-1,4-methanodibenzo[c,e][1,2]-
thiazin-5(1H)-one (4) according to the X-ray diffraction data.
1
(3201 cm–1). The H and 19F NMR spectra of 7 were
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 1 2016

VEREMEICHIK et al.
F1
94
tions with I ≥ 2σ(I)], Rw = 0.1166 (all reflections).
CCDC entry no. 1413121.
F2
C16
C9
O1
N-Sulfinyl-3-(trifluoromethyl)aniline (1) was
synthesized by reaction of 3-(trifluoromethyl)aniline
with an equimolar amount of thionyl chloride in boil-
ing benzene according to [12]. The product was dis-
tilled under reduced pressure, bp 105‒107°C (12 mm).
C11
C1
C4
C10
C2
C3
C8
F3
C14
C13
C7
C15
N6
8-Trifluoromethyl-2,3,4,4a,6,10b-hexahydro-5λ4-
1,4-methanodibenzo[c,e][1,2]thiazin-5(1H)-one (4).
A mixture of 10.4 g (0.05 mol) of compound 1 and
7.1 g (0.075 mol) of norbornene (2) was heated in
a sealed ampule on a water bath (95‒100°C) for 10 h.
After cooling, the mixture solidified and was treated
with petroleum ether, and the precipitate was filtered
off on a Büchner funnel, washed with cold petroleum
ether, and recrystallized from ethanol. Yield 86%,
mp 176‒177°C. IR spectrum, ν, cm–1: 3142 s (NH);
1121 v.s, 1172 s, 1327 s (CF3); 1055 s (S=O). 1H NMR
C12
S5
O5
O6
Fig. 2. Structure of the molecule of 8-trifluoromethyl-
2,3,4,4a,6,10b-hexahydro-5λ6-2,3-epoxy-1,4-methanodi-
benzo[c,e][1,2]thiazine-5,5(1H)-dione (7) according to the
X-ray diffraction data.
at 293 K. Corrections for absorption were applied
empirically using SADABS [13]. The structures were
solved by the direct method using SHELXS [14]. The
positions of non-hydrogen atoms were refined first in
isotropic and then in anisotropic approximation usng
SHELXL-97 [14]. Both structures showed disordering
of fluorine atoms in the trifluoromethyl group by two
positions with approximately equal populations. Hy-
drogen atoms attached to carbons were placed into
calculated positions which were refined according to
the riding model. The position of the NH hydrogen
atom in both structures was determined from the dif-
ference Fourier maps and was refined in isotropic
approximation. All calculations were performed with
the aid of WinGX [15] and APEX2 [16]. The X-ray
diffraction data for compounds 4 and 7 were deposited
to the Cambridge Crystallographic Data Centre.
2
spectrum, δ, ppm: 1.02 d (1H, 11-H, JHH = 10.0 Hz),
2
1.40‒1.55 m (4H, 2-H, 3-H), 1.60 d (1H, 11-H, JHH
=
10.0 Hz), 2.20 s and 2.42 s (1H each, 1-H, 4-H), 3.10 d
3
and 3.35 d (1H each, 4a-H, 10b-H, JHH = 8.6 Hz),
3
7.13 s (1H, 7-H), 7.28 d (1H, 9-H, JHH = 8.0 Hz),
7.43 d (1H, 10-H), 9.20 s (1H, NH). 19F NMR spec-
trum: δF ‒61.24 ppm, s (CF3). Found, %: C 55.78;
H 4.68; N 4.70; S 10.75. C14H14F3NOS. Calculated, %:
C 55.81; H 4.65; N 4.65; S 10.63.
8-Trifluoromethyl-1,2,3,4,4a,6,10b-hexahydro-
5λ6-1,4-methanodibenzo[c,e][1,2]thiazine-5,5(1H)-
dione (5). Compound 4, 3.0 g (0.01 mol), was dis-
solved by stirring in a minimal amount of warm (50°C)
glacial acetic acid. After complete dissolution, the
heating was turned off, and 15 mL of 30% hydrogen
peroxide was added. The mixture was kept for 24 h
and diluted with water, and the precipitate was
separated by decanting and recrystallized from ethanol.
Yield 65%, mp 162‒163°C. IR spectrum, ν, cm–1:
3172 s (NH); 1144 s, 1334 s (SO2); 1121 s, 1317 s
Compound 4. Triclinic crystal system, space group
P-1; C14H14F3NOS; unit cell parameters (20°C): a =
11.160(2), b = 12.291(2), c = 22.217(4) Å; α =
86.290(3), β = 76.229(3), γ = 70.234(2)°; V =
2785.0(9) Å3; Z = 8; dcalc = 1.437 g/cm3; μMo
=
1
(CF3). H NMR spectrum, δ, ppm: 1.17 d (1H, 11-H,
2.61 cm–1. Intensities of 21 492 reflections were
measured, including 6021 reflections with I ≥ 2σ(I).
Final divergence factors: R = 0.0613 [reflections with
I ≥ 2σ(I)], Rw = 0.1348 (all reflections). CCDC entry
no. 1413122.
2JHH = 10.3 Hz), 1.45‒1.62 m (4H, 2-H, 3-H), 1.78 d
2
(1H, 11-H, JHH = 10.3 Hz), 2.34 s and 2.72 s (1H
each, 1-H, 4-H), 3.33 s and 3.57 s (1H each, 4a-H,
3
10b-H), 7.08 s (1H, 7-H), 7.37 d (1H, 9-H, JHH
=
8.0 Hz), 7.52 d (1H, 10-H, 3JHH = 8.0 Hz), 10.25 s (1H,
NH). 19F NMR spectrum: δF ‒56.55 ppm, s (CF3).
Found, %: C 52.92; H 4.38; N 4.46; S 10.18.
C14H14F3NO2S. Calculated, %: C 53.00; H 4.42;
N 4.42; S 10.09.
Compound 7. Monoclinic crystal system, space
group P21/n; C14H12F3NO3S; unit cell parameters
(20°C): a = 11.20(1), b = 8.52(1), c = 14.61(2) Å; β =
91.714(15)°; V = 1394(3) Å3; Z = 4; dcalc = 1.579 g×
cm–3; μMo = 2.79 cm–1. Intensities of 7982 reflections
were measured, including 2122 reflections with
I ≥ 2σ(I). Final divergence factors: R = 0.0474 [reflec-
8-Trifluoromethyl-4,4a,6,10b-tetrahydro-5λ4-1,4-
methanodibenzo[c,e][1,2]thiazin-5(1H)-one (6) was
synthesized as described above for compound 4. Yield
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 1 2016

SYNTHESIS OF CYCLIC SULFONAMIDES
95
82%, mp 226‒228°C. IR spectrum, ν, cm–1: 3180 s
(NH); 1126 v.s, 1171 s, 1332 v.s (CF3); 1057 s (S=O).
1H NMR spectrum, δ, ppm: 1.15 d and 1.77 d (1H
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2
each, 11-H, JHH = 8.9 Hz), 2.82 s (1H, 1-H or 4-H),
2.87 d (1H, 4a-H or 10b-H, 3JHH = 8.7 Hz), 3.12 s (1H,
7. Frue, S.V., Curr. Top. Med. Chem., 2006, vol. 6, p. 405.
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10. Thaisrivongs, S., Skulnick, H.I., Turner, S.R., Stroh-
bach, J.W., Tommasi, R.A., Johnson, P.D., Aristoff, P.A.,
Judge, T.M., Gammill, R.B., Morris, J.R.,
Romines, K.R., Chrusciel, R.A., Hinshaw, R.R.,
Chong, K.-T., Tarpley, W.G., Poppe, S.M., Slade, D.E.,
Lynn, J.C., Horn, M.-M., Tomich, P.K., Seest, E.P.,
4-H or 1-H), 3.18 d (1H, 10b-H or 4a-H, JHH
=
8.7 Hz), 6.30‒6.40 m (2H, 2-H, 3-H), 7.18 s (1H, 7-H),
3
7.33 d (1H, 9-H, JHH = 7.8 Hz), 7.52 d (1H, 10-H,
19
3JHH = 7.8 Hz), 9.35 s (1H, NH). F NMR spectrum:
δF ‒61.20 ppm, s (CF3). Found, %: C 56.23; H 3.98;
N 4.60; S 10. 66. C14H12F3NOS. Calculated, %:
C 56.18; H 4.01; N 4.68; S 10.70.
8-Trifluoromethyl-2,3,4,4a,6,10b-hexahydro-5λ6-
2,3-epoxy-1,4-methanodibenzo[c,e][1,2]thiazine-
5,5(1H)-dione (7) was synthesized as described above
for compound 5. Yield 60%, mp 199‒201°C. IR spec-
trum, ν, cm–1: 3201 s (NH); 1175 s, 1330 s (CF3);
1
1141 s, 1325 s (SO2). H NMR spectrum, δ, ppm:
2
1.12 d and 1.38 d (1H each, 11-H, JHH = 10.7 Hz),
2.62 s and 3.00 s (1H each, 1-H, 4-H), 3.43 d and
Dolak,
L.A.,
Howe, W.J.,
Howard,
G.M.,
3
3.47 d (1H each, 2-H, 3-H, JHH = 3.2 Hz), 3.61 d and
Schwende, F.J., Ruwart, M.J., Koeplinger, K.A.,
Zhiyang, Z., Cole, S., Zaya, R.M., Kakuk, T.J.,
Janakiramn, M.N., and Watenpaugh, K.D., J. Med.
Chem., 1996, vol. 39, p. 4349.
3
3.68 d (1H each, 4a-H, 10b-H, JHH = 9.2 Hz), 7.13 s
(1H, 7-H), 7.42 d (1H, 9-H, 3JHH = 8.0 Hz), 7.57 d (1H,
3
10-H, JHH = 8.0 Hz), 10.40 s (1H, NH). 19F NMR
spectrum: δF ‒61.35 ppm, s (CF3). Found, %: C 50.66;
H 3.67; N 4.30; S 9.72. C14H12F3NO3S. Calculated, %:
C 50.76; H 3.63; N 4.23; S 9.67.
11. Veremeichik, Ya.V., Merabov, P.V., Lodochniko-
va, O.A., Krivolapov, D.V., Litvinov, I.A., Spiri-
khin, L.V., Lobov, A.N., and Plemenkov, V.V., Russ. J.
Gen. Chem., 2012, vol. 82, p. 1416.
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