A One-Pot Access to Benzo[b][1,4]selenazines from 2-Aminoaryl Diselenides

Article abstract of DOI:10.1002/ejoc.201600351

Different 2-sulfonylaminoaryl diselenides substituted with electron-withdrawing or -donating groups are transformed in one pot into benzo[b][1,4]selenazines. The reaction uses a substoichiometric amount of Cu(OTf)₂, and the mechanism involves a base-mediated 1,4-elimination at selenium with the generation of an o-iminoselenoquinone and a 2-sulfonylaminoselenolate anion. The former is a dienic species that can react with electron-rich dienophiles to give the target cycloadducts. The latter is oxidised by air back to the starting diselenide, allowing its complete consumption. A preliminary investigation of the GPx-like activity of a selected selenazine is also described.

Full text of DOI:10.1002/ejoc.201600351

DOI: 10.1002/ejoc.201600351
Full Paper
Selenium
A One-Pot Access to Benzo[b][1,4]selenazines from 2-Aminoaryl
Diselenides
Stefano Menichetti,[a] Antonella Capperucci,[a] Damiano Tanini,[a] Antonio L. Braga,[b]
Giancarlo V. Botteselle,[c] and Caterina Viglianisi*[a]
Abstract: Different 2-sulfonylaminoaryl diselenides substituted aminoselenolate anion. The former is a dienic species that can
with electron-withdrawing or -donating groups are transformed react with electron-rich dienophiles to give the target cycload-
in one pot into benzo[b][1,4]selenazines. The reaction uses a ducts. The latter is oxidised by air back to the starting disele-
substoichiometric amount of Cu(OTf)2, and the mechanism in- nide, allowing its complete consumption. A preliminary investi-
volves a base-mediated 1,4-elimination at selenium with the gation of the GPx-like activity of a selected selenazine is also
generation of an o-iminoselenoquinone and a 2-sulfonyl- described.
Introduction
erodiene with several electron-rich dienophiles to give, regio-
and stereoselectively, benzo[b][1,4]selenazines 4. Since selenol-
ate anion 2a, which acts as a leaving group, is oxidised by mo-
lecular oxygen (in air) back to the starting diselenide (i.e., 1a),
the starting diselenide is completely consumed during the
process.
Selenium is a very important element in organic chemistry, and
several reviews describe its utility in synthesis.[1] Moreover, it
is an essential dietary component for many living organisms,
including humans. Recently, selenium-containing compounds
have attracted increased attention as a result of their ability to
act as glutathione peroxidase (GPx) mimics, catalytic antioxid-
ants, and anticancer compounds.[2]
As part of our research on Diels–Alder reactions and the ap-
plications of electron-poor chalcogen-containing heterodi-
enes,[3] we recently reported[4] a simple procedure for the prep-
aration of benzo[b][1,4]selenazines from 2-N-sulfonylaminoaryl
diselenides based on the CuII-catalysed generation of o-imino-
selenones, a new class of transient electron-poor heterodienes.
The procedure allowed the effective isolation of benzofused
selenium-containing heterocycles under quite mild reaction
conditions, with complete consumption of both of the selen-
ium-containing subunits of a diselenide. The mechanism show-
ing how this could be achieved is given in Scheme 1.[4] Thus,
copper(II) activation of the Se–Se bond of the parent 2-N-
sulfonylaminoaryl diselenide (i.e., 1a), followed by base-medi-
ated 1,4-elimination at selenium of selenolate anion 2a, gener-
ates o-iminoselenoquinone 3a. This efficiently participates in
inverse-electron-demand hetero-Diels–Alder reactions as a het-
[a] Department of Chemistry “U. Schiff”, University of Florence,
Via della Lastruccia, 3–13, 50019 Sesto Fiorentino (FI), Italy
E-mail: caterina.viglianisi@unifi.it
Scheme 1. Synthetic one-pot procedure for the preparation of
benzo[b][1,4]selenazines
4 from the parent 2-N-sulfonylaminophenyl di-
selenide (1a). EDG = electron-donating group; LA = Lewis acid.
macromad.jimdo.com
[b] LabSelen – Lab. de Síntese de Pequenas Moléculas Quirais de Selênio e
Telúrio, Dpto de Química, CFM – UFSC,
Campus Universitário Trindade, 88040-900 Florianópolis, SC, Brazil
[c] Laboratório de Pesquisa em Química, Universidade Estadual do Oeste do
Paraná – UNIOESTE, Centro de Engenharias e Ciências Exatas, CECE,
85819-110 Toledo, PR, Brazil
The above procedure involving aminoaryl diselenides[4]
proved to be particularly efficient compared with those of the
corresponding aminoaryl disulfides[5] and hydroxy disulfides.[6]
Good yields of selenazines 4 were achieved with many different
dienophiles, including styrenes, enol ethers, vinyl amides, and
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600351
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1,3-dienes. Recently, some of us have optimised the preparation formation and cycloaddition of a dienic o-iminoselenone, and
of differently substituted 2-aminoaryl diselenides.[7] Thus, in this oxidation of the selenolate anion to give the diselenide. Thus an
paper, we report the scope and limitations of the procedure explanation of the effect of the substituents on the diselenide
shown in Scheme 1, studying the effect of substitution on the aromatic ring is very difficult. Clearly, o-iminoselenones 3 retain
nitrogen atom and on the diselenide ring. Additionally, a their ability to act as electron-poor dienes irrespective of the
benzoselenazine was selected for a preliminary study on the nature of the substituents (H; or electron-withdrawing group:
GPx-like activity of these derivatives.
Cl, Br, CF3; or electron-donating group: CH3). The best results in
terms of the final yield of selenazine (Scheme 2, derivatives 4d
and 4g), were obtained using 4-CF3 substituted diselenide 1d
as starting material, i.e., via the more electron-poor iminoselen-
one 3d. Thus, it is reasonable to consider the [4+2] process as
one of the possible rate-determining steps of the whole proce-
dure.
Results and Discussion
Using the optimised synthetic procedure mentioned above,[7]
we were able to prepare the parent unsubstituted 2-amino-
phenyl diselenide (5a), but also diselenides substituted with
electrong-withdrawing groups 5b–5d and electron-donating
groups 5e and 5f. These 2-aminophenyl diselenides 5 were
transformed into the corresponding NH-tosyl (NHTs) 1a–1e and
NH-o-nosyl (NHNs) 6 and 7 sulfonamides, as shown in Figure 1.
In fact, we were unable to transform 4-methoxy derivative 5f
into the corresponding 2-NHTs diselenide (i.e., 1f), since exten-
sive decomposition occurred during attempted sulfonamid-
ation. To verify the generality, scope, and limitations of the pro-
cedure shown in Scheme 1 we treated derivatives 1a–1e, 6, and
7 with Cu(OTf)2 (0.2 mol) as a suitable Lewis acid, Et3N (0.5 mol),
and p-methoxystyrene as a dienophile (2.0 mol). The previous
optimised conditions[4] used CHCl3 as the solvent at 60 °C; how-
ever, some of the new N-sulfonylaryl diselenides were only spar-
ingly soluble in chloroform, or needed very long reaction times.
Thus we optimised the reaction conditions, choosing the best
solvent and reaction time for each of the different diselenides.
Scheme 2. Benzo[b][1,4]selenazines 4a–4g prepared in this study.
The transformation of aminoaryl diselenides 5 into N-sulf-
onylaryl diselenides 1 is essential for the success of the proce-
dure, since in this way the deprotonation at nitrogen under
mild reaction conditions is possible with a weak base like Et3N.
Indeed, 2-N-acylamino- and 2-N-carbamoylaminoaryl diselen-
ides were completely unreactive under the same or harsher re-
action conditions. On the other hand, restoration of the amino
group from NTs cycloadducts 4 is not a trivial process, and sev-
eral attempts run using Na/naphthalene[9] or SmI2[10] as detosyl-
ating reagents were completely unsuccessful. This prompted us
to prepare NHNs derivatives 1f and 1g, which were successfully
used to synthesise NHNs-selenazines 4f and 4g (Scheme 2).
When these derivatives were treated with thioacetic acid and
Figure 1. 2-Aminoaryl diselenides 5a–5f and 2-N-sulfonylaryl diselenides 1a–
1e, 6, and 7 prepared and used in this study.
Satisfactorily, using nonpolar solvents (CHCl3 and toluene) or
polar aprotic solvents (DMSO and DMF),[8] we were able to iso-
late the expected benzo[b]selenazines (i.e., 4a–4g), as shown in
Scheme 2. The isolated yields, after a trivial work-up and col-
umn chromatography, were acceptable to good, and, in each
case, account for the consumption of both subunits of the di-
selenide residue. Taken together with previous results,[4] the
data reported in Scheme 2 definitively show that 2-sulfonyl-
aminoaryl diselenides are suitable starting materials for the syn-
thesis of differently substituted benzoselenazines. The mecha-
nism of this one-pot transformation involves several steps, i.e., LiOH in dry DMF,[11] we observed a clean denosylation, and N-
secondary sulfonamide deprotonation, Lewis acid/Se interac- unsubstituted selenazines 8 and 9 were isolated in reasonable
tion with Se–Se bond weakening, 1,4-elimination at selenium, yields, as shown in Scheme 3. As reported for related
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benzo[b][1,4]thiazine derivatives,[11b] the removal of the nosyl tures that are identical apart from the presence of the protect-
group causes a remarkable conformational change in these six- ing group on nitrogen, a feature that could modify the nucleo-
membered heterocycles.
philic character of the selenium atom. The catalytic activity of
these compounds was investigated following a literature proce-
dure[12] for the reaction between hydrogen peroxide (H2O2) and
reduced dithiothreitol (DTTred). The oxidation of the substrate
was monitored by 1H NMR spectroscopy. [D4]Methanol (CD3OD)
was selected as the solvent[13] for this assay. A control experi-
ment was carried out in the absence of catalyst. As shown in
Figure 2, when the reaction was carried out in the presence of
4b, 96 % of DTTred remained unreacted after 200 min. In con-
trast, when N-unsubstituted benzo[b]selenazine 8 was used as
the catalyst, 50 % of oxidised dithiothreitol (DTTox) was formed
within 150 min. These results showed that the catalytic function
of the heterocycles is strongly influenced by the nucleophilic
character of the selenium atom, and by the presence of free
amine groups. In this context, it has been reported that free
amines behave as good base catalysts for DTTred oxidation.[12a]
To compare the activity of our new compounds with a selenium
derivative commonly used as a standard,[14,15] we also meas-
ured the GPx-like catalytic activity of diphenyldiselenide; as ex-
pected, this was appreciably more active (Figure 2 purple line).
Scheme 3. Synthesis of N-unsubstituted benzoselenazines 8 and 9 and the
conformational consequences of substitution on nitrogen of the selenazines.
In fact, as shown in Scheme 3, the 1H NMR spectra of all
derivatives 4, and in particular of 4f and 4g (see the Exp. Sec-
tion for details), show for the proton on C-3 an apparent triplet,
3
from δ = 5.5 to 6.0 ppm, due to two similar J coupling con-
stants with the two protons on C-2 (J = 7.4 Hz for 4f, and J =
8.0 Hz for 4g). This means that the proton on C-3, occupies a
pseudoequatorial position, and the p-methoxyphenyl group is
pseudoaxial. This is only apparently incongruous. In fact, this
conformation ensures that there is less steric hindrance be-
tween the nosyl group on nitrogen and the aryl group on C-3.
After denosylation, the 1H NMR spectra of the secondary
amines (i.e., 8 and 9) show for the proton on C-3 a clean dou-
blet of doublets as the result of two quite different 3J constants
with the protons on C-2 (J = 9.9 and 2.6 Hz for 8, and J = 9.2
and 2.8 Hz for 9). In other words, in the secondary amines 8
and 9, after the removal of the bulky nosyl group on nitrogen,
the proton on C-3 is pseudoaxial, and the p-methoxyphenyl
group on C-3 occupies, as expected, a pseudoequatorial posi-
tion (Scheme 3 and Exp. Section).
Figure 2. GPx-like activity of compounds 4b, 8, and diphenyl diselenide in
the formation of DTTox from DTTred with H2O2 in CD3OD.
Finally, we transformed selenazines 4a and 8 into the corre-
sponding selenoxides using a stoichiometric amount of mCPBA
(m-chloroperbenzoic acid) in CH2Cl2 at 0 °C. The oxidation oc-
cured in quite good yields, and, similarly to the related sulfur-
containing heterocyclic systems already reported,[5,11] gave rea-
sonably stable and isolable selenoxides 10 and 11 as single 1,3-
trans stereoisomer (Scheme 4).
Conclusions
In this paper, we report an original yet general approach to the
preparation of benzo[b][1,4]selenazines from 2-sulfonylamino-
aryl diselenides. The procedure takes place in one pot using a
substoichiometric amount of Cu(OTf)2 and a weak base. The
reaction takes place through a 1,4-elimination at selenium of a
selenolate anion, resulting in the generation of an o-imino-
selenone. The former is oxidised by air to reform the starting
diselenide; the latter is trapped as an electron-poor diene in an
efficient [4+2] cycloaddition with electron-rich alkenes. Substi-
tution is well tolerated on the dienophile, the nitrogen, and the
diselenide aromatic ring. This opens the way to a wide variety
of benzo-fused selenazines.
Scheme 4. Synthesis of benzoselenazine selenoxides 10 and 11.
Experimental Section
With these new selenium-containing heterocycles in hand,
we decided to preliminarily test their GPx-like catalytic antioxid-
ant activity. We chose N-Ts derivative 4b and the corresponding
General Remarks: 1H and 13C NMR spectra were recorded with a
Varian Mercury Plus instrument at 400 and 100 MHz, respectively,
or with a Varian INOVA instrument at 400 and 100 MHz, respectively,
N-unsubstituted derivative (i.e., 8). Thus, we had a pair of struc- in CDCl3 or (CD3)2CO. The corresponding residual non-deuterated
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solvent was used as a reference. 77Se NMR spectra were recorded
in CDCl3 at 76 MHz with a Bruker Ultrashield 400 Plus instrument.
PhSeSePh was used as an external reference (δ = 461 ppm). FTIR
spectra were recorded with a Perkin–Elmer 1600 FTIR spectrometer
in CCl4 or CDCl3 solutions. Melting points were measured with a
Büuchi 510 melting-point apparatus. Elemental analysis was carried
out with a Perkin–Elmer 2400 series II elemental analyser. GC mass
sequence to a solution of 2-N-sulfonyl diselenide 1a–1e, 6, 7
(0.08 mmol, 1 equiv.) in dry solvent (0.03 M) in a reaction vial. The
mixture was heated at the right temperature until TLC showed com-
plete disappearance of the diselenide. Then, the reaction mixture
was diluted with dichloromethane (40 mL), washed with saturated
NH4Cl (40 mL), and dried with anhydrous Na2SO4, and the solvents
were evaporated to dryness. Purification by silica gel column chro-
spectra were recorded with a QMD 100 Carlo–Erba instrument. Re- matography gave derivative 4a–4g.
actions were monitored by TLC using commercially available pre-
4-Tosyl-3,4-dihydro-2H-benzo[b][1,4]selenazine (4a): The reac-
coated plates (silica gel 60 F 254), and products were visualised
with acidic vanillin solution. Silica gel 60, 230–400 mesh, was used
for column chromatography. Dry solvents were obtained using a
Pure Solv Micro system. CHCl3 and Et3N were purified following
standard procedures. Commercially available reagents and catalysts
were used as obtained from freshly opened containers without fur-
ther purification.
tion mixture was heated in dry CHCl3 at 60 °C for 72 h. Purification
by silica gel column chromatography (dichloromethane/petroleum
ether, 3:1, Rf = 0.70) gave derivative 4a (55 mg, 75 %) as a white
solid, m.p. 50–51 °C. 1H NMR (400 MHz, CDCl3): δ = 7.65 (dd, J =
8.0, 1.2 Hz, 1 H), 7.47–7.43 (m, 2 H), 7.34–7.30 (m, 2 H), 7.21 (dd, J =
7.6, 1.6 Hz, 1 H), 7.20–7.15 (m, 3 H), 7.04 (td, J = 7.6, 1.6 Hz, 1 H),
6.81–6.77 (m, 2 H), 5.74 (at, J = 6.6 Hz, 1 H), 3.75 (s, 3 H), 3.36 (dd,
J = 12.2, 6.6 Hz, 1 H), 3.04 (dd, J = 12.2, 6.6 Hz, 1 H), 2.40 (s, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 158.9, 143.5, 136.7, 135.5,
132.1, 131.3, 130.4, 129.3 (2 C), 128.8, 127.8, 127.5, 126.8, 126.6,
113.9, 59.7, 55.2, 27.0, 21.6 ppm. 77Se NMR (76 MHz, CDCl3): δ =
212 ppm. C22H21NOSSe (426.43): calcd. C 57.64, H 4.62, N 3.06;
found C 58.01, H 4.95, N 3.02.
A general procedure for the synthesis of 2-nitroaryl diselenides, 2-
aminoaryl diselenides 5, and 2-N-sulfonylaminoaryl diselenides 1[7]
is reported. Spectroscopic data for these compounds is available in
the Supporting Information. Derivatives 5a and 1a were prepared
as already reported.[4]
General Procedure for the Synthesis of 2-Nitroaryl Diselenides:
In a round-bottomed flask, a mixture of elemental selenium
(158 mg, 2.0 mmol) and KOH (224 mg, 4.0 mmol) was melted with
a thermal blower. The resulting mixture was cooled to room tem-
perature, and diluted with distilled water (4 mL). Then the corre-
sponding o-halonitrobenzene (1.0 mmol) and THF (1 mL) were
added, and the mixture was stirred for 0.5 to 2 h, depending on
the substrate. When the reaction was complete, the product was
extracted with EtOAc (20 mL), and the organic phase was washed
with H2O (3 × 20 mL). The organic phase was dried with MgSO4,
and filtered, and the solvent was removed under reduced pressure.
The product was purified by flash column chromatography eluting
with an appropriate mixture of hexane/ethyl acetate.
6-Chloro-3-(4-methoxyphenyl)-4-tosyl-3,4-dihydro-2H-benzo-
[b][1,4]selenazine (4b): The reaction mixture was heated in DMF
at 80 °C for 24 h. Purification by silica gel column chromatography
(dichloromethane/petroleum ether, 5:1, Rf = 0.70) gave derivative
1
4b (46 mg, 58 %) as a glassy solid. H NMR (400 MHz, CDCl3): δ =
7.66 (d, J = 2.2 Hz, 1 H), 7.50–7.48 (m, 2 H), 7.31–7.27 (m, 2 H), 7.21–
7.19 (m, 2 H), 7.13 (d, J = 8.3 Hz, 1 H), 7.01 (dd, J = 8.3, 2.2 Hz, 1 H),
6.82–6.78 (m, 2 H), 5.75 (at, J = 6.3 Hz, 1 H), 3.76 (s, 3 H), 3.37 (dd,
J = 12.2, 6.3 Hz, 1 H), 3.07 (dd, J = 12.2, 6.3 Hz, 1 H), 2.40 (s, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 159.2, 144.1, 136.7, 136.6,
131.9, 131.4, 131.0, 130.9, 129.6, 128.0, 127.6, 127.2, 126.6, 114.1,
59.1, 55.3, 26.4, 21.8 ppm. 77Se NMR (76 MHz, CDCl3): δ = 213 ppm.
IR: ν = 2935, 2260, 1611, 1513, 1461, 1352, 1251, 1165 cm–1
.
˜
General Procedure for the Synthesis of 2-Aminoaryl Diselenides
5: The appropriate 2-nitroaryl diselenide (1.0 mmol), methanol
(20 mL), FeSO4·7H2O (5.0 mmol, 1.390 g), and distilled water (20 mL)
were added to a two-necked round-bottomed flask equipped with
a reflux condenser. The reaction mixture was stirred at reflux for
1.5 h. After this time, NH4OH (10 mL) was added, and the mixture
was stirred under reflux for 10 min. A black mixture was formed
after the addition of the NH4OH. Then the mixture was cooled to
room temperature, diluted with ethyl acetate (50 mL), filtered, and
washed with H2O (3 × 20 mL). The organic phase was dried with
MgSO4, and filtered, and the solvent was removed under reduced
pressure. The product was purified by flash column chromatogra-
phy eluting with an appropriate mixture of hexane/ethyl acetate.
C22H20ClNO3SSe (492.88): calcd. C 53.61, H 4.09, N 2.84; found C
53.65, H 4.05, N 2.84.
6-Bromo-3-(4-methoxyphenyl)-4-tosyl-3,4-dihydro-2H-benzo-
[b][1,4]selenazine (4c): The reaction mixture was heated in DMF
80 °C for 24 h. Purification by silica gel column chromatography
(dichloromethane/petroleum ether, 3:1, Rf = 0.65) gave derivative
4c (52 mg, 60 %) as a glassy solid. 1H NMR (400 MHz, CDCl3): δ =
7.80 (d, J = 2.1 Hz, 1 H), 7.50–7.48 (m, 2 H), 7.30–7.28 (m, 2 H), 7.21–
7.19 (m, 2 H), 7.15 (dd, J = 8.3, 2.1 Hz, 1 H), 7.06 (d, J = 8.3 Hz, 1 H),
6.82–6.78 (m, 2 H), 5.75 (at, J = 6.3 Hz, 1 H), 3.76 (s, 3 H), 3.36 (dd,
J = 12.2, 6.3 Hz, 1 H), 3.07 (dd, J = 12.2, 6.3 Hz, 1 H), 2.41 (s, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 159.2, 144.1, 136.8, 136.7,
133.6, 131.4, 131.3, 130.0, 129.7, 128.0, 127.6, 127.3, 119.4, 114.2,
General Procedure for the Synthesis of 2-N-Sulfonylaminoaryl
Diselenides 1b–1e, 6, 7: A solution of sulfonyl chloride (1.75 mmol)
in dry CH2Cl2 (5 mL) was added dropwise under a nitrogen flow to
a solution of bis(2-aminophenyl) diselenide (0.73· mmol) in dry
CH2Cl2 (5 mL) and dry pyridine (0.118 mL, 1.46 mmol). The reaction
mixture was heated at reflux for 44 h, then it was cooled to room
temp. and diluted with CH2Cl2 (40 mL). The organic phase was
washed with H2O (3 × 40 mL), and saturated aq. NH4Cl (2 × 40 mL),
and dried with anhydrous Na2SO4. The solvents were evaporated
under vacuum. Purification by silica gel column chromatography
gave derivative 1b–1e, 6, 7.
59.1, 55.4, 26.4, 21.8 ppm. IR: ν = 2959, 2840, 2259, 1610, 1513,
˜
1460, 1353, 1252, 1165, 1090 cm–1. C22H20BrNO3SSe (537.33): calcd.
C 49.18, H 3.75, N 2.61; found C 49.27, H 3.79, N 2.67.
3-(4-Methoxyphenyl)-4-tosyl-6-(trifluoromethyl)-3,4-dihydro-
2H-benzo[b][1,4]selenazine (4d): The reaction mixture was heated
in CHCl3 at 60 °C for 120 h. Purification by silica gel column chroma-
tography (dichloromethane/petroleum ether, 1:1, Rf = 0.34) gave
derivative 4d (66 mg, 78 %) as a white solid, m.p. 192–198 °C. 1H
NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 1.2 Hz, 1 H), 7.51–7.48 (m,
2 H), 7.32–7.28 (m, 3 H), 7.24–7.20 (m, 3 H), 6.81–6.77 (m, 2 H), 5.82
(at, J = 5.8 Hz, 1 H), 3.74 (s, 3 H), 3.45 (dd, J = 12.1, 5.8 Hz, 1 H),
3.18 (dd, J = 12.1, 5.8 Hz, 1 H), 2.41 (s, 3 H) ppm. 13C NMR (100 MHz,
General Procedure for the Synthesis of Selenazines 4: Cu(OTf)2
(0.016 mmol, 20 mol-%), p-methoxystyrene (21 mg, 0.16 mmol, CDCl3): δ = 159.0, 144.1, 136.5, 135.6, 132.5, 130.4, 130.3, 129.6,
2
3
1 equiv.) and Et3N (8 mg, 0.08 mmol, 0.5 equiv.) were added in
128.6 (q, JC,F = 32 Hz), 127.8, 127.4, 127.3 (q, JC,F = 10 Hz), 123.7
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1
3
(q, JC,F = 270 Hz), 123.0 (q, JC,F = 10 Hz), 114.0, 57.7, 55.2, 25.4,
3 H), 3.27 (dd, J = 11.3, 9.9 Hz, 1 H), 2.94 (dd, J = 11.3, 2.6 Hz, 1 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 159.8, 145.5, 135.3, 131.6,
21.6 ppm. IR: ν = 2926, 2257, 1606, 1512, 1343, 1325, 1254, 1166,
˜
1133 cm–1. MS (EI): m/z = 526 [M]+. C23H20F3NO3SSe (526.43): calcd.
130.8, 127.9, 119.0, 115.8, 114.5, 108.5, 56.3, 55.5, 25.9 ppm. IR: ν =
˜
C 52.48, H 3.83, N 2.66; found C 52.51, H 3.79, N 2.60.
3365, 2939, 1583, 1512, 1465, 1251 cm–1. C15H14ClNOSe (338.69):
calcd. C 53.19, H 4.17, N 4.14; found C 53.12, H 4.20, N 4.10.
3-(4-Methoxyphenyl)-6-methyl-4-tosyl-3,4-dihydro-2H-benzo-
[b][1,4]selenazine (4e): The reaction mixture was heated in DMF
80 °C for 21 h. Purification by silica gel column chromatography
(dichloromethane/petroleum ether, 5:1, Rf = 0.50) gave derivative
3-(4-Methoxyphenyl)-6-(trifluoromethyl)-3,4-dihydro-2H-
benzo[b][1,4]selenazine (9): Thioacetic acid (4 μL, 0.06 mmol,
2.0 equiv.) and lithium hydroxide (3 mg, 0.12 mmol, 4.0 equiv.) were
added to a solution of 4g (17 mg, 0.03 mmol) in dry DMF (1.0 mL)
under nitrogen. The mixture was stirred at 60 °C for 24 h, then it
was diluted with EtOAc (20 mL), and washed with saturated aq.
NaHCO3 (15 mL). The organic phase was dried with anhydrous
Na2SO4, and the solvents were evaporated to dryness. Purification
by silica gel column chromatography (dichloromethane/petroleum
ether, 8:1, Rf = 0.67) gave derivative 9 (7 mg, 62 %) as a colourless
oil. 1H NMR [400 MHz,(CD3)2CO]: δ = 7.37–7.30 (m, 3 H), 7.06 (s, 1
H), 6.96–6.93 (m, 2 H), 6.82 (d, J = 8.0 Hz, 1 H), 5.76 (br. s, 1 H), 4.70
(dd, J = 9.2, 2.8 Hz, 1 H), 3.80 (s, 3 H), 3.30 (dd, J = 11.2, 9.2 Hz, 1
H), 3.07 (dd, J = 11.2, 2.8 Hz, 1 H) ppm. 13C NMR [100 MHz,(CD3)2CO]:
1
4e (57 mg, 75 %) as a pale yellow glassy solid. H NMR (400 MHz,
CDCl3): δ = 7.52 (d, J = 8.2 Hz, 1 H), 7.46–7.44 (m, 2 H), 7.32–7.29
(m, 2 H), 7.18–7.16 (m, 2 H), 7.03 (d, J = 1.3 Hz, 1 H), 6.97 (dd, J =
8.2, 1.3 Hz, 1 H), 6.81–6.77 (m, 2 H), 5.70 (at, J = 6.7 Hz, 1 H), 3.75
(s, 3 H), 3.32 (dd, J = 12.2, 6.7 Hz, 1 H), 3.01 (dd, J = 12.2, 6.7 Hz, 1
H), 2.40 (s, 3 H), 2.25 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
159.0, 143.6, 137.0, 132.9, 132.4, 131.1, 130.9, 129.4, 128.4, 127.9,
127.8, 127.6, 114.0, 59.7, 55.3, 29.8, 26.9, 21.7 ppm. IR: ν = 2962,
˜
2928, 2852, 1610, 1512, 1348, 1251, 1165 cm–1. C23H23NO3SSe
(472.46): calcd. C 58.47, H 4.91, N 2.96; found C 58.54, H 5.01, N
3.02.
2
δ = 161.5, 147.5, 137.3, 135.8, 131.8, 129.8, 129.4 (q, JC,F = 30 Hz),
6-Chloro-3-(4-methoxyphenyl)-4-[(2-nitrophenyl)sulfonyl]-3,4-
dihydro-2H-benzo[b][1,4]selenazine (4f): The reaction mixture
was heated in DMF 80 °C for 90 h. Purification by silica gel column
chromatography (dichloromethane/petroleum ether, 3:1, Rf = 0.70)
gave derivative 4f (60 mg, 72 %) as a brown glassy solid. 1H NMR
(400 MHz, CDCl3): δ = 7.70–7.66 (m, 1 H), 7.60 (d, J = 2.2 Hz, 1 H),
7.57–7.54 (m, 1 H), 7.49–7.45 (m, 1 H), 7.39–7.37 (m, 1 H), 7.30–7.25
(m, 3 H), 7.15 (dd, J = 8.3, 2.2 Hz, 1 H), 6.83–6.80 (m, 2 H), 5.94 (at,
J = 7.4 Hz, 1 H), 3.77 (s, 3 H), 3.53 (dd, J = 16.0, 7.4 Hz, 1 H), 3.11
(dd, J = 16.0, 7.4 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
159.4, 136.5, 134.1, 132.8, 132.0, 131.9, 131.8, 131.6, 131.2, 130.9,
1
3
126.5 (q, JC,F = 270 Hz), 115.9, 115.4 (q, JC,F = 10 Hz), 113.9 (q,
3JC,F = 10 Hz), 57.3, 56.6, 27.3 ppm. IR: ν = 2928, 1601, 1512, 1464,
˜
1325, 1250, 1173, 1127, 1079 cm–1. C16H14F3NOSe (372.25): calcd. C
51.63, H 3.79, N 3.76; found C 51.37, H 3.35, N 3.83.
3-(4-Methoxyphenyl)-4-tosyl-6-(trifluoromethyl)-3,4-dihydro-
2H-benzo[b][1,4]selenazine 1-Oxide (10): A solution of mCPBA
(9 mg, 0.054 mmol, 0.95 equiv.) in dry CH2Cl2 (1 mL) was added to
a solution of 4a (26 mg, 0.057 mmol) in dry CH2Cl2 (1 mL) at 0 °C.
The mixture was stirred at 0 °C for 20 min, then it was diluted with
CH2Cl2 (20 mL), washed with Na2SO3 (20 mL) and with saturated
aq. NaHCO3 (20 mL), and dried with anhydrous Na2SO4. The solvents
were evaporated to dryness to give derivative 10 (31 mg, 95 %)
without further purification, m.p. 55–57 °C. 1H NMR (CDCl3,
400 MHz): δ = 7.79–7.76 (m, 1 H), 7.56–7.52 (m, 3 H), 7.42–7.39 (m,
2 H), 7.26–7.23 (m, 2 H), 7.16–7.14 (m, 2 H), 6.82–6.79 (m, 2 H), 5.59
(dd, J = 9.8, 7.8 Hz, 1 H), 3.94 (dd, J = 11.8, 7.8 Hz, 1 H), 3.76 (s, 3
H), 2.99 (dd, J = 11.8, 9.8 Hz, 1 H), 2.42 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 159.4, 144.9, 135.2, 133.4, 131.8, 131.6, 131.2,
130.1, 129.0, 128.1, 127.1, 126.3, 114.3, 55.8, 55.3, 54.5, 21.6 ppm.
MS: m/z (%) = 459 (28), 304 (80), 223 (60), 134 (64), 91 (100).
C22H21NO4SSe (474.43): calcd. C 55.70, H 4.46, N 2.95; found C 55.83,
H 4.57, N 2.99.
129.0, 128.1, 123.9, 114.3, 61.2, 55.4, 28.6 ppm. IR: ν = 2931, 1544,
˜
1514, 1374, 1251, 1177 cm–1. C21H17ClN2O5SSe (523.85): calcd. C
48.15, H 3.27, N 5.35; found C 48.24, H 3.15, N 5.41.
3-(4-Methoxyphenyl)-4-[(2-nitrophenyl)sulfonyl]-6-(trifluoro-
methyl)-3,4-dihydro-2H-benzo[b][1,4]selenazine (4g): The reac-
tion mixture was heated in toluene at 110 °C for 240 h. Purification
by silica gel column chromatography (dichloromethane/petroleum
ether, 3:1, Rf = 0.70) gave derivative 4g (74 mg, 83 %) as a white
solid, m.p. 157–160 °C. 1H NMR (400 MHz, CDCl3): δ = 7.74–7.68 (m,
2 H), 7.60–7.58 (m, 1 H), 7.53–7.49 (m, 1 H), 7.46–7.42 (m, 2 H), 7.37–
7.35 (m, 1 H), 7.30–7.27 (m, 2 H), 6.80 (d, J = 8.0 Hz, 2 H), 5.97 (at,
J = 8.0 Hz, 1 H), 3.75 (s, 3 H), 3.63 (dd, J = 12.0, 8.0 Hz, 1 H), 3.23
(dd, J = 12.0, 8.0 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
159.2, 148.0, 135.5, 134.8, 134.2, 132.0, 131.3, 131.1, 130.9, 130.6,
6-Chloro-3-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4]-
selenazine 1-Oxide (11): A solution of mCPBA (4 mg, 0.022 mmol,
0.95 equiv.) in dry CH2Cl2 (0.5 mL) was added to a solution of 8
(8 mg, 0.024 mmol) in dry CH2Cl2 (0.5 mL) at 0 °C. The mixture was
stirred at 0 °C for 2 h. Purification by silica gel column chromatogra-
phy (EtOAc/MeOH, 10:1, Rf = 0.45) gave derivative 11 (4 mg, 50 %)
2
3
129.2 (q, JC,F = 30 Hz), 127.9, 127.8 (q, JC,F = 10 Hz), 123.9, (q,
2JC,F = 30 Hz), 123.5 (q, JC,F = 270 Hz), 114.1, 59.6, 55.2, 27.3 ppm.
1
IR: ν = 3650, 2932, 1545, 1513, 1326, 1176, 1136 cm–1
.
˜
C22H17F3N2O5SSe (557.40): calcd. C 47.40, H 3.07, N 5.03; found C
47.72, H 3.22, N 5.21.
1
as a white solid. H NMR (400 MHz, CDCl3): δ = 7.46 (d, J = 8.3 Hz,
6-Chloro-3-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4]-
selenazine (8): Thioacetic acid (17 μL, 0.24 mmol, 4.0 equiv.) and
lithium hydroxide (14 mg, 0.48 mmol, 8.0 equiv.) were added to a
solution of 4f (30 mg, 0.06 mmol) in dry DMF (3.0 mL) under nitro-
gen. The mixture was stirred at 60 °C for 72 h, then it was diluted
with EtOAc (20 mL), and washed with saturated aq. NaHCO3
(15 mL). The organic phase was dried with anhydrous Na2SO4, and
the solvents were evaporated to dryness. Purification by silica gel
column chromatography (dichloromethane/petroleum ether, 3:1,
Rf = 0.80) gave derivative 8 (11 mg, 55 %) as a colourless oil. 1H
NMR (400 MHz, CDCl3): δ = 7.29–7.26 (m, 2 H), 7.08 (d, J = 8.0 Hz,
1 H), 6.94–6.90 (m, 2 H), 6.62 (dd, J = 8.0, 2.0 Hz, 1 H), 6.49 (d, J =
2.0 Hz, 1 H), 4.63 (dd, J = 9.9, 2.6 Hz, 1 H), 4.08 (br. s, 1 H), 3.82 (s,
1 H), 7.43–7.40 (m, 2 H), 6.97–6.93 (m, 2 H), 6.76 (dd, J = 8.3, 1.9 Hz,
1 H), 6.72 (d, J = 1.9 Hz, 1 H), 5.12–5.08 (m, 1 H), 4.63 (s, 1 H), 3.84
(s, 3 H), 3.04–2.93 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
160.3, 146.3, 139.5, 134.2, 132.1, 128.6, 127.9, 118.6, 116.9, 114.9,
55.6, 47.2, 29.9 ppm. IR: ν = 3689, 2928, 2852, 2359, 2253, 1591,
˜
1512, 1466, 1251, 1092 cm–1. C15H14ClNO2Se (354.69): calcd. C 50.79,
H 3.98, N 3.95; found C 50.91, H 3.87, N 3.91.
GPx-Like Catalytic Activity:[12b] In the NMR assay, DTTred
(0.15 mmol) and Se catalyst (0.015 mmol) were dissolved in CD3OD
(1.1 mL), and the solution was added to H2O2 (35 % aq.; 15 μL,
0.15 mmol) to start the reaction. 1H NMR spectra were measured at
variable reaction times at 25 °C. The relative populations of DTTred
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and DTTox were determined by integration of the signals in the 1H
NMR spectra.
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Acknowledgments
This work was supported by a grant from Italian Ministero
dell'Università
e della Ricerca (MIUR) (PRIN 2010–2011
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Cycloaddition · Nitrogen heterocycles · Diselenides
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Received: March 21, 2016
Published Online: ■
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Full Paper
Selenium
2-Sulfonylaminoaryl diselenides are
transformed in one pot into
benzo[b][1,4]selenazines using a sub-
stoichiometric amount of Cu(OTf)2,
through a base-mediated 1,4-elimina-
tion at selenium, and generation of a
dienic o-iminoselenoquinone
S. Menichetti, A. Capperucci,
D. Tanini, A. L. Braga,
G. V. Botteselle,
C. Viglianisi* ......................................... 1–7
A One-Pot Access to Benzo[b][1,4]-
selenazines from 2-Aminoaryl Di-
selenides
DOI: 10.1002/ejoc.201600351
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