Aminoxyl radicals from N-phenyl-1-(2-oxo-1-azacycloalkyl)- methanesulfonamides

Article abstract of DOI:10.1007/s00706-006-0525-x

The synthesis and reaction with two oxidation agents is described for N-phenyl-1-(2-oxo-1-azacycloalkyl)methanesulfonamides. Their oxidation was carried out using RO₂? radicals and 3-chloroperbenzoic acid. In both cases, the EPR spectra of corr

Full text of DOI:10.1007/s00706-006-0525-x

Monatshefte f€ur Chemie 137, 1169–1175 (2006)
DOI 10.1007/s00706-006-0525-x
Aminoxyl Radicals from N-Phenyl-1-(2-
oxo-1-azacycloalkyl)-methanesulfonamides
2
Marek Burian1, Ladislav Omelka1;ꢀ, Oldrich Farsa ,
´
and Silvia Hrubanova
ˇ
2
1
Faculty of Chemistry, Technical University of Brno, Brno, Czech Republic
2
Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno,
Brno, Czech Republic
Received January 13, 2006; accepted (revised) February 13, 2006
Published online September 8, 2006 # Springer-Verlag 2006
Summary. The synthesis and reaction with two oxidation agents is described for N-phenyl-1-(2-oxo-
1-azacycloalkyl)methanesulfonamides. Their oxidation was carried out using RO radicals and 3-
2ꢁ
chloroperbenzoic acid. In both cases, the EPR spectra of corresponding aminoxyl radicals were
ꢁ
recorded. Their simulation confirmed that the ꢂSO2ꢂ group in the neighbourhood of the ꢂNO ꢂ
fragment does not prevent the interaction of the unpaired electron with the methylene protons and the
nitrogen atom of the heterocyclic ring.
Keywords. Aminoxyl radicals; EPR; Sulfonamides.
Introduction
Substituted N-phenyl-1-(2-oxo-1-azacycloalkyl)methanesulfonamides constitute a
group of compounds, which can be considered as potential candidates for the
therapy of neurodegenerative diseases. Their action is based on the strengthening
of the cognitive function. The presence of a secondary amino group in the molecule
represents the structural factor, which implies a tendency towards oxidation either
with peroxyradicals or peroxyacids. As a result, the formation of corresponding
arylsulfonaminoxyl radicals is expected in both oxidation reactions, where the first
one characteristically proceeds by a radical [1], the second one by a nonradical
mechanism [2]. Generally, the ability of studied compounds to form aminoxyl
radicals can be regarded as a measure of their readiness to scavenge various re-
active oxygen species (ROS), taking part in origin of many serious diseases like
diabetes, cancer, or Alzheimer disease.
Until now, only a limited number of EPR data characterizing this type of
aminoxyl radicals is available. Therefore, new information on the spin density
ꢀ
Corresponding author. E-mail: omelka@fch.vutbr.cz

1170
M. Burian et al.
distribution should be extracted from the detailed analysis of the experimental EPR
spectra.
Results and Discussion
Within the present EPR study compounds 1a–1d (Formulae) prepared according to
ꢁ
Scheme 2 were investigated. As a source of peroxy radicals, (CH3)3COO radicals
prepared by the decomposition of t-butylhydroperoxide on the surface of PbO2
Formulae
Scheme 1

Aminoxyl Radicals
1171
Scheme 2
were employed [3]. Simultaneously, 3-chloroperbenzoic acid was utilized as an
oxidation agent in benzene solution for the generation of aminoxyl radicals from
1a–1d. Application of both procedures proved the formation of the corresponding
aminoxyl radicals 2a–2d (Scheme 1).
The quality of the EPR spectra enabling their unambiguous interpretation using
spectral simulation was substantially better with aminoxyls prepared by oxidation
using 3-chloroperbenzoic acid. Also the achieved concentration of aminoxyls was
higher in this case. In Fig. 1 experimental and simulated EPR spectrum of the
aminoxyl radical 2a is shown. In Table 1 the splitting constants obtained by simu-
lation are presented.
From the values in Table 1 it follows that the ꢂSO2ꢂ group in the neighbour-
hood of the ꢂNOꢁꢂ fragment does not prevent the distribution of the spin density
to the –CH2–X moiety (X ¼ heterocyclic ring). The spin density is considerably
transferred to this group, what can be documented by the splitting constants of
the methylene protons in 2a–2d. The aH(CH2) splittings in the region 0.4–0.5 mT
are about 0.2 mT lower than those found in substituted aromatic aminoxyls
ꢁ
PhꢂNO ꢂCH2ꢂPh, prepared by spin-trapping of benzyl radicals [4]. Another
phenomenon observed with 2a–2d is the steric effect originating from carbonyl
group of the heterocyclic part of the molecule, which becomes evident by its
extension from a 5-membered (2a) to a 7-membered (2c) ring. While in 2a, 2b,
and 2d the methylene protons are fully equivalent, in 2c containing the 7-mem-
bered ring the partial unequivalency of the methylene protons (1ꢃaH ¼ 0.49 mT,
1ꢃaH ¼ 0.43 mT) has to be accounted for in a simulation of the experimental EPR
spectrum. A steric effect appears also in aminoxyl 2d where the presence of the
methyl group in ortho position of the phenyl ring leads, in comparison with unsub-
stituted aminoxyls 2a–2c, to a decrease of the splitting constants in ortho and para
position accompanied by an increase of the aN(NO) value. This can be reproduced
as a consequence of the reduced extent of conjugation between the ꢂNOꢁꢂ group

1172
M. Burian et al.
Fig. 1. Experimental and simulated EPR spectrum of the aminoxyl radical 2a in benzene solution
Table 1. EPR parameters of aminoxyl radicals 2a–2d in benzene solution (g ffi 2:0055)
Radical
aNðNOÞ
aHðo; pÞ
aHðmÞ
aHðCH2Þ
aNðhetÞ
mT
mT
mT
mT
mT
2a
2b
1.030
1.035
0.265
0.090
0.090
0.430
0.475
0.350
0.280
0.260 (2H)
0.290 (1H)
0.260 (2H)
0.290 (1H)
0.260 (2H)
0.295 (1H)
0.170 (2H)
0.180 (1H)
2ba
2c
1.062
1.035
1.145
0.090
0.098
0.080
0.510
0.280
0.293
0.431
0.430 (1H)
0.460 (1H)
0.480
2d
a
In CHCl3 solution

Aminoxyl Radicals
1173
and the phenyl ring, which results in the decline of spin density in the aromatic part
of the molecule. Similar effects have been reported in the case of different mono
ortho substituted diphenylaminoxyls, where the decrease of conjugation in an
ortho substituted phenyl ring leads to the considerably asymmetrical distribution
of spin density [5].
The stability of aminoxyl radicals 2a–2d characterized by the life-time of more
than 10 min, can be attributed not only to the presence of the ꢂSO2ꢂ group in the
neighbourhood of the ꢂNOꢁꢂ fragment, but the effect of the heterocyclic ring
must also be taken into account. This statement is supported by the fact that similar
experiments, aiming at the generation of aminoxyl radicals from bromo substituted
analogues 5 were unsuccessful. On the other side, replacing the ꢂSO2ꢂ group by
the –CO– group in structure 1, no aminoxyl radicals were observed using both
oxidation methods.
To summarize, the oxidation of N-phenyl-1-(2-oxo-1-azacycloalkyl)methane-
ꢁ
sulfonamides 1a–1d with t-BuO2 radicals and 3-chloroperbenzoic acid affords
the stable aminoxyl radicals 2a–2d. Their EPR parameters, confirmed by simu-
lation, point out the specific property of ꢂSO2ꢂ group. Relatively high splitting
constants aH(CH2), comparable with those in benzyl phenyl aminoxyl radicals
ꢁ
PhꢂNO ꢂCH2ꢂPh, document the effective transfer of spin density to –CH2–X
moiety (X ¼ heterocyclic ring), i.e. ꢂSO2ꢂ group does not significantly isolate the
–NOꢁ– fragment from methylene protons and N atom of heterocyclic ring. The
the size of heterocyclic ring were also observed.
steric effects, stemming either from the ortho substitution in phenyl ring or from
Experimental
The N-phenyl-1-(2-oxo-1-azacycloalkyl)methanesulfonamides 1a–1d were synthesized according to
the procedure described below. All other chemicals, including benzene, CHCl3, and oxidation agents
1
(t-butylhydroperoxide, PbO2, 3-chlorperbenzoic acid) were commercially available (Fluka). H and
13C NMR spectra were measured on the 200 MHz FT-NMR spectrometer Varian Gemini 2000 (Varian,
Palo Alto, CA, U.S.A.), and melting points were determined on the Boetius apparatus PHMK-05
(Rapido, Radebeul, Germany). EPR spectra were recorded with a SpectraNova (E-I-A Warenhandels
GmbH) spectrometer. The processing and simulation of experimental EPR spectra were performed
using WINEPR and SimFonia programs (Bruker).
N-Phenyl-1-(2-oxoazacycloalkyl)sulfonamides 1a–1d
The appropriate lactame (4mmol, pyrrolidin-2-one, piperidin-2-one, or azepan-2-one) was added to a
suspension of 0.9 g finely powdered KOH (16 mmol) in 3 cm3 DMSO. After 5 min stirring, 1 mmol of
the appropriate N-phenyl-1-bromomethanesulfonamide 5 was portionwise added and the stirring at
room temperature was continued for additional 3 h. Then, the reaction mixture was acidified with 12%
aqu acetic acid and stored with cooling, until a white precipitate appeared. This product was filtered
off, washed with H2O, and dried in vacuo.
N-Phenyl-1-(2-oxopyrrolidin-1-yl)methanesulfonamide (1a, C11H14N2O3S)
1
Yield 40% (100mg); mp 151–153ꢄC; H NMR (200 MHz, CDCl3): ꢀ ¼ 7.26–7.15 (m, 2H, m-arom)
6.80–6.72 (m, 3H, o-þp-arom) 4.76 (d, J ¼ 6.0 Hz, SO2CH2) 4.38 (s, NH) 3.40 (t, J ¼ 7.0 Hz,
5-CH2pyrr) 2.38 (t, J ¼ 8.0 Hz, 3-CH2pyrr) 2.03–1.92 (m, 4-CH2pyrr) ppm; 13C NMR (50 MHz,
CDCl3): ꢀ ¼ 175.41, 145.69, 129.41, 118.63, 113.26, 51.91, 45.92, 31.15, 17.77 ppm.

1174
M. Burian et al.
N-Phenyl-1-(2-oxopiperidin-1-yl)methanesulfonamide (1b, C12H16N2O3S)
Yield 31% (78 mg); mp 124–125ꢄC; 1H NMR (200 MHz, CDCl3): ꢀ ¼ 7.26–7.15 (m, 2H,
m-arom) 6.79–6.72 (m, 3H, o-þp-arom) 4.85 (d, J ¼ 5.0 Hz, SO2CH2) 4.56 (s, NH) 3.33
(t, J ¼ 6.0 Hz, 6-CH2pip) 2.38 (t, J ¼ 5.5 Hz, 3-CH2pip) 1.77–1.71 (m, 4 þ 5-CH2pip) ppm;
13C NMR (50 MHz, CDCl3): ꢀ ¼ 166.65, 137.96, 129.32, 124.76, 120.65, 55.62, 47.38, 38.91,
33.45, 19.22 ppm.
N-Phenyl-1-(2-oxoazepan-1-yl)methanesulfonamide (1c, C13H18N2O3S)
1
Yield 63% (178mg); mp 146–147ꢄC; H NMR (200 MHz, CDCl3): ꢀ ¼ 7.26–7.15 (m, 2H, m-arom)
6.79–6.70 (m, 3H, o-þp-arom) 4.82 (s, SO2CH2) 4.55 (s, NH) 3.37 (t, J ¼ 5.0 Hz, 7-CH2azep) 2.50
(t, J ¼ 6.0 Hz, 3-CH2azep) 1.64–1.47 (m, 4 þ 5 þ 6-CH2azep) ppm; 13C NMR (50 MHz, CDCl3):
ꢀ ¼ 146.13, 129.35, 118.66, 114.01, 57.56, 48.36, 37.56, 29.90, 28.48, 23.31 ppm.
N-(2-Methylphenyl)-1-(2-oxopiperidin-1-yl)methanesulfonamide (1d, C13H18N2O3S)
Yield 45% (127mg); mp 135–138ꢄC; 1H NMR (200 MHz, CDCl3): ꢀ ¼ 7.35–7.18 (m, 4H, arom), 4.85
(d, J ¼ 5.0 Hz, SO2CH2) 4.57 (s, NH) 3.33 (t, J ¼ 6.0 Hz, 6-CH2pip) 2.38 (t, J ¼ 5.5 Hz, 3-CH2pip) 2.32
(s, CH3) 1.77–1.71 (m, 4 þ 5-CH2pip) ppm; 13C NMR (50 MHz, CDCl3): ꢀ ¼ 166.65, 137.96, 129.32,
126.15, 124.76, 120.65, 119.42, 55.62, 47.38, 38.91, 33.45, 19.22, 17.75 ppm.
Bromomethanesulfonyl chloride (4)
Sodium bromomethanesulfonate (3, 19.7 g, 0.1 mol), prepared according to Ref. [6] was mixed with
21.9 g PCl5 (0.105 mol). A spontaneous exothermal reaction immediately started and after its
finishing (10–15 min), the reaction mixture was heated 45 min at 130–140ꢄC and additional
30 min at 70ꢄC. The reaction product was obtained by distillation at reduced pressure, bp 93–
1
95ꢄC=2.7 kPa (Ref. [7] 87–89ꢄC=2.0 kPa), yield 79% (15.3 g); H NMR (200 MHz, DMSO-d6):
ꢀ ¼ 5.11 (s, CH2) ppm.
N-Phenyl-1-bromomethanesulfonamides 5
Bromomethanesulfonyl chloride (4, 3.9g, 0.02mol) dissolved in 10cm3 toluene were dropwise added
to a stirred solution of 0.04 mol aniline or 2-methylaniline during 15min. The resulting reaction
mixture was refluxed for 5 h, then cooled, and the precipitate of anilinium chloride was filtered off.
The filtrate was extracted with 3% aqu HCl and H2O and then the desired 5 was extracted into 3%
NaOH solution. The alkaline H2O extract was acidified with HCl to pH ¼ 1 and the precipitated
product was isolated by filtration.
N-Phenyl-1-bromomethanesulfonamide (5a, C7H8NO2SBr)
Yield 50% (1.4 g); 1H NMR (200 MHz, DMSO-d6): ꢀ ¼ 10.34 (s, NH) 7.38–7.13 (m, 5H,
arom) 4.90 (s, CH2) ppm; 13C NMR (50 MHz, DMSO-d6): ꢀ ¼ 137.17, 129.13, 124.26, 120.38,
41.28 ppm.
N-(2-Methylphenyl)-1-bromomethanesulfonamide (5b, C8H10NO2SBr)
1
Yield 38% (2.0g); H NMR (200 MHz, DMSO-d6): ꢀ ¼ 9.65 (s, NH) 7.33–7.16 (m, 4H, arom) 4.88
(s, CH2) 2.33 (s, CH3) ppm; 13C NMR (DMSO-d6): ꢀ ¼ 134.73, 134.46, 130.67, 126.72, 126.41, 42.42,
17.99 ppm.
Oxidation of 1 with t-BuOOH=PbO2
Sulfonamides 1 were dissolved in a 0.01M benzene solution of t-BuOOH in a molar ratio
1=t-BuOOH ¼ 1=1. In 2 cm3 of this solution 10mg PbO2 were suspended and stirred for 1 min. After
the sedimentation of solid PbO2, 0.5 cm3 of the liquid phase were transferred into an EPR tube
(ø ¼ 5 mm), bubbled with N2, and measured.

Aminoxyl Radicals
1175
Oxidation of 1 with 3-Chloroperbenzoic Acid
A 0.01M benzene solution of 1 (1cm3) was mixed with the same volume of a 0.01 M benzene solution
of 3-chloroperbenzoic acid and stirred for 1 min. 0.5 cm3 of the reaction mixture were placed into an
EPR tube, bubbled with N2, and measured.
Acknowledgement
This paper was supported by Ministry of Education of the Czech Republic under research project
MSM 0021630501.
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