Preparation of 1-arylideneamino- and 1-alkylideneamino-3-phenoxypropan-2-ol N-oxides - A new type of nitrones

Article abstract of DOI:10.1081/SCC-200057982

The reaction of phenylglycidyl ether with hydroxylamine was evaluated, and the prepared 1-hydroxyamino-3-phenoxypropan-2-ol was used for the 1-arylideneamino- and 1-alkylideneamino-3-phenoxypropan-2-ol N-oxides syntheses. The title nitrones were tested as

Full text of DOI:10.1081/SCC-200057982

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Preparation of
1‐Arylideneamino‐ and
1‐Alkylideneamino‐3‐phenoxypropa
N‐Oxides—A New Type of
Nitrones
Katarzyna Da˛bkowska a , Paulina Da˛browska a
,
Jacek Drabik b , Dorota Kopczuk b , Jan Plenkiewicz
a , Joanna B. Strosznajder b & Monika Wielechowska
a
a Faculty of Chemistry, Warsaw University of
Technology, Noakowskiego, Warsaw, Poland
b Medical Research Center, Polish Academy of
Sciences, Pawinskiego, Warsaw, Poland
Version of record first published: 17 Dec 2010.
To cite this article: Katarzyna Da˛bkowska , Paulina Da˛browska , Jacek
Drabik , Dorota Kopczuk , Jan Plenkiewicz , Joanna B. Strosznajder &
Monika Wielechowska (2005): Preparation of 1‐Arylideneamino‐ and
1‐Alkylideneamino‐3‐phenoxypropan‐2‐ol N‐Oxides—A New Type of Nitrones, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 35:11, 1455-1459
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Synthetic Communicationsw, 35: 1455–1459, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200057982
Preparation of 1-Arylideneamino- and
1-Alkylideneamino-3-phenoxypropan-2-ol
N-Oxides—A New Type of Nitrones
Katarzyna Da˛bkowska and Paulina Da˛browska
Faculty of Chemistry, Warsaw University of Technology,
Noakowskiego, Warsaw, Poland
Jacek Drabik and Dorota Kopczuk
Medical Research Center, Polish Academy of Sciences,
Pawinskiego, Warsaw, Poland
Jan Plenkiewicz
Faculty of Chemistry, Warsaw University of Technology,
Noakowskiego, Warsaw, Poland
Joanna B. Strosznajder
Medical Research Center, Polish Academy of Sciences,
Pawinskiego, Warsaw, Poland
Monika Wielechowska
Faculty of Chemistry, Warsaw University of Technology,
Noakowskiego, Warsaw, Poland
Abstract: The reaction of phenylglycidyl ether with hydroxylamine was evaluated,
and the prepared 1-hydroxyamino-3-phenoxypropan-2-ol was used for the
Received in Poland January 10, 2005
Address correspondence to Jan Plenkiewicz, Faculty of Chemistry, Warsaw
University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland. E-mail:
plenki@ch.pw.edu.pl
1455

1456
K. Da˛bkowska et al.
1-arylideneamino- and 1-alkylideneamino-3-phenoxypropan-2-ol N-oxides syntheses.
The title nitrones were tested as antioxidants in biological systems.
Keywords: Free radical scavengers, nitrones, oxidative stress
In the search for new biologically active free-radical scavengers and anti-
oxidants, we concerned ourselves with compounds capable of dissolving in
aqueous media. According to our expectations, some alcohols possessing a
nitrone moiety, for example, b-hydroxynitrones, might exhibit the desired
properties.
To prepare these compounds, we decided to use b-hydroxy-N-substituted
hydroxylamines as the substrates and to react them with aldehydes. Opening
of the appropriate oxirane derivative with the hydroxylamine base was con-
sidered as the simplest method for preparing these substrates. In this
research we used the reaction of phenylglycidyl ether with hydroxylamine
as described almost half a century ago.[1,2] According to the authors,[1] the
sole product of the reaction, obtained by them in the yield of 95%, has to
be 1-hydroxyamino-3-phenoxypropan-2-ol (1). Following the literature
procedure, we repeated the reaction several times and found that the yield
and the melting point of the crude reaction product were close to the litera-
1
ture[1] data, but the H NMR spectrum was much too complicated for such
a simple molecule. The TLC analysis showed at least five substances
present: two in large amounts and three other in traces. After separation by
means of silica-gel column chromatography and recrystallization, the two
main products were identified as the expected monosubstituted hydroxylamine
derivative 1 (45–50% yield) and its symmetrical N,N-disubstituted analog (2)
formed according to Scheme 1.
The structures of both compounds were confirmed by IR, MS, 1H NMR,
and 13C NMR spectra, and C,H,N elemental analyses.
Pure 1-(hydroxyamino)-3-phenoxypropan-2-ol (1) refluxed in an ethanol
solution with an equimolar amount of an aromatic aldehyde gave the corre-
sponding 1-arylideneamino-3-phenoxypropan-2-ol N-oxides (3–4) accor-
ding to Scheme 2.
The reaction also proceeded well with aliphatic aldehydes to yield the
corresponding 1-(alkylideneamino)-3-phenoxypropan-2-ol N-oxides (5,6).
All of the prepared nitrones (3–6) are crystalline compounds, which, upon
concentration of the reaction mixture, separate almost pure. The yields of
Scheme 1.

New Type of Nitrones
1457
Scheme 2.
the nitrones were high, ranging up to 95% of the theory, and their structures
1
were confirmed by IR, H NMR, and 13C NMR spectra, as well as by CHN
elemental analyses. Analysis of the NMR spectra allowed us to confirm that
the compounds exist as single isomers with E configuration on the C55N
double bond[3–6] and to rule out the cyclic 1,3-oxadiazolidine structure
suggested by Kliegel.[7]
The antioxidant activity of the b-hydroxynitrones was examined by deter-
mination of the index of lipid peroxidation.[8] The oxidative stress was
induced in vitro in the Sparque–Dawley rat’s cerebral cortex homogenate
by Fenton’s reaction with FeCl2 and L(þ)-ascorbic acid solutions. In vivo
experiments were preformed using 2-VO model (two vessel occlusion) on
gerbils (Merinos unquiculatus). In both methods concentrations of thiobarbi-
turic acid reactive substances (TBARS), including malondialdehyde (MDA),
were spectrometrically recorded as an index of lipid peroxidation. The IC50
values obtained by regression analysis showed the activity of compound 6
is close to that exhibited by known antioxidants, for example, Carvedilol
and Trolox.
The chemical and biological properties of the b-hydroxynitrones, as well
as the extention of this reaction to other hydroxyaminoalcohols, are under
investigation in our laboratories.
EXPERIMENTAL
Preparation of 1-(hydroxyamino)-3-phenoxypropan-2-ol (1): Sodium
(6.90 g, 0.3 mol) was dissolved in methanol (200 mL) and the solution was
added dropwise to a solution of hydroxylamine hydrochloride (20.85 g,
0.3 mol) in methanol (200 mL). The resulting NaCl was filtered off and the
solution of hydroxylamine was treated with 15 g (0.1 mol) of phenylglycidyl
ether. The mixture was refluxed for 2.5 h and, upon cooling to room tempera-
ture, the inorganic solid was removed, and the solvent was evaporated under
reduced pressure. The residue was recrystallized twice from 2-propanol to
1
yield 8.97 g (49%) of 1 as a colorless solid. Mp ¼ 111.5–112.58C. H NMR
(DMSO-d6) d: 2.78 (dd; 1Ha; CHaHbN; Jgem ¼ 12.8 Hz; J1 ¼ 6.8 Hz); 2.86
(dd; 1Hb; CHaHbN; J2 ¼ 5.2 Hz); 3.85 (dd; 1Hc; OCHcHd; Jgem ¼ 9.6 Hz;
J3 ¼ 6.2 Hz); 3.97 (dd; 1Hd; OCHcHd; J4 ¼ 3.6 Hz); 4.00 (m; 1H; CH); 4.94
(d; 1H; OH; J3 ¼ 4.8 Hz); 5.68 (s; 1H; OH); 6.88–6.92 (m; 3H; Ph); 7.24–
7.28 (m; 3H; Ph þ NH); 13C NMR (DMSO-d6) d: 56.75; 66.06; 70.74;

1458
K. Da˛bkowska et al.
114.41; 120.38; 129.44; 158.73; IR (Nujol mull; cm21) 3400; 3350; 1595;
1495; 1455; 1250; 1045; 745; 690. Anal. calcd. for C9H13NO3: C, 59.00%;
H, 7.15%; N, 7.65%. Found: C, 58.90%; H, 7.07%; N, 7.60%. The residual
liquor after separation of 1 was evaporated, chromatographed on silica-gel
column with 98 : 2 v/v chloroform/methanol and recrystallized from 2 : 3 v/
v cyclohexane/diethyl ether to give 2 (30%) as a colorless solid. Mp ¼ 89–
1
928C; H NMR (CDCl3) d: 2.90–3.04 (m; 4H; 2 ꢀ CH2N); 3.93–4.04 (m;
4H; 2 ꢀ CH2O); 4.34–4.43 (m; 2H; 2 ꢀ CH); 6.78–6.90 (m; 4H; Ph); 6.93–
6.97 (m; 2H; Ph); 7.23–7.27 (m; 4H; Ph); 13C NMR (CDCl3) d: 63.30; 63.44;
67.46; 68.09; 69.91; 70.02; 114.56; 121.13; 129.48; 158.47; IR (Nujol mull;
cm21). Anal. calcd. for C18H23NO5: C, 64.85%; H, 6.95%; N, 4.20%. Found:
C, 64.95%; H, 6.97%; N, 4.27%.
General method of 1-(arylideneamino)- and 1-(alkylideneamino)-3-
phenoxypropan-2-ol N-oxides (3–6) preparation: Hydroxylamine deriva-
tive 1 (1.0 g; 5.45 mmol) was refluxed for 1.5 h. with an equimolar amount
of the appropriate aldehyde in 50 mL of ethanol. After evaporation of approxi-
mately 20 mL of the solvent, the formed crystals were separated and recrystal-
lized from ethanol to give nitrones 3 or 4, or from 3 : 7 v/v benzene/hexane to
give nitrones 5 or 6.
(E)-1-(benzylideneamino)-3-phenoxypropan-2-ol N-oxide (3): Mp ¼
146.5–148.08C; 1H NMR (CDCl3) d: 3.97 (dd; 1Ha; Jgem ¼ 9.6 Hz;
J ¼ 7.2 Hz; –CHaHbN55); 4.14 (dd; 1Hb; J ¼ 4.8 Hz; –CHaHbN55); 4.17
(dd; 1Hc; Jgem ¼ 12.4 Hz; J ¼ 7.2 Hz; –OCHcHd–); 4.28 (dd; 1Hd;
J ¼ 2.6 Hz; –OCHcHd–); 4.56 (m; 1H; CH); 5.18 (d; 1H; J ¼ 5.2 Hz; OH);
6.91 (m; 2H; Ph); 6.98 (m; 1H; Ph); 7.29 (m; 2H; Ph); 7.41 (s; 1H; Ha);
7.43 (m; 3H; Ph); 8.19 (m; 2H; Ph); 13C NMR (CDCl3) d: 67.37; 68.39;
68.44; 114.46; 121.33; 128.57; 129.07; 129.57; 129.64; 131.09; 136.90;
158.16; IR (Nujol mull; cm21) 3220 (nOH); 1600 (nC55N); 1100 (nNO);
MS (ES; MeOH): 272.1 (M þ 1); 294.1 (M þ 23); calcd.: 271.314. Anal.
calcd. for C16H17NO3: C, 70.83%; H, 6.32%; N, 5.16%. Found: C, 70.59%;
H, 6.34%; N, 5,19%.
(E)-1-(4-nitrobenzylideneamino)-3-phenoxypropan-2-ol N-oxide (4):
1
Mp ¼ 151.5–152.58C; H NMR (CDCl3) d: 4.01 (dd; 1Ha; Jgem ¼ 9.6 Hz;
J ¼ 7.2 Hz; –CHaHbN55); 4.16 (dd; 1Hb; J ¼ 4.8 Hz; –CHaHbN55); 4.25
(dd; 1Hc; Jgem ¼ 12.4 Hz; J ¼ 7.2 Hz; –OCHcHd–); 4.32 (d; 1H; J ¼ 5.2 Hz;
OH); 4.34 (dd; 1Hd; J ¼ 3.0 Hz; –OCHcHd–); 4.60 (m; 1H; CH); 6.91 (m;
2H; Ar); 6.99 (m; 1H; Ar); 7.30 (m; 2H; Ar); 7.56 (s; 1H; Ha); 8.26 (m; 2H;
Ar); 8.37 (m; 2H; Ar); 13C NMR (CDCl3) d: 68.31; 68.41; 68.60; 114.45;
121.59; 123.81; 129.32; 129.67; 134.57; 135.26; 148.25; 158.04; IR (Nujol
mull; cm21) 3450 (nOH); 1650 (nC55N); 1515 (nasym NO2); 1345 (nsym
NO2). Anal. calcd. for C16H16N2O5: C, 60.74%; H, 5.11%; N, 8.86%. Found:
C, 60.76%; H, 5.20%; N, 8.80%.
(E)-1-(2,2-dimethylpropylideneamino)-3-phenoxypropan-2-ol N-oxide
1
(5): Mp ¼ 86.5–88.58C; H NMR (CDCl3) d: 0.93 (s; 9H; 3 ꢀ CH3); 2.98
(dd; 1Ha; Jgem ¼ 12.7Hz; J ¼ 10.7Hz; –CHaHbN55); 3.41 (dd; 1Hb;

New Type of Nitrones
1459
J ¼ 4.7 Hz; –CHaHbN55); 4.10 (dd; 1Hc; Jgem ¼ 10.4Hz; J ¼ 4.8 Hz;
–OCHcHd–); 4.16 (dd; 1Hd; J ¼ 4.8 Hz; –OCHcHd–); 4.50–4.55 (m; 2H;
CH þ OH); 6.43 (s; 1H; Ha); 6.91–6.96 (m; 3H; Ph); 7.26–7.31 (m; 2H;
Ph); 13C NMR (CDCl3) d: 25.28; 34.54; 60.77; 67.86; 74.03; 110.65; 114.54;
120.98; 129.44; 158.70; IR (Nujol mull; cm21) 3240 (nOH); 1630 (nC55N);
1110 (nNO); MS (ES; MeOH): 252.1 (M þ 1); 274.1 (M þ 23); calcd.
251.324. Anal. calcd. for C14H21NO3: C, 66.91%; H, 8.42%; N, 5.57%.
Found: C, 66.81%; H, 8.63%; N, 5.35%.
(E)-1-(ethylideneamino)-3-phenoxypropan-2-ol N-oxide (6): Mp ¼
1
105.5–107.08C; H NMR (CDCl3) d: 2.07 (d; 3H; J ¼ 6 Hz; CH3); 3,90 (dd;
1Ha; Jgem ¼ 9.6 Hz; J ¼ 7.8 Hz; –CHaHbN55); 3.99 (dd; 1Hc; Jgem ¼ 12.5Hz;
J ¼ 7 Hz; –OCHcHd–); 4.12 (m; 1Hb þ 1Hd); 4.44 (m; 1H; CH); 5.54 (d; 1H;
J ¼ 3.6 Hz; OH); 6.85 (q; 1H; J ¼ 5.8 Hz; Ha); 6.87–6.91 (m; 2H; Ph); 6.97
(m; 1H; Ph); 7.26–7.31 (m; 2H; Ph); 13C NMR (CDCl3) d: 12.61; 65.54; 68.00;
68.27; 114.38; 121.29; 129.56; 137.87; 158.15; IR (Nujol mull; cm21); MS
(ES; MeOH): 210.1 (M þ 1); 232.1 (M þ 23); calcd. 209.243. Anal. calcd. for
C11H15NO3: C, 63.14%; H 7.23%; N, 6.69%. Found: C, 62.58%; H, 7.51%; N,
6.47%.
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