One-pot synthesis and hydroxylaminolysis of asymmetrical acyclic nitrones

Article abstract of DOI:10.1080/00397910500191169

Aromatic aldehydes 1 were reductively aminated to the corresponding secondary amines 2 using NaBH₄ in methanol in good yields. Amines 2 were oxidized with H₂O₂-WO₄^2- regioselectively to nitrones 3, the structures of which were easily determined by reacting them with hydroxylamine hydrochloride as well as by spectral means. The products of hydroxylaminolysis in ether proved to be the corresponding benzaldehyde oximes 4 and benzyl or methyl hydroxylamine hydrochlorides 5. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/00397910500191169

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One‐Pot Synthesis and
Hydroxylaminolysis of
Asymmetrical Acyclic Nitrones
Necdet Coşkun a & Aydın Parlar a
a Uludağ University, Department of Chemistry,
Görükle Bursa, Turkey
Published online: 18 Aug 2006.
To cite this article: Necdet Coşkun & Aydın Parlar (2005) One‐Pot Synthesis and
Hydroxylaminolysis of Asymmetrical Acyclic Nitrones, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 35:18,
2445-2451
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Synthetic Communicationsw, 35: 2445–2451, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500191169
One-Pot Synthesis and Hydroxylaminolysis
of Asymmetrical Acyclic Nitrones
Necdet Cos¸kun and Aydın Parlar
˘
¨ ¨
Uludag University, Department of Chemistry, Gorukle Bursa, Turkey
Abstract: Aromatic aldehydes 1 were reductively aminated to the corresponding
secondary amines 2 using NaBH4 in methanol in good yields. Amines 2 were
oxidized with H2O2-WO242 regioselectively to nitrones 3, the structures of which
were easily determined by reacting them with hydroxylamine hydrochloride as well
as by spectral means. The products of hydroxylaminolysis in ether proved to be
the corresponding benzaldehyde oximes 4 and benzyl or methyl hydroxylamine
hydrochlorides 5.
Keywords: Acyclic nitrone, alkyl hydroxylamine hydrochloride, oxidation
INTRODUCTION
Nitrones are well known 1,3-dipoles in thermal cycloaddition reactions with a
wide variety of carbon–carbon, carbon–nitrogen, carbon–sulphur, and
nitrogen–phosphorus multiple-bond systems that provide various heterocyclic
five-membered ring systems.[1] The cycloadducts of di- and triarylimidazoline
3-oxides[2] with variety of dipolarophiles[3] give bicyclic compounds with
potentially interesting biological activity. (A series of tetrahydroimidazo
compounds including tetrahydroimidazooxadiazolones were tested for their
anticancer activity and found to be quite active at 1025 molar concentrations.)
Conversely, they are a source of new heterocyclic compounds via interesting
ring-opening reactions.[4] As a continuation of our interest in the synthesis
of five-membered heterocycles and their ring-opening reactions, we needed
to prepare acyclic nitrones. Condensation of an N-alkylhydroxylamine with
Received in the U.K. January 16, 2005
Address correspondence to Necdet Cos¸kun, Uludag University, Department of
¨ ¨
Chemistry, 16059 Gorukle Bursa, Turkey. E-mail: coskun@uludag.edu.tr
˘
2445

2446
N. Cos¸kun and A. Parlar
a carbonyl compound and oxidation of N,N-dialkylhydroxylamine and dialkyl-
amines are the most common methods for the synthesis of nitrones.[5] N-Alkyl
hydroxylamines are accessible via reduction of aldoximes and ketoximes with
NaBH3CN at pH 3–4.[6] Recently primary amines were converted to the
corresponding N-monoalkylhydroxylamines by
a three-step protocol
involving the selective mono-cyanomethylation of primary amines, regioselec-
tive formation of nitrones by m-CPBA oxidation, and hydroxylaminolysis of
the nitrones with hydroxylamine hydrochloride.[7]
RESULTS AND DISCUSSION
We report herein the synthesis of asymmetrical acyclic nitrones 3 via
oxidation of secondary amines 2 with H2O2-WO242 in methanol at room
temperature. The hydroxylaminolysis of compounds 3 serve as a useful tool
for the determination of the regiochemistry of the oxidation. The hydroxyl-
amine hydrochlorides were reacted with the corresponding aldehydes to
give the corresponding nitrones.
Aldehydes 1 were reductively aminated[8] to the corresponding secondary
amines 2 using NaBH4 in methanol in good yields. These compounds were
oxidized with H2O2-WO242 in methanol at room temperature to the corres-
ponding nitrones 3 (Scheme 1, Table 1) in moderate yields, which were
isolated and purified by recrystallization. The structures of the nitrones
prepared were easily determined by reacting them with hydroxylamine hydro-
chloride in ether. The products of the reaction proved to be the correspond-
ing benzaldehyde oximes 4 and benzyl or methyl hydroxylamine hydrochlo-
rides 5 (Scheme 2, Table 1). This reaction, beside its usefulness in the
structure determination of nitrones, is also a good alternative to the limited
methods for the synthesis of synthetically important N-alkyl(benzyl)-
substituted hydroxylamines.
In addition to the chemical method of structure determination, all new
compounds were fully characterized by analytical and spectral means. The
1
elemental analyses and IR, H, and 13C NMR spectral data are in agreement
with the proposed nitrone structures. The structures of the newly prepared
N-substituted hydroxylamines were proven spectrally as well as by converting
them to the corresponding nitrones in THF at room temperature.
Scheme 1.

Asymmetrical Acyclic Nitrones
2447

2448
N. Cos¸kun and A. Parlar
Scheme 2.
In the cases of 2a, c the oxidation occurs at the benzylic carbon, leading to
the more stable C-aryl nitrones 3a, c. It is surprising that the main products in
the case of 3d, e are formed at the more electron-deficient benzylic carbon
whereas the opposite is true for 3f. The oxidation of secondary amines to
nitrones is expected to proceed through corresponding hydroxylamine as an
intermediate. In our recent report we were able to isolate intermediate hydro-
xylamines from the oxidation of tetrahydroquinazolines.[9] The probable next
step in the oxidation of the hydroxylamine is the formation of corresponding
N-oxide A (see Scheme 3), which could lose water to give the corresponding
nitrone. The regioselectivity of the oxidation in the cases of 2c, d, f, is
probably determined by the ortho substituents, which probably favor the
water elimination of the N-oxide (see Scheme 3).
EXPERIMENTAL
Melting points were taken on an Electrothermal Digital melting-point
apparatus. Infrared spectra were recorded on a Mattson 1000 FTIR. Proton
magnetic-resonance spectra were recorded on a Bruker Dpx 400-MHz
spectrometer. Visualization was effected with UV light. Freshly prepared
nitrones were used after recrystallization from ether–petroleum ether. The
elemental analyses were performed on a EuroEA 3000 CHNS analyzer.
Synthesis of Nitrones 3, Method A, General Procedure
To a solution of aldehyde 1 (10 mmol) in methanol (15 mL), benzyl or methyl-
amine (10 mmol) dissolved in methanol (2 mL) was added dropwise. The
mixture was stirred at room temperature for 10 min in the cases of methylamine
Scheme 3.

Asymmetrical Acyclic Nitrones
2449
and 1 h for benzylamines. An equimolar amount of NaBH4 was added
portionwise and the reduction was completed within 1 h. The solvent was
evaporated, and the residue dissolved in hydrochloric acid and extracted
with ether (3 Â 15 mL). The water phase was basified with ammonia and
extracted with ether (4 Â 15 mL). The combined extracts were dried over
anhydrous Na2SO4 and filtered, and the solvent evaporated. The residue was
dissolved in MeOH (15 mL), and 35% H2O2 (40 mmol) and 5 mol %
Na2WO4 were added to the solution. The mixture was stirred at room tempera-
ture for 1 h and poured into water (25 mL), and then extracted with chloroform
(4 Â 15 mL). The combined extracts were dried (anhydrous Na2SO4) and
filtered, and the solvent evaporated. The residue was treated with ether to
give the crystalline nitrone after cooling in a refrigerator.
C-(3,4-Dimethoxyphenyl)-N-methyl-nitrone 3a. IR (KBr) nC55N
1
1594 cm21; H NMR (CDCl3) d 3.81 (3H, s), 3.86 (3H, s), 3.87 (3H, s),
6.84 (1H, d, J ¼ 8.3), 7.26 (1H, s), 7.40 (1H, d, J ¼ 8.3), 8.26 (1H, s).
13C NMR d 54.41; 56.31; 56.40; 109.39; 110.80; 111.27; 123.35; 127.21;
148.89; 151.21. Anal. calcd. for C10H13NO3 (195.22): C, 61.53; H, 6.71;
N, 7.18. Found: C, 60.83; H, 6.74; N, 6.84.
C-(2-Nitrophenyl)-N-methyl-nitrone 3b. IR (KBr) nC55N 1581 cm21
;
1H NMR (CDCl3) d 3.87 (3H, s), 7.45 (1H, t, J ¼ 7.6), 7.62 (1H, t,
J ¼ 7.6), 7.93 (2H, m), 9.05 (1H, d, J ¼ 7.9). Anal. calcd. for C8H8N2O3
(180.16): C, 53.33; H, 4.48; N, 15.55. Found: C, 53.46; H, 4.66; N, 15.02.
1
C-Phenyl-N-benzyl-nitrone 3c. IR (KBr) nC55N 1581 cm21; H NMR
(CDCl3) d 4.95 (2H, s), 7.30 (7H, m), 7.35 (2H, m), 8.12 (2H, m).
13C NMR d 71.67; 128.86; 129.01; 129.37; 129.62; 130.01; 130.84; 130.88;
133.71; 134.62. Anal. calcd. for C14H13NO (211.26): C, 79.59; H, 6.20;
N, 6.63. Found: C, 79.50; H, 6.36; N, 6.58.
C-(2-Nitrophenyl)-N-(2,3-dimethoxybenzyl)-nitrone 3d. IR (KBr)
1
nC55N 1576cm21; H NMR (CDCl3) d 3.79 (3H, s), 3.84 (3H, s), 5.08 (2H,
s), 6.90 (1H, m), 7.00 (2H, s), 7.40 (1H, t, J ¼ 7.5), 7.52 (1H, t, J ¼ 7.5),
7.91 (1H, t, J ¼ 8.0), 8.05 (1H, s), 9.08 (1H, d, J ¼ 8.0). 13C NMR d 56.26;
61.35; 67.26; 114.29; 123.42; 124.67; 125.27; 125.69; 126.66; 128.59;
129.75; 130.32; 133.68; 147.60; 148.27; 153.12. Anal. calcd. for C16H16N2O5
(316.31): C, 60.75; H, 5.10; N, 8.86. Found: C, 60.68; H, 5.26; N, 8.62.
C-(2-Nitrophenyl)-N-benzyl-nitrone 3e. IR (KBr) nC55N 1581 cm21
;
1H NMR (CDCl3) d 5.02 (2H, s), 7.34–7.43 (6H, m), 7.60 (1H, t, J ¼ 7.6),
7.94 (1H, d, J ¼ 7.9), 8.00 (1H, s), 9.05 (1H, d, J ¼ 7.9). 13C NMR
d 72.81; 124.78; 125.22; 128.61; 129.46; 129.63; 129.79; 130.50; 132.66;
133.01; 133.79; 147.55. Anal. calcd. for C14H12N2O3 (256.26): C, 65.62;
H, 4.72; N, 10.93. Found: C, 65.49; H, 4.86; N, 10.45.
C-(2,3-Dimethoxyphenyl)-N-benzyl-nitrone 3f. IR (KBr) nC55N
1
1581 cm21; H NMR (CDCl3) d 3.72 (3H, s), 3.80 (3H, s), 5.04 (2H, s),
6.95 (1H, m), 7.05 (1H, m), 7.31 (3H, m), 7.43 (2H, m), 7.76 (1H, s), 8.72
(1H, d, J ¼ 7.5). Anal. calcd. for C16H17NO3 (271.31): C, 70.83; H, 6.32;
N, 5.16. Found: C, 70.39; H, 6.52; N, 5.16.

2450
N. Cos¸kun and A. Parlar
Synthesis of N-Methyl and N-Benzyl Hydroxylamine
Hydrochlorides, General Procedure
To a solution of nitrone 3 (1mmol) in ether (20 mL) was added equimolar
amount of hydroxylamine hydrochloride dissolved in methanol (4mL).
The reaction mixture was stirred for 4 h. The solvent was evaporated and
the product hydroxylamine solidifies after addition of ether. The product
was filtered and dried under vacuum. The filtrate contains the corresponding
benzaldoxime, which was isolated and compared with authentic samples.
N-Methyl hydroxylamine hydrochloride obtained from the reactions of
nitrones 3a, b and N-Benzyl hydroxylamine hydrochloride obtained from
the reactions of nitrones of 3c, e, f were identical with the commercially
available products. These compounds were used in the synthesis of nitrones 3
by method B.
N-(2,3-Dimethoxybenzyl) hydroxylamine hydrochloride. From the
reaction of (2-nitrobenzylidene)-(2,3-dimethoxybenzyl)-amine oxide 3d. IR
1
(KBr) nOH 3424 cm21; H NMR (DMSO-d6) d 3.79 (3H, s), 3.81 (3H, s),
4.29 (2H, s), 7.05–7.10 (3H, m), 10.98 (1H, s), 11.58 (2H, brs). 13C NMR
d 49.25; 56.55; 61.25; 114.81; 123.64; 123.99: 124.61; 148.30; 152.96.
Anal. calcd. for C9H14ClNO3 (219.67): C, 49.21; H, 6.42; N, 6.38. Found:
C, 49.60; H, 6.06; N, 6.05.
Synthesis of Nitrones 3, Method B, General Procedure
To a solution of N-methyl or N-benzylhydroxylamine hydrochlorides 5
(1mmol) in THF (20mL), aldehyde (1mmol) was added, and the mixture
stirred at room temperature for 4 h. The solvent was evaporated and water
was added (10 mL) to the residue and extracted with CHCl3 (2 Â 15mL).
The combined extracts were dried and filtered, and the solvent evaporated
under vacuum. The residue was treated with ether to give crystalline nitrones
3, which were collected by filtration. The melting points and the IR spectra
of the prepared nitrones were identical with those prepared by Method A.
ACKNOWLEDGMENT
˘
The financial support of Uludag University Research Fund is gratefully
acknowledged (Project 2001/2).
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