Fast method for synthesis of alkyl and aryl-N-methylnitrones

Article abstract of DOI:10.3390/molecules16086677

A simple, fast, efficient and eco-friendly procedure was developed for the synthesis of alkyl and aryl-N-methylnitrones. The corresponding nitrones of aromatic aldehydes, aliphatic aldehydes and alicyclic carbonyl compounds were prepared from N-methylhydr

Full text of DOI:10.3390/molecules16086677

Molecules 2011, 16, 6677-6683; doi:10.3390/molecules16086677
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Fast Method for Synthesis of Alkyl and Aryl-N-Methylnitrones
Serkan Yavuz 1, Hamdi Ozkan 2, Naki Colak 3 and Yilmaz Yildirir 1,*
1
Chemistry Department, Faculty of Science, Gazi University, Ankara 06500, Turkey
2
Chemistry Department, Faculty of Science, Çankırı Karatekin University, Çankırı 18100, Turkey
3
Chemistry Department, Faculty of Science and Arts, Hitit University, Çorum 19030, Turkey
* Author to whom correspondence should be addressed; E-Mail: yildirir@gazi.edu.tr;
Tel.: +90-0312-202-11-16; Fax: +90-0312-212-22-79.
Received: 20 June 2011; in revised form: 18 July 2011 / Accepted: 19 July 2011 /
Published: 8 August 2011
Abstract: A simple, fast, efficient and eco-friendly procedure was developed for the
synthesis of alkyl and aryl-N-methylnitrones. The corresponding nitrones of aromatic
aldehydes, aliphatic aldehydes and alicyclic carbonyl compounds were prepared from
N-methylhydroxylamine hydrochloride and Na2CO3-Na2SO4 by simply grinding at room
temperature without using solvent.
Keywords: nitrone; grinding; solid-phase synthesis; solventless
1. Introduction
Nitrones are important intermediates in synthetic organic chemistry because they give easily
1,3-dipolar cycloaddition reactions with alkenes, alkynes, isocyanates, isothiocyanates, phosphoranes
and sulphenes compounds [1]. Especially, the 1,3-dipolar cycloaddition reactions of nitrone-olefin are
interesting due to they can create three new contiguous stereogenic centers in a single step [2,3].
Intermolecular and intramolecular nitrone cycloaddition reactions are also useful methods for the
formation of biologically active heterocyclic compounds [4-7].
A number of methods have been developed for the synthesis of nitrones. Among these,
dehydrogenation of N,N-disubstituted hydroxylamines, alkylation of oximes and condensation of
N-methylhydroxylamine hydrochloride with aromatic aldehydes are the most commonly used
methods [8]. These methods usually need warming or even refluxing in organic solvents. Moreover

Molecules 2011, 16
6678
these methods mostly suffer from water in which is formed during condensation diminishing the yield
of synthesized nitrones. On the other hand, solvent-free reaction procedures have been attracted much
more interest for condensation reactions affording near quantitative yields with little or no waste [9-13].
Solvent-free conditions for the synthesis of α-aryl-N-methylnitrones are generally catalyzed by
molecular sieves or silica gel-NaOH, a method first introduced by Bigdeli [14,15]. However, these
methods are not successful for the synthesis of the corresponding nitrones of alicyclic and aliphatic
carbonyl compounds. Recently, Colacino and co-workers have reported a solvent free synthesis of
nitrones by a mechanochemical approach [16]. In that work, nitrone compounds were synthesized after
a relatively long reaction time (0.5–2 h) using an automatic ball-milling machine. Herein, we report a
simple and solvent-free grinding method for the synthesis of corresponding nitrone compounds of
aromatic aldehydes, aliphatic aldehydes and alicyclic ketones by the interaction of carbonyl
compounds and N-methylhydroxylamine hydrochloride with Na2CO3-Na2SO4. Overall conversions
were completed in a relatively short time (3–10 min).
2. Results and Discussion
The aromatic aldehydes 1a-l and N-methylhydroxylamine hydrochloride were ground at room
temperature in the presence of Na2CO3-Na2SO4 under solvent-free conditions. In addition, nitrones of
aliphatic aldehydes (3m, 3n) and alicyclic ketones (3o, 3p) could also be synthesized by our simple
grinding method.
Aromatic heterocyclic aldehydes and aromatic aldehydes having electron-donating or
electron-withdrawing substituents were converted to the corresponding nitrones in high yields in a few
minutes. These nitrones were recrystallized from petroleum ether. The condensation reaction between
carbonyl compounds and N-methylhydroxylamine hydrochloride can also take place in the presence of
Na2CO3. However, the yield of the reaction was lower than yield of the reaction performed in the
presence of Na2CO3-Na2SO4, because Na2SO4 absorbed the water formed in the condensation
reactions. The substituted N-methylnitrones were synthesized as depicted in Scheme 1. Melting points,
yields and reaction times of substituted N-methyl nitrones are given in Table 1.
Scheme 1. Synthesis of substituted N-methyl nitrones.
H
O
Na2CO3, Na2SO4
Grinding
CH3NHOH.HCl
C
N(O)CH3
3a-n
R
H
R
1a-n
2
R: Aryl or alkyl
O
N(O)CH3
[ ]n
Na2CO3, Na2SO4
Grinding
[ ]n
CH3NHOH.HCl
3o, 3p
1o, 1p
n: 1, 2
2

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6679
Table 1. Reaction time, melting points and yields.
Reaction
mp (or bp)
(°C)
mp (or bp)
(°C) Lit.
Yield
Substrate
1a
Entry
Products
3a
Time (min)
(%)
CHO
4
5
82–84
82–84 [14]
94
CHO
1b
3b
204–205
210–212 [13]
93
O2N
CHO
CHO
1c
5
5
3c
129–130
102–103
129–130 [17]
103–104 [17]
95
98
N
1d
1e
3d
S
CHO
7
3e
148–149
148–150 [18]
98
N
S
S
CHO
1f
4
5
3f
118–119
90–91 †
118–119 [17]
-
96
96
S
CHO
1g
3g
CHO
CHO
1h
1i
8
6
3h
3i
135–136 ‡
193–195 †
-
-
98
91
S
Ph
Ph
S
CHO
CHO
1j
1k
1l
6
3
3j
3k
3l
113–114 †
89–90
oil †
-
93
94
92
62
O
89–90 [14]
O
CHO
CHO
5
-
-
1m
10
3m
oil ‡
CHO
1n
1o
10
10
3n
3o
oil ‡
-
76
71
O
(72 °C,
0.1 torr)
(70 °C,
0.1 torr) [19]

Molecules 2011, 16
6680
Table 1. Cont.
Substrate
1p
Entry
Reaction
Products mp (or bp)
(°C)
mp (or bp)
(°C) Lit.
Yield
Time (min)
(%)
O
(88 °C, 0.1
(80 °C, 0.1
torr) [19]
10
3p
68
torr)
All compounds are characterized on the basis of IR, 1H-NMR, 13C-NMR and HR-MS spectral data.
† Compounds not found in the literature. Their spectral data are given in the Experimental section.
‡
Compound found in the literature, but melting (or boiling) points and spectral data not found.
Their spectral data are given in the Experimental section.
3. Experimental
All carbonyl compounds, Na2CO3, Na2SO4, N-methylhydroxylamine hydrochloride and other
chemicals were purchased from Merck. All mps were determined in sealed capillaries and are
uncorrected. Boiling points were determined in a vacuum distillation apparatus. FT-IR spectra were
1
recorded on a Mattson 1000 spectrometer as KBr pellets or Nujol mulls. H-NMR spectra were
recorded on a Varian Gemini 300 (300 MHz) NMR spectrometer in CDCl3. Mass spectra
measurements were obtained on a Thermo Finnigan Trace DSQ. MS was performed by means of a
Waters ACQUITY UPLC analyser combine with a Micromass LCT Premier TM XE TOF-MS and
electrospray ionization (ESI); results agreed satisfactorily with calculated values.
3.1. General Method for the Synthesis of Compounds 3a-l
A mixture of aromatic aldehyde (10 mmol), N-methylhydroxylaminehydrochloride (1.65 g,
20 mmol), sodium carbonate (2.33 g, 22 mmol) and sodium sulphate (0.71 g, 5 mmol) were added in a
mortar and ground rapidly with a pestle at room temperature. The reaction was monitored by TLC.
Diethylether (10 Ml) was added to the crude product mixture and filtered. The solvent was evaporated
under vacuum and the residue was crystallized from petroleum ether.
C-(5-Methyl-2-thienyl)-N-methylnitrone (3g, C7H9NOS): Yield: 96%; mp. 90-91 °C; IR (KBr, ν,
cm−1): 1595 (C=N), 1186 (N→O); 1H-NMR (CDCl3, δ, ppm): 7.79 (s, 1H, CH), 7.28 (d, J = 3.72 Hz,
1H, Ar-H), 6.83 (d, J = 3.75 Hz, 1H, Ar-H), 3.88 (s, 3H, NCH3), 2.53 (s, 3H, CH3); 13C-NMR (CDCl3,
δ, ppm): 15.4, 51.8, 126.0, 130.7, 131.0, 132.0, 144.9; HR-MS (EI): 156.0494 ([M+H]+, C7H10NOS+
,
calc. 156.0483).
C-(3-Methyl-2-thienyl)-N-methylnitrone (3h, C7H9NOS): IR (KBr, ν, cm−1): 1590 (C=N), 1188
1
(N→O); H-NMR (CDCl3, δ, ppm): 7.81 (s, 1H, CH), 7.40 (d, J = 5.04 Hz, 1H, Ar-H), 6.96 (d,
J = 5.05 Hz, 1H, Ar-H), 3.92 (s, 3H, NCH3), 2.41 (s, 3H, CH3); 13C-NMR (CDCl3, δ, ppm): 14.6, 52.1,
127.7, 129.0, 130.0, 130.5, 140.1; HR-MS (EI): 156.0449 ([M+H]+, C7H10NOS+, calc. 156.0483).
C-(4-Phenyl-2-thienyl)-N-methylnitrone (3i, C12H11NOS): IR (KBr, ν, cm−1): 1598 (C=N), 1185
1
(N→O); H-NMR (CDCl3, δ, ppm): 7.91 (s, 1H, CH), 7.34-7.70 (m, 7H, Ar-H), 3.92 (s, 3H, NCH3);

Molecules 2011, 16
6681
13C-NMR (CDCl3, δ, ppm): 40.3, 52.2, 124.5, 127.2, 128.5, 130.0, 131.4, 134.6, 136.0, 142.0; HR-MS
(EI): 218.0651 ([M+H]+, C12H12NOS+, calc. 218.0640).
C-(5-Phenyl-2-thienyl)-N-methylnitrone (3j, C12H11NOS): IR (KBr, ν, cm−1): 1590 (C=N), 1183
(N→O); 1H-NMR (CDCl3, δ, ppm): 7.85 (s, 1H, CH), 7.73 (d, J = 1.37 Hz, 1H, thienyl-Ar-H), 7.71 (d,
J = 1.31 Hz, 1H, thienyl-Ar-H), 7.30-7.70 (m, 5H, phenyl-Ar-H), 3.90 (s, 3H, NCH3); 13C-NMR
(CDCl3, δ, ppm): 52.0, 123.6, 127.0, 128.8, 129.8, 131.2, 131.9, 132.4, 135.0, 147.5; HR-MS (EI):
218.0624 ([M+H]+, C12H12NOS+, calc. 218.0640).
C-(5-Methyl-2-furanyl)-N-methylnitrone (3l, C7H9NO2): IR (Nujol, ν, cm−1): 1528 (C=N), 1192
1
(N→O); H-NMR (CDCl3, δ, ppm): 7.58 (d, J = 3.37 Hz, 1H, Ar-H), 7.40 (s, 1H, CH), 6.08 (d,
J = 3.39 Hz, 1H, Ar-H), 3.72 (s, 3H, NCH3), 2.24 (s, 3H, CH3); 13C-NMR (CDCl3, δ, ppm): 13.6, 52.3,
108.7, 116.8, 126.3, 145.2, 154.1; HR-MS (EI): 140.0736 ([M+H]+, C7H10NO2 , calc. 140.0712).
+
3.2. General Method for the Synthesis of Compounds 3m-p
A mixture of carbonyl compound (10 mmol), N-methylhydroxylamine hydrochloride (1.65 g,
20 mmol), sodium carbonate (2.33 g, 22 mmol) and sodium sulphate (0.71 g, 5 mmol) were added in a
mortar and ground rapidly with a pestle at room temperature. The reaction was monitored by TLC. The
10 mL of diethyl ether was added to the crude product mixture and filtered. After the solvent was
evaporated under vacuum and the oily product was taken. The column chromatography was applied to
the oily product and purify product was obtained.
C-(3-Phenylpropylidene)-N-methylnitrone (3m, C10H13NO): IR (Nujol, ν, cm−1): 1561 (C=N), 1176
1
(N→O); H-NMR (CDCl3, δ, ppm): 7.18-7.36 (m, 5H, Ar-H), 7.05 (t, J = 6.41 Hz, 1H, CH), 3.68
(s, 3H, NCH3), 2.44-2.84 (m, 4H, CH2CH2); 13C-NMR (CDCl3, δ, ppm): 28.4, 33.0, 64.7, 129.1, 129.8,
133.5, 142.3, 154.3; HR-MS (EI): 164.1062 ([M+H]+, C10H14NO+ calc. 164.1075).
,
C-(2-Phenylpropylidene)-N-methylnitrone (3n, C10H13NO): IR (Nujol, ν, cm−1): 1588 (C=N), 1189
1
(N→O); H-NMR (CDCl3, δ, ppm): 7.21-7.50 (m, 5H, Ar-H), 6.81 (d, J = 7.74 Hz, 1H, CH), 3.65
13
(s, 3H, NCH3), 2.74-2.84 (m, 1H, CH); 1.4 (d, J = 7.33 Hz, 3H, CH3); C-NMR (CDCl3, δ, ppm):
27.3, 31.9, 62.8, 123.7, 127.0, 136.6, 149.2, 153.7; HR-MS (EI): 164.1099 ([M+H]+, C10H14NO+, calc.
164.1075).
4. Conclusions
In conclusion, we have developed an environmentally friendly procedure for the synthesis of
N-methylnitrones in the absence of solvent at room temperature by a grinding method.
Na2CO3-Na2SO4 was used in this condensation reaction for the first time. In comparison with the
classical heating reactions, this procedure has advantageous of milder reaction conditions, shorter
reaction times, easier work-up and better yields. In addition, the main advantage of our procedure is
to be able to synthesize nitrones of aliphatic aldehydes and alicyclic carbonyl compounds in a
solventless medium.

Molecules 2011, 16
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Acknowledgment
The authors gratefully acknowledge financial support from the Scientific and Technical Research
Council of Turkey (TUBITAK, Project No. 107T676).
References
1. Black, D.S.C.; Crozier, R.F.; Davis, V.C. 1,3-Dipolar cycloaddition reactions of nitrones.
Synthesis 1975, 1975, 205-221.
2. Dondas, H.A.; Cummins, J.E.; Grigg, R.; Thornton, P.M. X=Y–ZH Systems as potential
1,3-dipoles. Part 53: Sequential nucleophilic ring opening-1,3-dipolar cycloaddition reactions of
Z-oxime anions with aziridines and dipolarophiles. Tetrahedron 2001, 57, 7951-7961.
3. Alibes, R.; Blanco, P.; de March, P.; Figueredo, M.; Font, J.; Alvarez-Larena, A.; Piniella, J.F.
Synthesis and 1,3-dipolar cycloadditions of a new enantiopure cyclic nitrone. Tetrahedron Lett.
2002, 44, 523-525.
4. Kumar, K.R.R.; Mallesha, H.; Rangappa, K.S. Synthesis of novel isoxazolidine derivatives and
studies for their antifungal properties. Eur. J. Med. Chem. 2003, 38, 613-619.
5. Gothelf, K.V.; Jorgenson, K.A. Asymmetric 1,3-Dipolar cycloaddition reactions Chem. Rev.
1998, 98, 863-909.
6. Broggini, G.; Zecchi, G. Pyrrolizidine and indolizidine syntheses involving 1,3-Dipolar
cycloadditions. Synthesis 1999, 1999, 905-917.
7. Mulzer, J. Organic Synthesis Highlights; Verlag Chemie: Weinheim, Germany, 1991; pp. 3-4.
8. Huisgen, R.; Grashey, R.; Sauer, J. The Chemistry of Alkenes; Wiley Interscience: London, UK,
1964; pp. 806-807.
9. Tania, R.A.; Gareth, W.V.C.; Colin, L.R. Benign approaches for the synthesis of bis-imine schiff
bases. Green Chem. 2006, 8, 50-53.
10. Kumar, S.; Sharma, P.; Kapoor, K.K.; Hundal, M.S. An efficient, catalyst- and solvent-free, four
component, and one-pot synthesis of polyhydroquinolines on grinding. Tetrahedron 2008, 64,
536-542.
11. Longhi, K.; Moreira, D.N.; Marzari, M.R.B.; Floss, V.M.; Bonacorso, H.G.; Zanatta, N.;
Martins, M.A.P. An efficient solvent-free synthesis of NH-pyrazoles from
β-dimethylaminovinylketones and hydrazine on grinding. Tetrahedron Lett. 2010, 51, 3193-3196.
12. Heravi, M.M.; Poormohammad, N.; Beheshtiha, Y.S.; Baghernejad, B. Efficient synthesis of
2,4-Disubstituted thiazoles under grinding. Synth. Commun. 2011, 41, 579-582.
13. Andrade, M.M.; Barros, M.T.; Pinto, R.C. Exploiting microwave-assisted neat procedures:
Synthesis of N-aryl and N-alkylnitrones and their cycloaddition en route for isoxazolidines.
Tetrahedron 2008, 64, 10521-10530.
14. Bigdeli, M.A.; Nikje, M.M.A. An efficient and rapid chemoselelective synthesis of
α-aryl-N-methylnitrones in dry media. Monatsh. Chem. 2001, 132, 1547-1549.
15. Nikje, M.M.A.; Bigdeli, M.A. A microwave assistedoxidation of benzaldehydes under
solvent-free condition usingoxone/wet-alumina. Phosphorus Sulfur Silicon Relat. Elem. 2004,
179, 1445-1448.

Molecules 2011, 16
6683
16. Colacino, E.; Nun, P.; Colacino, F.M.; Martinez, J.; Lamaty, F. Solvent-free synthesis of nitrones
in a ball-mill. Tetrahedron 2008, 64, 5569-5576.
17. Colonna, S.; Piront, V.; Carrea, G.; Pasta, P.; Zambianchi, F. Oxidation of secondary amines by
molecular oxygen and cyclohexanone monooxygenase. Tetrahedron 2004, 60, 569-575.
18. Coutouli, A.E.; Malamidou, X.E.; Stampelos, X.N.; Alexopoulou, I.N. Formation and reduction
reactions of 3-indol-3-yl-isoxazolidines. Tetrahedron 1997, 53, 707-718.
19. Cummins, H.C.; Coates, R.M. α-Oxygenation of aldehydes and cyclic ketones by acylation &
arrangement of nitrones. J. Org. Chem. 1983, 48, 2070-2076.
Sample Availability: Samples of the substituted N-methyl nitrones 3a-p are available from the authors.
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