2-Substituted nitrones and isomeric hydroxylamines - obtained via aluminium amalgam reduction of nitro nitriles and ketones-a new access to convenient intermediates for nitroso carbonyl compounds preparation

Article abstract of DOI:10.1016/j.tet.2010.03.023

Substituted five-membered cyclic nitrones (pyrroline N-oxides) have been obtained in good to high yields from tertiary γ-nitro ketones and nitriles employing aluminium amalgam as a reducing agent in moist diethyl ether or THF. Attempts to obtain cyclic amino nitrones from α- or β-nitro nitriles failed and only the corresponding hydroxylamines have been isolated. Both nitrones and hydroxylamines have been used for synthesis of tertiary C-nitroso nitriles or ketones.

Full text of DOI:10.1016/j.tet.2010.03.023

Tetrahedron 66 (2010) 3608–3613
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2-Substituted nitrones and isomeric hydroxylamines – obtained via aluminium
amalgam reduction of nitro nitriles and ketonesda new access to convenient
intermediates for nitroso carbonyl compounds preparation
,
b
,
c,
*
Karol Grela a , Leszek Konopski
*
a Department of Chemistry, Warsaw University, Pasteura 1, 02-093 Warsaw, Poland
b Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
c Institute of Industrial Organic Chemistry, Annopol 6, 03-236 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Substituted five-membered cyclic nitrones (pyrroline N-oxides) have been obtained in good to high
Received 30 November 2009
Received in revised form 16 February 2010
Accepted 8 March 2010
yields from tertiary
moist diethyl ether or THF. Attempts to obtain cyclic amino nitrones from
only the corresponding hydroxylamines have been isolated. Both nitrones and hydroxylamines have
been used for synthesis of tertiary C-nitroso nitriles or ketones.
Ó 2010 Elsevier Ltd. All rights reserved.
g
-nitro ketones and nitriles employing aluminium amalgam as a reducing agent in
- or -nitro nitriles failed and
a
b
Available online 17 March 2010
Keywords:
Nitro nitriles
Hydroxylamines
Cyclic nitrones
Aluminium amalgam reduction
Nitroso nitriles
1. Introduction
2-Alkyl derivatives of DMPO have been obtained by reduction of
the appropriate
g
-nitro ketones using usually Zn dust,6 in most
Five-membered cyclic nitrones (pyrroline N-oxides) have been
widely used in organic syntheses1 as well as in free radical studies
employing an Electron Paramagnetic Resonance (EPR) technique.2
3,4-Dihydro-2,2-dimethyl-2H-pyrrole-1-oxide (or 5,5-dimethyl-1-
pyrroline-1-oxide, DMPO) and its derivatives were originally in-
troduced in 1973 by Janzen;3 these compounds have been largely
applied as radical scavengers.2 Over the past few years some DMPO
derivatives with a 2-alkyl or 2-aryl substituent have acquired im-
portance.4 5,5-Dialkyl-2-alkylpyrroline-1-oxides may be as well
cases with aq ammonium chloride.4a,7 Catalytical (Pd on charcoal)
hydrogenation in methanol has also been successfully applied.8
2-Amino derivatives of DMPO have been also employed as
model compounds in EPR studies on biological systems.9 2-Amino
nitrones have usually been obtained by reduction of the appro-
priate g
-nitro nitriles (Scheme 1).10 However, the most often used
systems such as Fe/HCl,10 Zn/NH4Cl aq,5,10 Zn/AcOH,11 or catalytical
hydrogenation10 are not convenient due to the long reduction time,
zinc activation requirement, and the troublesome isolation of
highly polar and hygroscopic products from the aqueous or alco-
holic reaction mass. Buckley and co-workers10 suggested that an
convenient intermediates for the preparation of tertiary
g-nitroso
carbonyl compounds.5
Scheme 1. General method to obtain the cyclic amino nitrone from a nitro nitrile.10
intermediate hydroxylamine was the primary reduction product
and the cyclization to the appropriate amino nitrone subsequently
occurred via its tautomeric form. Attempts to isolate the in-
termediate hydroxylamine failed10 (Scheme 1).
* Corresponding authors. Tel.: þ48 22 822 02 11; fax: þ48 22 922 59 96 (K.G.);
tel.: þ48 22 811 21 44; fax: þ48 22 811 07 99 (L.K.); e-mail addresses: klgrela@
gmail.com (K. Grela), konopski@ipo.waw.pl (L. Konopski).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.023

K. Grela, L. Konopski / Tetrahedron 66 (2010) 3608–3613
3609
During our research, some unstable aliphatic tertiary C-nitroso
nitriles and ketones had to be obtained for the purpose of some
mass spectrometric (MS) and 14N NMR studies.12 Since the direct
reduction of aliphatic nitro compounds to corresponding nitroso
compounds usually does not occur,13 we needed a quick and effi-
amounts of the appropriate aldehyde and some other de-
composition products. Instead of this, we used a modified phos-
phorus trichloride reduction method21 in dry pyridine at rt, and 3-
methyl-3-nitrobutanenitrile (1b) was smoothly obtained in
81% yield (Scheme 3).
cient method for reduction of the tertiary a-, b- and g-nitro car-
bonyl compounds to intermediates, e.g., hydroxylamines or
nitrones, and then oxidation to the appropriate C-nitroso com-
pounds. In this paper, such a method is described and discussed.
2. Results and discussion
The nitro compounds 1 were reduced with aluminium amalgam
to afford corresponding hydroxylamines 2 and/or nitrones 3 (the
latter in the case of the
dized to the nitroso compounds 4 (Scheme 2).
g-nitro compounds). 2 and/or 3 were oxi-
Scheme 3. Reduction of 3-methyl-1,3-dinitrobutane to 3-methyl-3-nitrobutanenitrile
(1b), (i): NaBH2S3/THF, reflux, 5 h, 62%, (ii): PCl3/pyridine, rt, two days, 81%.
Scheme 2. Synthesis of the target nitroso compounds 4 from the corresponding nitro compounds 1; (i): Al/Hg, Et2O/H2O, rt, 18–85%; (ii): Cl2/H2O, 0 ꢀC or MCPBA/CHCl3, 0 ꢀC or
NaIO4/H2O, rt, 21–92%, (iii): Al/Hg, THF/H2O, rt, 92%, (iv): NaIO4/H2O, rt, 77%.
2.1. Syntheses of starting nitro compounds
2.2. Reduction of nitro compounds
2-Methyl-2-nitropropanenitrile (1a) was obtained by oxida-
tive substitution of 2-nitropropane sodium salt in water with
sodium cyanide/potassium ferricyanide in 67% yield according to
Ref. 14.
5-Methyl-5-nitrohexan-2-one (1c) and 4-methyl-4-nitro-
pentanenitrile (1d) were synthesized via Michael addition of
2-nitropropane to methyl vinyl ketone15 or acrylonitrile,16 re-
spectively, using catalytic amounts of 40% aq tetrabutyl ammonium
hydroxide (TBA).
5-(2-Cyanoethyl)-2,2-dimethyl-5-nitro-1,3-dioxane (1e) was
obtained in a four step synthesis starting from aldolization of ni-
tromethane and formaldehyde, then cyclization of the resulting
nitro triol with acetone followed by dehydrometylation and even-
tually Michael addition to acrylonitrile.17,18
To the best of our knowledge, the synthesis of 3-methyl-3-
nitrobutanenitrile (1b) has not been described in the literature. In
order to successfully synthesise the compound, the following re-
action pattern was developed. Acetylation of 2-nitroethanol fol-
lowed by elimination of acetic acid gave not isolated nitroethene,
which was subsequently condensed with 2-nitropropane to afford
3-methyl-1,3-dinitrobutane according to Troitskaya.19 Attempts at
the selective reduction of CH2NO2 group to nitrile in 3-methyl-1,3-
dinitrobutane with NaBH2S3 in tetrahydrofuran (Lalancette
method20) gave the nitro nitrile 1b in 62% yield with considerable
We used the aluminium amalgam to reduce the nitro derivatives
1. In our hands, the precipitated aluminium oxide was filtered off
after the reduction, and the practically pure nitrone and/or hy-
droxylamine were obtained after removing the solvent from the
filtrate. This technique avoids the inconvenient product isolation
from an aqueous solution after the reaction.
Tertiary g-nitro ketones with the keto group protected as a di-
methyl ketal were reduced with aluminium amalgam in moist
diethyl ether22 affording the corresponding hydroxylamines.23 In
this paper, the modified reduction procedure with aluminium
amalgam was applied to an unprotected
g-nitro ketone as well as
a series of -, - and -nitro nitriles. The appropriate hydroxyl-
a
b
g
amines and/or nitrones were synthesized in mostly good to high
yields. The results obtained for the reduction of 1a–e are presented
in Table 1.
The aluminium amalgam reduction of the
a-nitro nitrile 1a
afforded significant amounts of decomposition products and
2-hydroxylamino-2-methylpropanenitrile (2a) was only isolated in
poor yield (18%) (Table 1). Among the decomposition products we
searched for the hypothetical cyclic three-membered amino
nitrone (unknown to date) but no evidence for such compounds
were noticed. The same hydroxylamine 2a was obtained by the
direct addition of hydrocyanic acid to acetone oxime24 in slightly
better yield (27%).

3610
K. Grela, L. Konopski / Tetrahedron 66 (2010) 3608–3613
Table 1
The possibility of the hydrogen bond existence was confirmed in
the 1H NMR spectra carried out in different solvents. Thus, the
signals in the hydroxylamine 2e spectrum were strongly shifted
after changing the solvent from CDCl3 chloroform into protic
CD3OD whereas the chemical shifts in the spectrum of nitrone 3e
did not practically depend on the applied solvent.
Preparation of hydroxylamines 2 and nitrones 3 by the reduction of nitro ketones
and nitriles 1 using aluminium amalgam
1
Starting material
X
Y
Isolated product Reaction Yield
(nitro group position)
2 and/or 3
time, h
[%]
a
b
c
d
e
(
(
(
(
(
a
b
g
g
g
)
)
)
)
)
CN
CN
n/a 2a
n/a 2b
0.75
1
0.5
0.75
2
18
74
88
85
92
C(O)CH3 CH3 3c
CN
CN
2.3. Oxidation of hydroxylamines and nitrones to nitroso
compounds
NH2 2d/3d
NH2 2eþ3e (7:3)
All hydroxylamines 2a, b, d, e, and nitrones 3c–e were sub-
The aluminium amalgam reduction was checked for a
b
-nitro
sequently smoothly oxidized:
nitrile as well. 3-Methyl-3-nitrobutanenitrile 1b was smoothly re-
duced, but as distinct of the -nitro nitriles, only the corresponding
g
ꢂ into the
a
-nitroso nitrile 4a using chlorine in iced water29,30 in
92% yield,12a
hydroxylamine, 3-hydroxylamino-3-methylbutanenitrile (2b) was
isolated in 74% yield. No cyclization of compound 2b affording the
cyclic 2-amino nitrone has been observed, although a limited
number of four-membered cyclic nitrones have been described in
the literature.1d
ꢂ into
b- and g-nitroso nitriles 4b, 4d, 4e using sodium iodate in
water5 in 21-77% yield,
ꢂ into the corresponding
g-nitroso ketone 4c using m-chloro-
perbenzoic acid (m-CPBA) in chloroform31 in 66% yield,
The Al(Hg) reduction of 5-methyl-5-nitrohexan-2-one (1c) affor-
appropriately.
ded directly
a nitroned3,4-dihydro-2,2,5-trimethyl-2H-pyrrole
1-oxide (3c). No intermediate hydroxylamine 2c has been isolated.
The reduction of 4-methyl-4-nitropentanenitrile (1d) afforded
a viscous, colourless, slowly solidifying oil. The comparison of the
properties of the obtained colourless crystals with the literature
data showed that the solid was practically pure 2,3-dihydro-2,2-
dimethyl-4H-pyrrol-5-ylamine 1-oxide (or 2-amino-5,5-dimethyl-
1-pyrroline 1-oxide) (3d). The following assumption has been
made: the first reduction product was the oily hydroxylamine 2d,
which subsequently slowly cyclized affording the crystalline
nitrone 3d. Actually, since in some cases the oil obtained after re-
duction did not solidify rapidly we could record its IR spectrum. As
distinct from the solid product, only weak bands characteristic of
amino nitrone:25 C]N at 1686 cmꢁ1 and N–O at 1200 cmꢁ1 were
found, whereas a strong C^N group band at 2243 cmꢁ1 was ob-
served in the spectrum. Only after solidification did the obtained
crystals give the IR, 1H NMR, and mass spectra completely consis-
tent with the nitrone literature data.25–27 This observation fully
confirmed the above assumption that the direct aluminium amal-
gam reduction product was hydroxylamine 2d, which subsequently
cyclized into amino nitrone 3d.
After Al(Hg) reduction of 5-(2-cyanoethyl)-2,2-dimethyl-5-ni-
tro-1,3-dioxane (1e), an equilibrium mixture containing both the
hydroxylamine 2e and the spirocyclic nitrone 3e in the ratio of ca.
7:3 (1H NMR) was obtained. As distinct from the compound 2d, the
hydroxylamine 2e was very stable and did not fully cyclize even
after four months and several crystallization attempts. Only reflux
of crude reduction product in the presence of tetramethylguanidine
(TMG) for 5 h afforded pure spirocyclic nitrone – 8,8-dimethyl-1-
oxy-7,9-dioxa-1-azaspiro[4.5]dec-1-en-2-ylamine (3e). On the
analogy of 5-hydroxy-1,3-dioxane derivatives,28 the high stability
of the hydroxylamine 2e can be explained by a bifurcated intra-
molecular hydrogen bond formation between NHO–H group and
oxygen atoms in the dioxolane ring (Scheme 4).
All nitroso compounds 4a–e were isolated as crystalline uncol-
oured dimers (Table 2):
Table 2
Preparation of nitroso compounds 4 by oxidation of nitrones or hydroxylamines
Starting material
2 and/or 3
Oxidation
conditions
Isolated
Product, 4
Reaction
time, min
Yield
[%]
2a
2b
3c
2d, 3d
2e, 3e
Cl2/H2O, 0 ꢀ
C
4a
4b
4c
4d
4e
5
92
21
66
35
77
NaIO4, H2O, rt
m-CPBA, CHCl3, 0 ꢀ
NaIO4, H2O, rt
NaIO4, H2O, rt
30
120
30
30
C
2R0—N]O%R0—ðO)ÞN]Nð/OÞ—R0
In solution, after melting and even in the gas phase12a the di-
mers are in equilibrium with deep blue monomers R0-N]O. All
dimers showed in the IR spectra the characteristic (O))N]N(/O)
band at 1216–1296 cmꢁ1. In the MS of the aliphatic tertiary
C-nitroso carbonyl compounds and nitriles, there have been
ꢂ
observed neither dimer 2Mþ nor monomer Mþꢂ molecular ions, but
only the specific MHþ ions were found. The MHþ ions intensities
were not strongly concentration dependent, so they were not
chemical auto-ionization products, but rather ions that were
formed in the fragmentation patterns of the absent from the EI
ꢂ
mass spectra dimer molecular ions 2Mþ 12a
.
3. Conclusions
The modified aluminium amalgam reduction of g-nitro ketones
and nitriles was checked as an alternative method for the corre-
sponding five-membered nitrones (2-substituted DMPO
Scheme 4. Reduction of 5-(2-cyanoethyl)-2,2-dimethyl-5-nitro-1,3-dioxane (1e) affording hydroxylamine 2e and nitrone 3e (7:3 mol/mol), (i): Al(Hg), THF/H2O, rt, 2 h, 92%; (ii):
TMG/THF, reflux, 5 h.

K. Grela, L. Konopski / Tetrahedron 66 (2010) 3608–3613
3611
derivatives) preparation. The reduction of the lower homologues,
- and -nitro nitriles, afforded only corresponding hydroxyl-
amines, and no cyclic nitrone formation has been observed.
Nitrones and hydroxylamines were easily transformed into corre-
sponding tertiary C-nitroso ketones or nitroso nitriles.
methyl-3-nitrobutanenitrile
(1b)
(62%),
3-methyl-3-nitro-
b
a
butyraldehyde (27%), 2-methyl-4-nitrobut-2-ene (6%), sen-
ecioaldehyde (CH3)2C]CH–CHO (2%) and some minor
components.
4.2. General procedure for reduction of nitro compounds
1a–e with aluminium amalgam
4. Experimental
4.1. General
4.2.1. Aluminium amalgam (modified procedure22). Commercial al-
uminium foil (0.255 g, 9.58 mmol) was cut into ca. 20 strips, and
each strip was rolled into a cylinder about 5 mm in diameter using
a glass tube. Each of the aluminium foil cylinders was degreased by
immersing it in ethyl ether, dried in air for several seconds, and
amalgamated by immersing one by one for 15 s in a solution of
mercury (II) chloride (0.07 g) in water (4 mL). Each amalgamed
cylinder was then quickly transferred into a three neck flask con-
taining diethyl ether (15 mL) and water (0.13 mL). The reaction
mixture was stirred vigorously for 30 min at rt before the reduction
was carried out.
1H nuclear magnetic resonance (NMR) spectra were recorded on
a Varian Gemini-200 spectrometer at 200 MHz in CDCl3, unless
otherwise stated. Chemical shifts values are given in
d [ppm] units
relative to TMS. 14N NMR spectra were measured with a Bruker
AM500 spectrometer at 36.14 MHz in acetone at 35 ꢀC, nitrogen
chemical shifts values were measured in
d [ppm] units using ni-
tromethane as an internal standard. The Fourier-transform infrared
(FTIR) spectra were recorded on a Perkin-Elmer FTIR 1640 spec-
trophotometer; nmax in cmꢁ1. The electron ionization mass spectra
(EIMS) at 70 eV and fast ion bombardment (Csþ) mass spectra (FIB-
MS) were recorded on an AMD-604 mass spectrometer.
Unless otherwise stated, commercial grade chemicals were used
without further purification. Commercial aluminium foil, thickness
13 mm was used. Flash chromatography and chromatographic fil-
4.2.2. Aluminium amalgam reduction. A solution of the appropriate
nitro compound 1a–e (5 mmol) in diethyl ether or tetrahydrofuran
(5 mL) was added dropwise to a flask containing Al(Hg) at such
a rate that the solvent refluxed briskly. The reaction mixture was
stirred for 0.5–7 h at rt until all the starting material was consumed.
The cellulose powder (Whatman, 0.1 g) was subsequently added
into resulted white-grey suspension and the reaction mixture was
filtered through a cellulose bed. The alumina precipitate was
washed in the case of nitro ketones with ethyl ether (5 mLꢃ5), and
in the case of nitro nitriles subsequently with ethyl ether (5 mLꢃ2),
dichloromethane (5 mLꢃ2) and dichloromethane/methanol 1:1 (v/
v) (5 mLꢃ3). The solvent was removed under vacuum, and the
obtained crude products were purified by distillation (2c) or crys-
tallization (2a, 2d,e) (Table 1).
tration were performed using a 230–400 mesh silica gel (Merck).
The solvents were purified and/or distilled before use and stored
under dry argon, when necessary.
The known nitro compounds 1a,14 1c,15 1d10 and 1e18 were
prepared according to the literature.
4.1.1. 3-Methyl-3-nitrobutanenitrile (1b). Phosphorus trichloride
(6.3 g, 4 mL, 45.8 mmol) was slowly added with stirring at rt to
a solution of 3-methyl-1,3-nitrobutane19 (3.141 g, 19.4 mmol) in dry
pyridine (20 mL) under argon. The red-brown reaction mixture was
stirred under argon for two days at rt, then cooled to 0 ꢀC and di-
luted hydrochloric acid (3 mol/L, 120 mL) was carefully added. The
reaction mixture was washed with ethyl ether (20 mLꢃ5). The
combined separated organic layers were washed with diluted
hydrochloric acid (3 mol/L, 20 mLꢃ2) and dried over magnesium
sulfate. The solution was concentrated under vacuum, affording
a yellow oil that solidized at rt. After vacuum distillation (60 ꢀC/
4.2.3. 2-Hydroxylamino-2-methylpropanenitrile (2a) (starting from
compound 1a14 according to the general procedure). A solution of 2-
methyl-2-nitropropanenitrile (1a, 570 mg, 5 mmol) in diethyl ether
(5 mL) was added dropwise with stirring to a flask containing
Al(Hg) freshly prepared from aluminium foil and mercury (II)
chloride, following the general procedure. The crystallization of the
crude product (33% pentane/Et2O) gave the title compound 2a
(90 mg, 18%) as a white solid, mp 90–92 ꢀC (lit.24 98–99 ꢀC). FTIR
(KBr pellet): 3260 (O–H, N–H), 2990 (C–H), 2240 (C^N), 1065 (N–
0.3 Torr), a colourless, viscous, solidifying oil of the b-nitro nitrile
1b (2.015 g, 15.7 mol) was obtained in 81% yield. Mp. 65–68.5 ꢀC
(white solid, petroleum ether); FTIR (film): 2975 (C–H), 2252
(C^N), 1545 (NO2), 856 (C–N); 1H NMR: 1.72 (s, 6H, 2CH3), 2.92 (s,
2H, CH2); 14N NMR:12b ꢁ17.47 (NO2), 126.54 (CN); MS, m/z (int.%):32
ꢂ
O); MS, m/z (int.%): 100 (30, Mþ ), 84 (23, [MꢁCN]þ), 69 (61), 57
(100).
ꢂ
82 (100, [MꢁNO2]þ), 81 (5, [MꢁHNO2]þ ), 55 (93, C4Hþ7 ), 41 (49);
elemental analysis: found C 47.05, H 6.50, N 21.98, calculated for
C5H8N2O2, C 46.87, H 6.29, N 21.86%.
4.2.4. 3-Hydroxylamino-3-methylbutanenitrile (2b) (starting from
compound 1b according to the general procedure). A solution of 3-
methyl-3-nitrobutanenitrile (1b, 640 mg, 5 mmol) in diethyl ether
(5 mL) was added dropwise with stirring to a flask containing
Al(Hg) freshly prepared from aluminium foil and mercury (II)
chloride, following the general procedure. Yield of the title com-
pound 2b 422 mg (74%), a bluish oil, directly oxidized to the cor-
4.1.2. 3-Methyl-3-nitrobutanenitrile (1b). Compound 1b via the
Lalancette reduction (according to20 with some modifications). To
a mixture of sodium borohydride (0.756 g, 0.02 mol) and sulfur
(1.92 g, 0.06 mol), 15 mL of dry tetrahydrofuran was rapidly added
without cooling and with stirring. 3-Methyl-1,3-dinitrobutane19
(3.24 g, 0.02 mol) in 5 mL of THF was added dropwise to the
obtained resulting suspension of 0.02 mol of NaBH2S3. The reaction
mixture was heated to reflux for 5 h. The temperature was then
allowed to cool to rt and the reaction mixture was hydrolyzed by
addition of 10% aq hydrochloric acid (10 mL) and stirring overnight
at rt. The product was extracted with methylene chloride and the
organic phase was washed twice with water (10 mLꢃ2), dried
(Na2SO4) and filtered. The solvent was removed under reduced
pressure using a rotary evaporator, affording the oily product
(2.43 g). FTIR (film): 2250 (C^N), 1700 (C]O), 1545 (NO2).
According to the GC–MS analysis, the product was a mixture of 3-
responding b-nitroso nitrile 4b. FTIR (film): 3259 (O–H, N–H), 2978
(C–H), 2250 (C^N); 1H NMR: 1.25 (s, 6H, 2CH3), 2.60 (s, 2H, CH2);
ꢂ
MS, m/z (int.%): 114 (0.2, Mþ ), 99 (5, [MꢁCH3]þ), 82 (18), 74 (100),
56 (35).
4.2.5. 2,2,5-Trimethyl-1-oxy-3,4-dihydro-2H-pyrrole (3c) (starting
from compound 1c15 according to the general procedure). A solution
of 5-methyl-5-nitrohexan-2-one (1c, 795 mg, 5 mmol) in diethyl
ether (5 mL) was added dropwise with stirring to a flask containing
Al(Hg) freshly prepared from aluminium foil and mercury (II)
chloride, following the general procedure. Yield of the title com-
pound 2c 559 mg (88%). A colourless oil, bp 48–50 ꢀC/1 Torr (lit.33

3612
K. Grela, L. Konopski / Tetrahedron 66 (2010) 3608–3613
71–72 ꢀC/2 Torr). FTIR (film): 2971 (C–H), 1605 (C]N), 1236 (N–O);
1H NMR: 1.40 (s, 6H, 2CH3), 2.00 (t, 2H, J 7.5 Hz, C–CH2CH2), 2.03 (s,
3H, COCH3), 2.59 (t, 2H, J 7.5 Hz, C-CH2CH2); MS, m/z (int.%): 127
After 30 min, the reaction mixture was washed with hexane
(10 mLꢃ6), the combined organic layers dried over anhydrous
magnesium sulfate and filtered, affording a blue solution of
nitroso nitrile monomers. In case of all other compounds, the
white solid precipitate of the oxidation product (nitroso nitrile
dimer) was filtered off after 1 h (except compounds 2e and
3edafter 2 h), washed with water (5 mLꢃ3) and dried in vac-
uum. The resulting grayish precipitate, containing some in-
organic salts was washed with hot chloroform (50 ꢀC, 5 mLꢃ3)
and filtered. The blue solution containing the appropriate nitroso
nitrile monomer was filtered through a layer of silica gel for
chromatography, and the solvent was removed in vacuum at rt,
affording a deep blue oil of the nitroso compound monomer, that
solidified quickly into the colourless dimer.
ꢂ
(78, Mþ ), 112 (35, [MꢁCH3]þ), 95 (25), 69 (23), 55 (46), 41 (100).
4.2.6. 5,5-Dimethyl-1-oxy-4,5-dihydro-3H-pyrrol-2-ylamine
(3d)
(starting from compound 1d10 according to the general procedure). A
solution of 4-methyl-4-nitropentanenitrile (1d, 710 mg, 5 mmol) in
diethyl ether (5 mL) was added dropwise with stirring to a flask
containing Al(Hg) freshly prepared from aluminium foil and mer-
cury (II) chloride, following the general procedure. Yield of the title
compound 3d 544 mg (85%). A colourless, viscous oil of 2d solidified
into white crystals of 3d. Mp 218–220 ꢀC (dec), white plates, lit.10
238 ꢀC (dec). FTIR (KBr pellet): 3200 (N–H), 2970 (C–H), 1690
(C]N),1200 (N–O); 1H NMR (CD3OD): 1.31 (s, 6H, 2CH3),1.98 (t, 2H,
J 7.5 Hz, C–CH2CH2), 2.65 (t. 2H, J 7.5 Hz, C–CH2CH2); MS, m/z
4.3.1. 3-Methyl-3-nitrosobutanenitrile dimer (4b) (starting from hy-
droxylamine 2b according to the general procedure). A solution of 3-
methyl-3-hydroxylaminobuta-nenitrile 2b (222 mg, 1.95 mmol)
and sodium hydrogen carbonate (0.25 g, 2.97 mmol) in water
(7.5 mL) was treated with a solution of sodium periodate (0.59 g,
2.75 mmol) in water (10 mL). Yield 46 mg (21%), blue oil solidifying
after recrystallization (10% chloroform/hexane), mp 59–62 ꢀC
(white plates). FTIR (KBr pellet): 2998 (C–H), 2250 (C^N), 1262
(N2O2, nitroso dimer); 1H NMR: 1.47 (s, 6H, 2CH3, monomer), 1.56
(s, 6H, 2CH3, dimer), 2.65 (s, 2H, CH2); 14N NMR:12b ꢁ576.95 (NO),
ꢂ
(int.%): 128 (100, Mþ ), 113 (43, [MꢁCH3]þ), 111 (24), 96 (58), 82 (9),
69 (20).
4.2.7. 5-(2-Cyanoethyl)-2,2-dimethyl-5-hydroxylamine-1,3-dioxane
(2e) and 2-amino-8,8-dimethyl-1-oxy-1-aza-7,9-dioxaspiro[4.5]dec-
2-ene (3e). A solution of the nitrile 1e (0.783 g, 3.66 mmol) in
tetrahydrofuran/ether (15 mL, 2:1 v/v) was added to Al(Hg) pre-
pared from aluminium foil (0.187 g, 7 mmol) and mercury (II)
chloride (0.05 g) in THF (11 mL) containing water (0.1 mL)
according to the general procedure. A colourless solid, mp 170–
174 ꢀC dec, (33% chloroform/hexane), containing the hydroxyl-
amine 2e (70%) and the spirocyclic nitrone 3e (30%). FTIR (film):
3443 (N–H, O–H), 2994 (C–H), 2257 (C^N), 1692 (C]N), 1198 (N–
O), 1087 (C–O); 1H NMR (CD3OD): 2e 70%: 1.36, 1.43 (2s, 6H, hy-
droxylamine (CH3)2), 1.75 (t, 2H, J 8 Hz, CH2CH2CN), 2.53 (t, 2H, J
8 Hz, CH2CH2CN), 3.75 (s, 4H, hydroxylamine 2OCH2); 3e
(30%):1.34, 1.52 (2s, 6H, nitrone (CH3)2), 2.23 (t, 2H, J 8 Hz, nitrone
C–CH2CH2), 2.70 (t, 2H, J 8 Hz, nitrone C–CH2CH2), 3.52 (d, 2H, J
11.5 Hz, nitrone O–CH2–C–CH2–O), 4.38 (d, 2H, J 11.5 Hz, nitrone
O–CH2–C–CH2–O); MS, m/z (int.%): 2e 167 (34), 149 (100), 132 (2),
113 (7), 57 (19); 3e 184 (2), 169 (6), 153 (1), 112 (25), 96 (100), 69
(23); elemental analysis: found C 54.10, H 7.93, N 13.96, C9H16N2O3
requires C 53.99, H 8.08, N 13.99%.
ꢂ
127.45 (CN); EIMS:12a m/z (int.%): 113 (0.2, MHþ), 112 (0.3, Mþ ), 82
(61, [MꢁNO]þ), 72 (22), 55 (100), 54 (38), 53 (11), 42 (13), 41 (40),
39 (36); elemental analysis: found C 53.48, H 7.39, N 25.15, calcu-
lated for C10H16N4O2, C 53.56, H 7.19, N 24.98%.
4.3.2. 4-Methyl-4-nitrosopentanenitrile dimer (4d) (starting from
nitrone 3d according to the general procedure). A solution of 5,5-
dimethyl-1-oxy-4,5-dihydro-3H-pyrrol-2-ylamine 3d (250 mg,
1.95 mmol) and sodium hydrogen carbonate (0.25 g, 2.97 mmol)
in water (7.5 mL) was treated with a solution of sodium periodate
(0.59 g, 2.75 mmol) in water (10 mL). Yield 86 mg (35%), grayish
solid, mp 61–62 ꢀC (white plates, 20% chloroform/hexane). FTIR
(KBr pellet): 2990 (C–H), 2240 (C^N), 1280 (N2O2, nitroso di-
mer); 1H NMR: 1.47 (s, 6H, CH3, monomer), 1.62 (s, 6H, CH3,
dimer), 2.23–2.47 (m, 4H, CH2CH2); 14N NMR:12b ꢁ598.58 (NO),
ꢂ
4.2.8. 2-Hydroxylamino-2-methylpropanenitrile (2a). Compound
2a via the Miller method.24 Hydrocyanic acid (4 g, 4.4 mL,
0.148 mol) was cooled to 0 ꢀC in a round bottom flask. (CAUTION!
The reagent is extremely toxic and volatile (bp 26 ꢀC), work only in
an efficient fume hood). Water (1.2 mL) was added dropwise
resulting 77% hydrocyanic acid and acetone oxime (6 g, 0.082 mol)
was rapidly added with stirring. The reaction mixture was kept for
five days at 6 ꢀC and the HCN was carefully evaporated at rt under
a mild nitrogen stream in a fume hood. The resulting semisolid was
washed with pentane (2ꢃ10 mL) to remove unreacted acetone
oxime and the residue was crystallized from 33% pentane/diethyl
ether affording white needles, yield 2.25 g (27%). Mp 90–92 ꢀC
(lit.24 98–99 ꢀC). FTIR and MSdsee Section 4.2.1.
131.45 (C^N); EIMS, m/z (int.%):12a 127 (0.5, MHþ ), 126 (0.1,
ꢂ
M
þ ), 96 (53, [MꢁNO]þ), 69 (34), 68 (14), 57 (41), 56 (11), 55
(100), 54 (9), 53 (15), 42 (23), 41 (57), 39 (16); FIB-MS: 275 (27,
[2MþNa]þ), 253 (67, [2MþH]þ); elemental analysis: found C
56.64, H 7.79, N 21.86, calculated for C12H20N4O2, C 57.12, H 7.99,
N 22.20%.
4.3.3. 5-(2-Cyanoethyl)-2,2-dimethyl-5-nitroso-1,3-dioxane dimer
(4e) (starting from mixture of hydroxylamine 2e and amino nitrone
3e according to the general procedure). A solution obtained in the
procedure 4.2.5 mixture of 5-(2-cyano-ethyl)-2,2-dimethyl-5-hy-
droxylamine-1,3-dioxane (2e) and 2-amino-8,8-dimethyl-1-oxy-1-
aza-7,9-dioxaspiro[4.5]dec-2-ene (3e) (390 mg, 1.95 mmol) and
sodium hydrogen carbonate (0.25 g, 2.97 mmol) in water (7.5 mL)
4.3. General procedure for oxidation of nitrones or
hydroxylamines 2b, 2d, 3d, 2e and 3e to nitroso compounds
4b, 4d, 4e with sodium periodate (according to5 with some
modifications)
was treated with a solution of sodium periodate (0.59 g,
2.75 mmol) in water (10 mL). Yield 297 mg (77%), greyish solid, mp
56–58 ꢀC (white plates, 33% chloroform/hexane). FTIR (KBr pellet):
2990 (C–H), 2247 (C^N),1278 (N2O2, nitroso dimer); 1H NMR: 1.32,
1.43 (2s, 6H, 2CH3, monomer), 1.39, 1.40 (s, 6H, 2CH3, dimer), 2.11–
2.29 (m, 4H, CH2CH2CN monomer), 2.35–2.58 (m, 4H, CH2CH2CN
dimer), 3.87 (d, 2H, J 12.6 Hz, O–CH2–C–CH2–O monomer), 3.96 (d,
2H, J 12.9 Hz, O–CH2–C–CH2–O dimer), 4.55 (d, 2H, J 12.9 Hz, O–
CH2–C–CH2–O dimer), 4.58 (d, 2H, J 12.6 Hz, O–CH2–C–CH2–O
monomer); 14N NMR:12b ꢁ595.78 (NO), 130.25 (C^N); EIMS:12a
m/z (int.%): 168 (8, [MꢁNO]þ), 153 (7), 111 (18), 110 (17), 82 (43),
80 (12), 59 (100), 55 (24), 54 (20), 53 (25), 43 (30), 41 (9); elemental
A
solution of appropriate hydroxylamine or nitrone
(1.95 mmol) and sodium hydrogen carbonate (0.25 g, 2.97 mmol)
in water (7.5 mL) was placed in a flask protected against light
with aluminium foil. Then, a solution of sodium periodate
(0.59 g, 2.75 mmol) in water (10 mL) was slowly added with
stirring at rt. In the case of
b-hydroxylamino nitrile 2b, the oxi-
dation product was a blue oil (nitroso compound monomer).

K. Grela, L. Konopski / Tetrahedron 66 (2010) 3608–3613
3613
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wards Heterocycles and Natural Products, Series: Chemistry of Heterocyclic Com-
pounds; Padwa, A., Pearson, W. H., Eds.; Wiley: New York, NY, 2002; Vol. 59,
pp 1–81; (c) Merino, P. Nitrones and Cyclic Analogues. In Compounds with
Two Carbon-Heteroatom Bonds: Heteroatom Analogues of Aldehydes and Ke-
tones, in Science of Synthesis; Padwa, A., Ed.; Georg Thieme: Stuttgart, 2004;
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analysis: found C 53.91, H 7.17, N 14.53, calculated for C18H24N4O6, C
54.53, H 7.12, N 14.88%.
4.3.4. 2-Methyl-2-nitrosopropanenitrile dimer (4a) (according to29
with some modifications). A cooled 0 ꢀC solution of 2-hydroxyl-
amino-2-methylpropanenitrile (2a) (0.56 g, 5.6 mmol) in water
(6 mL) was saturated with gaseous chlorine with stirring during
5 min. The deep blue oil of monomer of
a-nitroso nitrile pre-
cipitated and solidified into colourless solid. The crude compound
was filtered off, washed with cold pentane (3 mLꢃ2) and dried,
affording white solid of 2-cyano-2-nitrosopropane dimer (4a), yield
0.51 g, 92%. Mp 48–49 ꢀC (pentane), lit.34 53 ꢀC. FTIR (KBr pellet):
2996 (C–H), 2244 (C^N), 1296 (N2O2 nitroso dimer); 1H NMR: 1.76
(s, 6H, 2CH3); 14N NMR:12b ꢁ512.57 (NO), 117.96 (C^N); MS, m/z
ꢂ
(int.%):12a 98 (0.4, Mþ ), 68 (39, [MꢁNO]þ), 66 (12), 52 (18), 42 (25),
41 (100), 40 (8), 39 (33), 38 (6), 30 (23, NOþ).
4.3.5. 5-Methyl-5-nitrosohexan-2-one dimer (4c) (according to31
with some modifications). To a cooled to 0 ꢀC solution of 2,2,5-tri-
methyl-1-oxy-3,4-dihydro-2H-pyrrole (3c) (0.39 g, 3.07 mmol) in
chloroform (10 mL), a solution of m-chloroperbenzoic acid (purity
85%, 0.69 g, 3.40 mmol) in chloroform was slowly added with
stirring. The reaction mixture was stirred at 0 ꢀC for next 2 h, di-
luted with chloroform (10 mL), and washed with 5% aqueous so-
dium hydroxide (10 mLꢃ3) and water (10 mLꢃ2). The organic
phase was dried over anhydrous magnesium sulfate, and filtered
through a short column filled with silica gel. The blue solution was
concentrated affording a deep blue oil of the monomer that solid-
ified into a colourless dimer of the title compound 4c (0.29 g, 66%).
Mp 58–60 ꢀC (hexane), lit.23 53–55 ꢀC. FTIR (KBr pellet): 2980 (C–
H), 1720 (C]O), 1216 (N2O2 of nitroso compound dimer); 1H
NMR:12b 1.13 (s, 6H, 2CH3, monomer), 1,55 (s, 6H, 2CH3, dimer), 2.13
(s, 4H, CH2CH2, monomer and dimer), 2.28, 2.36 (2s, 3H, COCH3,
monomer and dimer); 14N NMR:12b ꢁ604.71 (NO); MS, m/z
(int.%):23 144 (1.5, MHþ), 113 (67), 95 (18), 55 (56), 43 (100).
13. Gowenlock, B. G.; Richter-Addo, G. B. Chem. Rev. 2004, 104, 3315–3340.
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Acknowledgements
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References and notes
1. For reviews, see e.g.: (a) Torssell, K. B. G. In Nitrile Oxides, Nitrones, and Nitro-
nates in Organic Synthesis; Feuer, H., Ed.; VCH: Weinheim, 1988; (b) Jones, R. C. F.