Synthesis of acetonine nitroxide radical and 1-hydroxy-2,2,4,6,6- pentamethyl-1,2,5,6-tetrahydropyrimidine

Article abstract of DOI:10.1016/S0040-4039(99)02049-3

An oxidation of acetonine with hydrogen peroxide 30% in strong basic water media in the presence of sodium tungstate with subsequent reduction of reaction product with hydrazine hydrate afforded up to 50% yields of the title hydroxyderivative. Mild oxidat

Full text of DOI:10.1016/S0040-4039(99)02049-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 179–181
Synthesis of acetonine nitroxide radical and 1-hydroxy-2,2,4,6,6-
pentamethyl-1,2,5,6-tetrahydropyrimidine
Leonid Volodarsky and Vilen Kosover b
a,∗
a
Free-lance, 1640 Ocean Ave #6N, Brooklyn, NY 11230, USA
Uniroyal Chemical Company, Middlebury, CT 06749, USA
b
Received 8 September 1999; revised 20 October 1999; accepted 21 October 1999
Abstract
An oxidation of acetonine with hydrogen peroxide 30% in strong basic water media in the presence of sodium
tungstate with subsequent reduction of reaction product with hydrazine hydrate afforded up to 50% yields of the
title hydroxyderivative. Mild oxidation of this compound with MnO2 in ether gave acetonine nitroxide radical
quantitatively. © 1999 Elsevier Science Ltd. All rights reserved.
Keywords: pyrimidine-1,2,5,6-tetrahydro; nitroxide; nitrone; hydroxylamines.
The ‘acetonine’, isolated from the reaction of acetone and ammonia, was finally identified as 2,2,4,6,6-
1
pentamethyl-1,2,5,6-tetrahydropyrimidine 1. Excellent yields resulted when acetone and liquid ammo-
nia were kept at 20°C for 24 h in the presence of calcium or ammonium chloride as a catalyst and other
1
ammonium salts as promoters. The synthesis of acetonine 1 can be also carried out without excess
pressure of ammonia with good yield (82–88%), that is more convenient for the laboratory scale.2
Acetonine 1 has attracted the attention of researchers and polymer companies as a basic compound
3
for manufacturing triacetonamine 2 on an industrial scale; 2 is widely used as an initial compound
for the synthesis of light stabilizers and nitroxide radicals of the piperidine and pyrrolidine series. By
reaction of 1 with acetone in the presence of Lewis acids, such as zinc, ammonium, or calcium chloride,
triacetonamine 2 is formed in yields higher than 90% (Scheme 1).3
Scheme 1.
∗
Corresponding author. Tel: (718) 253 8534; fax: (718) 758 0091; e-mail: leovol@excite.com (L. Volodarsky)
0
040-4039/00/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02049-3
tetl 15977

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Acetonine forms a crystalline monohydrate in which the C_N and >NH< groupings still exist. The
similarity of the >NH< grouping and its surrounding in molecules 1 and 2 prompted us to search the
possibility to oxidize acetonine 1 the same way as triacetonamine 2 was oxidized by hydrogen peroxide
3
into stable nitroxide radicals 3 (Scheme 1). We could not find information about the synthesis of
acetonine nitroxide radical 4 or corresponding hydroxylamine 5. However it was evident that these
compounds could be initial ones for a new series of derivatives, and would be an open challenge to
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combine the chemistry of nitroxide radicals with the chemistry of heterocyclic compounds (cf. ). This
compound could be initial one for synthesis of spin labeled analogues of cytosine and thymine.
Nitroxide radical, 2,2,4,6,6-pentamethyl-1,2,5,6-tetrahydropyrimidine-3-oxide-1-oxyl 6 was synthesi-
zed by oxidation of 1-hydroxy-2,2,4,6,6-pentamethyl-1,2,5,6-tetrahydropyrimidine-3-oxide 7 with lead
5
dioxide. The synthesis of 7 was based on the condensation of prepared from mesityl oxide 1,3-
hydroxylaminooxime 8 with acetaldehyde; subsequent interaction of the formed 1,3-oximinonitrone with
methylmagnesium iodide gave N-isopropylhydroxylaminooxime 9. A mild oxidation of 9 with air oxygen
led to the cyclic compound 7. Reduction of the unstable radical 6 by hydrazine in organic solvent also
gave quantitatively stable hydroxylamine 7, m.p. 156–158°C (Scheme 2).5
Scheme 2.
An oxidation of acetonine 1 with hydrogen peroxide 30% in strong basic water media in the presence of
sodium tungstate at 20–40°C lead to nitroxide radical 4 with yields of 24 to 50% (GLC), which strongly
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depends on the temperature and the rate of work up. The orange water solution was saturated with
potassium carbonate and extracted with ether. As radical 4 in solution decomposes, an ether solution,
containing 4, was worked up with an excess of hydrazine which gave a colorless precipitate, 1-hydroxy-
2
,2,4,6,6-pentamethyl-1,2,5,6-tetrahydropyrimidine 5 with the same yield of 24 to 50% (Scheme 3).6
Compound 5 is quite stable and has a comparatively high m.p. 142–144°C (ethylacetate). In its NMR
spectrum (CDCl ) there is a peak at 1.20 m.d. 6,6- (CH ) , a peak at 1.67 m.d. 2,2- (CH ) , a peak at
3
3 2
3 2
2
.10 m.d. 4-CH , a peak at 2.46 m.d. CH and a band with center at 9 m.d., which disappear in CD OD.
3
2
3
−1
−1
In the IR spectrum of 5 (KBr) there is a weak band at 1620 sm (C_N) and a broad band at 3300 sm
(OH). According to MS molecular weight of hydroxylamine 5 is 170 and of radical 4 is 169.
Scheme 3.
Pure radical 4 was prepared by oxidation of 5 with MnO in ether at room temperature as a red
2
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oil. In the refrigerator this oil gives red crystals of radical 4, which melted at 20°C. During storage of
liquid radical 4 or its saturated solution in organic solvent the crystals of hydroxylamine 5 separated
out, evidently due to the redox reaction. During the storage of crystals of 5 in the presence of air in
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refrigerator for one month orange color emerged and the substance had approximately 10% of radical 4
(GLC). However in absense of air compound 5 can be stored for months without any decomposition.

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