Improved synthesis of 1-hydroxy-2,2,5,5-tetramethyl-3-imidazoline 3-oxide (HTIO)

Article abstract of DOI:10.1080/00397910600767272

A simple, efficient, mild, and reproducible method for the synthesis of 1-hydroxy-2,2,5,5-tetramethyl-3-imidazoline 3-oxide is described. The method is based on the condensation of 2-hydroxyamino-2-methylpropanal oxime with 2,2-diethoxypropane in the presence of an equimolar quantity of acetic acid. Costeffectiveness of the condensation procedure could be also achieved by replacing 2,2-diethoxypropane with less expensive 2,2-dimethoxypropane. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600767272

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Improved Synthesis of
1‐Hydroxy‐2,2,5,5‐tetramethyl‐3‐imidazoline
3‐Oxide (HTIO)
Julya F. Polienko a , Thomas Schanding b , Maxim A. Voinov a & Igor A.
Grigor'ev a
a Novosibirsk Institute of Organic Chemistry, Novosibirsk, Russia
b Department of Chemistry, University of Kaiserslautern, Kaiserslautern,
Germany
Version of record first published: 16 Feb 2007.
To cite this article: Julya F. Polienko , Thomas Schanding , Maxim A. Voinov & Igor A. Grigor'ev
(2006): Improved Synthesis of 1‐Hydroxy‐2,2,5,5‐tetramethyl‐3‐imidazoline 3‐Oxide (HTIO), Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:19,
2763-2768
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Synthetic Communicationsw, 36: 2763–2768, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600767272
Improved Synthesis of 1-Hydroxy-2,2,5,5-
tetramethyl-3-imidazoline 3-Oxide (HTIO)
Julya F. Polienko
Novosibirsk Institute of Organic Chemistry, Novosibirsk, Russia
Thomas Schanding
Department of Chemistry, University of Kaiserslautern,
Kaiserslautern, Germany
Maxim A. Voinov and Igor A. Grigor’ev
Novosibirsk Institute of Organic Chemistry, Novosibirsk, Russia
Abstract: A simple, efficient, mild, and reproducible method for the synthesis of
1-hydroxy-2,2,5,5-tetramethyl-3-imidazoline 3-oxide is described. The method is
based on the condensation of 2-hydroxyamino-2-methylpropanal oxime with
2,2-diethoxypropane in the presence of an equimolar quantity of acetic acid. Cost-
effectiveness of the condensation procedure could be also achieved by replacing
2,2-diethoxypropane with less expensive 2,2-dimethoxypropane.
Keywords: Aldonitrone, 2,2-dialkoxypropane, HTIO, 3-imidazoline 3-oxide, nitroxide
INTRODUCTION
1-Hydroxy-2,2,5,5-tetramethyl-3-imidazoline 3-oxide 2,[1] abbreviated as
HTIO,[2] is a compound whose molecular structure combines an aldonitrone
and sterically hindered hydroxylamino groups. HTIO is widely used as a
precursor for 1-oxyl-2,2,5,5-tetramethyl-3-imidazoline 3-oxide 3 (OTIO), the
stable nitroxide bearing aldonitrone group.[1] An unique combination of these
groups makes OTIO a useful starting compound in a series of chemical
Received in the U.K. October 7, 2005
Address correspondence to Maxim A. Voinov, Novosibirsk Institute of Organic
Chemistry, Novosibirsk, Russia. E-mail: mvoynov@ncsu.edu
2763

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J. F. Polienko et al.
transformations. OTIO was shown to be the only one of its kind capable for spin-
labeling through the 1,3-dipolar cycloaddition reaction to the compounds with
unsaturated carbon–carbon bonds.[3] An elegant approach to the synthesis of
4-R-amino-2,2,5,5-tetramethyl-3-imidazoline 1-oxyls—nitroxides with pH-
dependent electron paramagnetic resonance (EPR) spectra (pH-sensitive spin
probes)—was elaborated through the 1,3-dipolar cycloaddition of OTIO to iso-
cyanates.[4] HTIO was utilized in the synthesis of paramagnetic chelate[5] and
imidazoline disulfide biradical[6]—the thiol-specific reagent for EPR determi-
nation of SH-groups in high- and low-molecular-weight compounds. HTIO
was shown to be of great effectiveness in the redox-based EPR method for per-
oxidase activity determination.[2] More than decade ago, HTIO has appeared in
the list of commercially available products,[7] evidence of its practical utility.
In spite of extensive synthetic and analytical applications of the titled
compound, only one procedure that describes the preparation of HTIO has been
reported.[1] The procedure involves the condensation of 2-hydroxyamino-2-
methylpropanal oxime 1 (HAO) with 2,2-diethoxypropane (DEP) (Scheme 1).[1]
The desired product was obtained in a low yield of 25%. Unfortunately,
no data indicate whether the reported yield is given for a solid product preci-
pitated from the reaction mixture or for the isolated compound.[1] To our
knowledge, the contamination of the product with 2,2,5,5-tetramethyl-2,5-
dihydropyrazine 1,4-dioxide is an unavoidable feature of the synthesis. As
follows from our own experience, the success of the reported procedure sub-
stantially depends on whether the desired product precipitates. Otherwise, the
reaction mixture has to be discarded without chance for product recovery.
Another procedure for the synthesis of 1-hydroxy-4-R-2,2,5,5-tetramethyl-
3-imidazoline 3-oxides, the condensation of a-hydroxyamino oximes with
acetone in the sealed ampule at high temperature,[1] has been reported, but
it was found to be inappropriate for HTIO preparation. It has been shown
recently that NH4OAc promotes the condensation of a-hydroxyamino
oximes with ketones,[8] but in the case of HAO 1 this finding does not work
either. These prerequisites prompted us to focus our efforts on improving
the procedure involving the condensation of HAO 1 with acetone acetals.
Use of HAO acetates in the reaction with DEP instead of free HAO results
in increasing yield of the condensation product.[1] To the best of our
knowledge, the acetate salt of HAO 1 has never been utilized in HTIO
preparation.
Scheme 1.

1-Hydroxy-2,2,5,5-tetramethyl-3-imidazoline 3-Oxide
RESULTS AND DISCUSSION
2765
Herein we report our results on HTIO preparation. We suggest a simple,
efficient, and reproducible procedure to obtain HTIO through the condensation
of HAO 1 with 2,2-dialkoxypropanes in the presence of an equimolar amount
of acetic acid. To the best of our knowledge, the method suggested here is the
most efficient one.
At first, we have shown that the condensation of HAO with DEP in the
presence of an equimolar amount of glacial CH3COOH readily affords the
desired product in a good yield (about 45%). To make the procedure more
convenient, we modified it so that it does not depend on whether the
desired product precipitates. We found that the solvent removal at reduced
pressure with the following triturating of the residue with ether repetitively
yields crystalline solid with high content of 2 (96% according to HPLC).
Recrystallization of the resulting solid from the water gives analytically
pure HTIO (98þ% according to HPLC), which melts in the range of 172–
1748C (lit.[1] 162–1638C). However, the overpriced cost of DEP makes this
synthesis economically unfavorable in day-to-day laboratory practice. As
we discovered, the replacement of DEP with less expensive 2,2-dimetho-
xypropane (DMP) readily affords the desired product in moderate yield
(30%). No literature data shows that DMP has ever been introduced into con-
densation with a-hydroxyamino oximes. Typically, refluxing of the mixture of
HAO, CH3COOH, and DMP yields the solid product with 83% HTIO content
(according to HPLC) after the work-up procedure. Recrystallization of the
crude solid from water gives 96% pure HTIO (according to HPLC). Further-
more, the acid-catalyzed condensation suggested here allows one to use 2,2-
dialkoxypropane in less excess as compared with the published procedure
(1.6 equiv. vs. 2.3 equiv.[1]). The lower yield and the main compound
content as compared with the case when DEP (bp 1158C) was utilized are
most likely the result of the lower boiling point of DMP (bp 838C). Table 1
summarizes results on the condensation of HAO 1 with 2,2-dialkoxypropanes
depending on the amount of 1 and the 2,2-dialkoxypropane used.
When optimizing condensation conditions, we found that refluxing the
reaction mixture over the critical time results in increasing the 2,2,5,5-tetra-
methyl-2,5-dihydropyrazine 1,4-dioxide content. Using acetic acid in a less
than equimolar amount increases the total reaction time and also results in
further contamination of the product with 2,2,5,5-tetramethyl-2,5-dihydropyr-
azine 1,4-dioxide. The optimized condensation conditions are given in the
Experimental section.
Note that the reported yield for preparation of 3 by oxidation of HTIO
does not exceed 35%.[1] The procedure described here provides compound
2 of sufficient purity to be used directly in the oxidation step. We have
shown that oxidation of the crude 2 (83% of the main compound content)
with MnO2 in CHCl3 affords 3 in 66% yield (after purification by column
chromatography).

2766
J. F. Polienko et al.
Table 1. Condensation of 2-hydroxyamino-2-methylpropanal oxime
with 2,2-dialkoxypropanes
Amount
of 1 (g)
2,2-Dialkoxy-
propane
Amount of solid
precipitated (g)
Yield
(%)a
Entry
1
2
3
4
5
6
7
8
9
5
10
10
10
20
20
50
5
DMP
DMP
DMP
DMP
DMP
DMP
DMP
DEP
1.9
4.4
3.9
4.0
9.3
7.8
28.7
3.1
6.0
23.6
26.8
23.9
24.8
28.8
24.2
35.6
44.2
42.8
10
DEP
aBased on the main compound content obtained from the HPLC data.
In conclusion, this improved procedure provides 1-hydroxy-2,2,5,5-tetra-
methyl-3-imidazoline 3-oxide in a yield higher than the reported one. The ease
and reproducibility of the condensation procedure, the simplicity of workup
procedure and product purification, and mild reaction conditions indicate
this is a promising alternative to the existing method. The cost-effectiveness
of the procedure could be also achieved when 2,2-dimethoxypropane
instead of more expensive 2,2-diethoxypropane is utilized.
EXPERIMENTAL
The IR spectra were recorded with a Bruker Vector 22 FT-IR spectrometer in
KBr pellets (the concentration was 0.25%; the pellet sickness was 1 mm).
NMR spectra were recorded on a Bruker AC-200 spectrometer operating at
1
200.132 MHz for H and 50.323 MHz for 13C in DMSO-d6 using residual
solvent signal as internal standard (dH ¼ 2.50 ppm, dC ¼ 39.51 ppm). High
Performance Liquid Chromatography (HPLC) data were acquired with a
Milichrom A-02 EcoNova chromatograph. A 70% H2O–30% CH3OH
mixture was used as a mobile phase. Mass spectrum was obtained with a
Finnigan MAT 8200 spectrometer. The spectroscopic characteristics of
compounds 2 and 3 are identical with those reported in the literature.[1]
Elemental analyses are correct.
Condensation of 2-Hydroxyamino-2-methylpropanal Oxime
with 2,2-Dialkoxypropanes (General Procedure)
HAO 1 (0.01 mol) and 2,2-dialkoxypropane (0.016 mol) were placed into a
round-bottomed flask equipped with a magnetic stirrer, and glacial

1-Hydroxy-2,2,5,5-tetramethyl-3-imidazoline 3-Oxide
2767
CH3COOH (0.01 mol) was added dropwise to the mixture upon stirring. The
flask was fitted with a condenser and placed into a preheated (T ¼ 110–
1158C) oil bath. After complete dissolution of HAO, the resulting mixture
was refluxed for 20 min and cooled to the ambient temperature. The
solvents were removed under reduced pressure. The residue was triturated
with dry ether; the precipitate formed was collected on the filter and washed
with ether twice to give 1-hydroxy-2,2,5,5-tetramethyl-3-imidazoline
3-oxide 2. Colorless crystals, mp 172–1748C (water) (lit.[1] 162–1638C);
HPLC: 99.05%; Prontosil 120-5C18AQ column, retention time 3.087 min;
IR (KBr): 1603 (C55N); 1H NMR (DMSO-d6), d ¼ 1.23 (s, 6H, 2CH3),
1.34 (s, 6H, 2CH3), 6.92 (s, 1H, H), 8.12 (s, 1H, OH). 13C NMR (DMSO-
d6), d ¼ 23.64, 24.23 (CH3), 64.19 (C-5), 91.43 (C-2), 134.16 (C55N).
Anal. calcd. for C7H14N2O2: C, 53.16; H, 8.86; N, 17.72. Found: C, 53.04;
H, 8.66; N, 17.63.
Oxidation of 1-Hydroxy-2,2,5,5-tetramethyl-3-imidazoline 3-Oxide
MnO2 (0.035 mol) was added to a suspension of HTIO (0.01 mol) in 30 ml of
CHCl3, and the resulting mixture was vigorously stirred for 1 h. The course of
the reaction was monitored by chromatography on thin layer chromatography
(TLC) plates (SiO2, CHCl3 þ 2% CH3OH). The oxidant was filtered off, and
the solvent was removed under reduced pressure. The solid residue was
purified by chromatography on silica gel (eluting with CHCl3) to give
2,2,5,5-tetramethyl-3-imidazoline-1-oxyl 3-oxide 3 (66% yield, lit.[1] 35%).
Orange crystals, mp 116–1188C (hexane–EtOAc) (lit.[1] 100–1038C);
Rf ¼ 0.75 (SiO2, CHCl3 þ 2% CH3OH); HPLC: 96.4%, ZORBAX Eclipse
XDB C8 column, retention time was 3.848 min; IR (KBr): 1588 (C55N),
3168 (55C-H); anal. calcd. for C7H13N2O2: C, 53.50; H, 8.28; N, 17.83.
Found: C, 53.57; H, 8.55; N, 17.44. Mass spectrum (Mþ) calcd. for
C7H13N2O2: 157.09770. Found: 157.09742.
ACKNOWLEDGMENTS
We thank Elena I. Chernyak (Novosibirsk) for technical assistance in HPLC
experiments. Authors acknowledge the contribution made by Dmitry
G. Mazhukin for assistance with the NMR spectra acquisition.
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