Synthesis of 4H-imidazole-5-carbaldoxime 3-oxides and 4H-imidazole-5- carbonitrile 3-oxides

Article abstract of DOI:10.1007/s11172-008-0196-3

The condensation of 3-hydroxyamino-3-methylbutan-2-one or 3-ethyl-3-hydroxyamino-pentan-2-one with aldehydes and ammonia afforded a series of new 1-hydroxy-4-methyl-2,5-dihydroimidazoles, whose oxidation gave rise to the corresponding 5-methyl-4H-imidazole 3-oxides. The latter, like 1-hydroxy-4-methyl-2,5-dihydroimidazoles, react with PrⁱONO in the presence of bases to form 4H-imidazole-5-carbaldoxime 3-oxides, which are transformed into 4H-imidazole-5-carbonitrile 3-oxides in the reaction with TsCl in the presence of Et₃N. The by-products produced in different steps of the synthesis were isolated and characterized.

Full text of DOI:10.1007/s11172-008-0196-3

Russian Chemical Bulletin, International Edition, Vol. 57, No. 7, pp. 1516—1533, July, 2008
1516
Synthesis of 4Hꢀimidazoleꢀ5ꢀcarbaldoxime 3ꢀoxides
and 4Hꢀimidazoleꢀ5ꢀcarbonitrile 3ꢀoxides
I. A. Kirilyuk,a D. A. Morozov,a,b Yu. S. Tabatchikova,a V. S. Medvedev,a,b A. V. Lebedev,a G. V. Romanenko,c
T. V. Rybalova,a and I. A. Grigor´eva,b
aN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences,
9 prosp. Akad. Lavrent´eva, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383) 330 9752. Eꢀmail: kirilyuk@nioch.nsc.ru
bNovosibirsk State University,
2 ul. Pirogova, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383) 330 2237. Eꢀmail: m_falcon@nioch.nsc.ru
cInternational Tomography Center, Siberian Branch of the Russian Academy of Sciences,
3a ul. Institutskaya, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383) 330 9752
The condensation of 3ꢀhydroxyaminoꢀ3ꢀmethylbutanꢀ2ꢀone or 3ꢀethylꢀ3ꢀhydroxyaminoꢀ
pentanꢀ2ꢀone with aldehydes and ammonia afforded a series of new 1ꢀhydroxyꢀ4ꢀmethylꢀ2,5ꢀ
dihydroimidazoles, whose oxidation gave rise to the corresponding 5ꢀmethylꢀ4Hꢀimidazole 3ꢀoxides.
The latter, like 1ꢀhydroxyꢀ4ꢀmethylꢀ2,5ꢀdihydroimidazoles, react with PriONO in the presence of
bases to form 4Hꢀimidazoleꢀ5ꢀcarbaldoxime 3ꢀoxides, which are transformed into 4Hꢀimidazoleꢀ5ꢀ
carbonitrile 3ꢀoxides in the reaction with TsCl in the presence of Et3N. The byꢀproducts produced
in different steps of the synthesis were isolated and characterized.
Key words: αꢀhydroxyamino ketones, 4Hꢀimidazole 3ꢀoxides, nitrosation, nitrones, 2,5ꢀdihydꢀ
roimidazoles.
The reactivity of 4Hꢀimidazole Nꢀoxides imposes
limitations on the reaction conditions and the nature
of the reagents for the synthesis of functional derivaꢀ
tives of this series. In particular, these compounds
readily react with nucleophilic reagents both in acidic1,2
and alkaline3 media and can easily undergo oneꢀelecꢀ
tron oxidation.4,5 Recently, we have developed conveꢀ
nient methods for nitrosation of 5ꢀmethylꢀ4Hꢀimidꢀ
azole 3ꢀoxides at the methyl group, which allowed
the synthesis of the previously inaccessible derivatives of
this series, for example, of 4Hꢀimidazoleꢀ5ꢀcarboꢀ
nitrile 3ꢀoxides 1. These compounds readily react with
amines, resulting in the replacement of the cyano group.
These transformations made it possible to prepare variꢀ
ous promising pHꢀsensitive spin probes for biophysical
and biomedical studies.6—9 At the same time, the ease
of replacement of the cyano group in compounds 1 ofꢀ
fers great possibilities for the synthesis of various
functional derivatives, including fungicidally active
3,5ꢀdihydroimidazolꢀ4ꢀones,10,11 as well as other poꢀ
tentially biologically active derivatives. In the present
study, we considered the characteristic features of the
synthesis of the previously unknown 4Hꢀimidazoleꢀ5ꢀ
carbonitrile 3ꢀoxides 1 serving as key compounds in
the synthesis of functional derivatives of 4Hꢀimidazole
3ꢀoxide.
New 4Hꢀimidazoleꢀ5ꢀcarbonitrile 3ꢀoxides 1a—l were
synthesized by analogy with the methods described
Scheme 1
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1487—1503, July, 2008.
1066ꢀ5285/08/5707ꢀ1516 © 2008 Springer Science+Business Media, Inc.

Synthesis of 4Hꢀimidazoleꢀ5ꢀcarbonitrile 3ꢀoxides
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
1517
in our earlier study.6 The general approach is presented
in Scheme 1.
Table 1. Methods of synthesis and the yields of compounds 2a—l
Comꢀ
pound
R
R´
Method
Yield
(%)
1ꢀHydroxyꢀ2,5ꢀdihydroimidazoles 2a—j were syntheꢀ
sized by condensation of αꢀhydroxyamino ketones 3a,b
with aldehydes in ethanol in the presence of a 25% aqueꢀ
ous ammonia solution (see the Experimental section,
method A) or an ammonium acetate solution (method B)
or, alternatively, in a saturated ammonia solution in
methanol (method C) (Scheme 2, Table 1).
2a
Me
2ꢀThienyl
A
B
C
A
C
A
A
B
B
A
B
B
A
A
A
A
A
30
40
75
25
72
85
35
75
80
35
80
70
80
75
70
85*
50*
2b
Me
2ꢀFuryl
2c
2d
Me
Me
4ꢀО2NC6H4
4ꢀМеОС6Н4
In all cases, the condensation of αꢀhydroxyamino keꢀ
tones 3a,b with aldehydes and ammonia according to
the method A affords 1ꢀhydroxyꢀ2,5ꢀdihydroimidazoles 2;
however, the yields of the target compounds in the reacꢀ
tions with aldehydes containing electronꢀdonating subꢀ
stituents R´ are low. In some cases, the use of the method
B results in an increase in the yield of compounds 2;
however, the yields of the products prepared by condenꢀ
sation with thiopheneꢀ2ꢀcarbaldehyde and furfural reꢀ
main low. It should be noted that we succeeded in isolatꢀ
ing nitrone 4 from the reaction mixture. Earlier,12 we
have reported that the condensation of 2ꢀhydroxyaminoꢀ
2ꢀmethylꢀ1ꢀphenylpropanꢀ1ꢀone with thiopheneꢀ2ꢀcarbꢀ
aldehyde and ammonia affords exclusively 2ꢀmethylꢀ1ꢀ
phenylꢀ2ꢀ(thiophenꢀ2ꢀylmethyleneamino)propanꢀ2ꢀone
Nꢀoxide (6). Attempts to transform the latter compound
into the corresponding 1ꢀhydroxyꢀ2,5ꢀdihydroimidazole
failed. Unlike compound 6, ketonitrone 4 can undergo
cyclization in the presence of a saturated ammonia soluꢀ
tion in methanol to give 1ꢀhydroxyꢀ2,5ꢀdihydroimidazole
2a; however, several weeks are required to achieve a high
conversion in this reaction (cf. Ref. 13). The condensaꢀ
tion of αꢀhydroxyamino ketone 3a with aldehydes acꢀ
cording to the method C made it possible to substantially
increase the yield of the target compounds 2a,b.
2e
2f
Et
Me
Ph
2ꢀHOC6H4
2g
2h
2i
2j
2k
2l
Me
Me
Me
Et
Me
Me
4ꢀ(NCCH2O)С6Н4
H
Me
CH2CH2C(Me)2NO2
3ꢀPyridyl
2,3,4ꢀ(MeO)3C6H2
* The yield of the corresponding 4Hꢀimidazole 3ꢀoxide, which was
prepared by oxidation of 1ꢀhydroxyꢀ2,5ꢀdihydroimidazole without
isolation of the latter.
The synthesis of compounds 2 is also accompanied by
the formation of 2,2,3,5,5,6ꢀhexamethylꢀ2,5ꢀdihydꢀ
ropyrazine 1,4ꢀdioxide (5) as a byꢀproduct.14 For exꢀ
ample, the reaction of compound 3a with acetaldehyde
and ammonia produces 5 in 15% yield.
The spectroscopic characteristics of 2,5ꢀdihydroꢀ
imidazoles 2a—j are consistent with those of the related
compounds described earlier6—8,12 (Tables 2—4).
The oxidation of hydroxylamines 2a—g with lead diꢀ
oxide in chloroform smoothly affords stable crystalline
4Hꢀimidazole 3ꢀoxides 7a—g (Scheme 3). It is not necesꢀ
sary to isolate the corresponding 1ꢀhydroxyꢀ2,5ꢀdihydꢀ
roimidazoles 2 in the free state for the synthesis of
4Hꢀimidazole 3ꢀoxides 7. In some cases, for example, in
the case of condensation of αꢀhydroxyamino ketone 3a
with 3ꢀpyridinecarbaldehyde, 2,3,4ꢀtrimethoxybenzalꢀ
It should be noted that the best yield of 1ꢀhydroxyꢀ
4,5,5ꢀtrimethylꢀ2,5ꢀdihydroimidazole (2h) in the conꢀ
densation of 3ꢀhydroxyaminoꢀ3ꢀmethylbutanꢀ2ꢀone oxiꢀ
me (3a) with formaldehyde and ammonia is achieved
within 3 h after mixing of the reagents (method A).
An increase in the reaction time leads to a substantial
decrease in the yield of the target product.
Scheme 2
3: R = Me (a), Et (b)

1518
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
Kirilyuk et al.
dehyde, and ammonia, the resulting mixture of comꢀ
pounds was oxidized in chloroform without separation
(see Scheme 3). 4HꢀImidazole 3ꢀoxides 7k,l were isoꢀ
lated by chromatography. The spectroscopic characterisꢀ
tics of the reaction products are given in Tables 2, 5, and
6 and are in good agreement with those of the known
derivatives of this series.6—8,15
It should be noted that samples of compounds 7 synꢀ
thesized according to this method can have a bright color
(orange, crimson, or brown) due to the formation
of inseparable impurities. The intensity of the color
increases in the presence of a large excess of an oxiꢀ
dizing agent.
Unlike compounds 2a—g containing an aromatic or
heteroaromatic substituent at position 2 of the heteroꢀ
cycle, imidazoline 2h is oxidized with lead or manganese
dioxides to give a complex mixture of colored products,
among which compound 7h was not detected. The slow
portionwise addition of an oxidizing agent to a solution of
compound 2i resulted in the formation of the reaction
mixture containing the corresponding 4Hꢀimidazole
3ꢀoxide 7i. The 1H NMR spectroscopic data for comꢀ
pound 7i are given in Table 5. However, 7i is unstable and
attempts to isolate this compound in the pure state failed.
In the presence of a larger excess of the oxidizing agent,
4Hꢀimidazole 3ꢀoxide 7i is not accumulated in the reacꢀ
tion mixture, and 1,2ꢀbis(2,4,4ꢀtrimethylꢀ4Hꢀimidazolꢀ
5ꢀyl 3ꢀoxide)ethylene (8) is formed as the major reaction
product (see Scheme 3). The UV spectrum of compound
8 has longꢀwavelength absorption maxima at 459 and
301 nm close to those observed in the spectrum of the
structurally similar dimer synthesized earlier.16 In the
1H NMR spectrum, the signals of the geminal methyl
groups and the methylnitrone group are shifted downfield
by ~0.1 ppm compared to those in the spectrum of comꢀ
pound 7i. In addition, the singlet at δ 7.11 corresponding
Scheme 3
7: R = Me (a—d, f, g, i, k, l), Et (e); R´ = 2ꢀthienyl (a),
2ꢀfuryl (b), 4ꢀO2NC6H4 (c), 4ꢀMeOC6H4 (d), Ph (e),
2ꢀHOC6H4 (f), 4ꢀ(NCCH2O)C6H4 (g), Me (i), 3ꢀpyridyl (k),
2,3,4ꢀ(MeO)3C6H2 (l)
Scheme 4

Synthesis of 4Hꢀimidazoleꢀ5ꢀcarbonitrile 3ꢀoxides
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
1519
Table 2. Melting points, elemental analysis data, and the IR and UV spectroscopic data
Comꢀ
pound
M.p./°C
(solvent)
Found
Calculated
Molecular
formula
IR, ν/cm–1
UV,
max/nm (logε)
(%)
λ
С
Н
N
1a
1b
1c
1d
133—138
(hexane)
54.95
54.78
4.02
4.14
18.98
19.16
C10H9N3OS
C10H9N3O2
C12H10N4O3
C13H13N3O2
2223 (C≡N);
1555, 1518
(C=N, C=C)
413 (3.40),
296 (4.17)
105—110
(hexane)
58.80
59.11
4.43
4.46
20.37
20.68
2224 (C≡N); 1596,
1551, 1527, 1501
(C=N, C=C)
410 (3.48),
292 (4.25)
198—202
(hexane)
55.86
55.81
3.95
3.90
21.93
21.70
2229 (C≡N);
1596 (C=N);
1517, 1344 (NO2)
382 (3.89),
266 (4.19)
117—120
(hexane)
64.32
64.19
5.49
5.39
17.35
17.27
2224 (C≡N); 1606,
1577, 1536, 1517
(C=N, C=C)
410 (2.93),
295 (3.92)
1e
1f
57—59
(hexane)
69.74
69.69
6.29
6.27
17.45
17.41
C14H15N3O
C12H11N3O2
2221 (C≡N); 1527,
1511 (C=N, C=C)
396 (3.78),
275 (3.87)
65—68
(hexane)
62.95
62.87
4.91
4.84
18.34
18.33
2231 (C≡N); 1613,
1578, 1555, 1520
(C=N, C=C)
312 (3.78),
246 (4.20)
1g
112—115
(hexane—
AcOEt,
1 : 1)
61.77
62.00
6.10
5.81
12.40
12.76
C17H19N3O4
2221 (C≡N); 1759,
1725 (C=O); 1604,
1574, 1519
407 (3.32),
294 (4.18)
(C=N, C=C)
1h
1i
89—91
(hexane)
52.27
52.55
5.10
5.14
30.23
30.64
C6H7N3O
2227 (C≡N);
1524 (C=N)
353 (3.90),
240 (3.07)
25—29
(hexane)
55.89
55.62
6.38
6.00
27.67
27.80
C7H9N3O
2217 (C≡N);
1597, 1542 (C=N)
367 (3.35),
306 (3.44)
1j
Oil
55.36
55.70
7.34
7.19
19.74
19.99
C13H20N4O3
C11H10N4O
2218 (C≡N);
1540, 1375 (NO2)
373 (3.79)
1k
126—128
(hexane)
61.81
61.67
4.78
4.71
26.21
26.15
2229 (C≡N);
1588, 1570, 1528,
380 (3.67),
290 (3.94)
1509 (C=C, C=N)
1l
128—130
(hexane)
59.24
59.40
5.69
5.65
13.44
13.85
C15H17N3O4
2216 (C≡N);
1597, 1529, 1503
392 (3.37),
294 (3.93)
(C=C, C=N)
2a
2b
2c
177—178
(EtOH)
57.03
57.11
6.76
6.71
13.24
13.32
C10H14N2OS
C10H14N2O2
C12H15N3O3
1640 (C=N)
1647 (C=N)
—
154—157
(AcOEt)
61.88
61.84
7.30
7.27
14.40
14.42
—
192—194
(AcOEt)
57.64
57.82
6.29
6.07
17.01
16.86
1638 (C=N);
268 (4.02)
1522, 1349 (NO2)
1632 (C=N)
2d
2e
2f
146—148
(AcOEt)
66.70
66.64
7.94
7.74
11.70
11.96
C13H18N2O2
C14H20N2O
281 (3.06),
274 (3.12)
143—147
(AcOEt)
72.11
72.38
8.72
8.68
11.92
12.06
1643 (C=N)
1641 (C=N)
252 (2.73),
257 (2.70)
188—191
(AcOEt)
64.34
64.12
7.46
7.40
12.38
12.46
C12H16N2O2•
•0.25H2O
278 (3.44)
2g
2h
153—155
(EtOH)
64.79
64.85
6.83
6.61
16.10
16.20
C14H17N3O2
1638 (C=N);
2090 (C≡N)
271 (3.07),
278 (3.01)
82—84
(hexane)
56.00
56.22
9.54
9.44
22.06
21.86
C6H12N2O
1650 (С=N)
—
(to be continued)

1520
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
Kirilyuk et al.
Table 2 (continued)
Comꢀ
pound
M.p./°C
(solvent)
Found
Calculated
Molecular
formula
IR, ν/cm–1
UV,
λmax/nm (logε)
(%)
С
Н
N
2i
2j
4
69—71
(hexane)
127—129
(hexane)
—
59.50
59.12
57.34
57.54
56.70
56.85
10.02
9.92
9.56
9.29
6.20
6.20
19.71
19.70
15.25
15.49
6.56
C7H14N2O
1645 (C=N)
—
C13H25N3O3
C10H13NO2S
1650 (C=N);
1538, 1374 (NO2)
1723 (C=O);
1573, 1502
—
318 (4.13)
6.63
(С=N, С=С);
3145, 3080,
3074 (H—C=)
1587, 1558
(C=N, C=C)
1576, 1555,
7a
7b
90—94
(hexane)
87—89
57.93
57.67
62.20
62.49
6.02
5.81
6.39
6.29
13.70
13.45
14.59
14.57
C10H12N2OS
C10H12N2O2
345 (3.78),
263 (4.24)
342 (3.92),
263 (4.32)
(hexane)
1522 (C=N,
C=C)
7c
144—147
(AcOEt)
58.17
58.29
5.73
5.30
16.65
16.99
C12H13N3O3
1596, 1570
367 (3.96),
263 (4.11)
(C=N, C=C);
1516, 1344 (NO2)
1604, 1587,
1540 (C=N, C=C)
1588, 1570,
1527 (C=N, C=C)
1610, 1589,
1553 (C=N, C=C)
1605, 1587,
7d
7e
7f
65—68
(hexane)
103—105
(hexane)
125—126
(hexane)
176—178
(AcOEt)
67.24
67.22
73.22
73.01
66.32
66.04
65.54
65.35
7.12
6.94
7.99
7.88
6.53
6.47
5.98
5.88
11.98
12.06
12.17
12.16
12.75
12.84
16.20
16.33
C13H16N2O2
C14H18N2O
C12H14N2O2
C14H15N3O2
340 (3.96),
268 (4.37)
332 (3.79),
246 (4.26)
314 (3.33),
247 (3.83)
335 (3.90),
262 (4.36)
7g
1567, 1543
(С=N, С=С);
2070 (C≡N)
7k
96—99
(hexane)
153—156
(AcOEt)
220—222
(hexane)
225—235
(AcOEt)
205—211
(AcOEt)
234—237
(AcOEt)
64.77
65.01
61.53
61.63
60.95
60.85
48.48
48.77
54.25
54.29
51.87
52.17
6.38
6.45
9.65
9.58
7.32
7.30
4.59
4.91
5.18
5.01
4.30
4.38
16.26
16.08
7.01
C11H13N3O
C15H20N2O4
C14H20N4O2
1584, 1560,
1520 (C=N, C=C)
1595, 1585,
1532 (C=N, C=C)
1536 (C=N, C=C)
332 (3.90),
241 (4.28)
329 (3.73),
261 (4.11)
459 (4.31),
301 (3.58)
382 (3.58),
288 (4.48)
389 (3.64),
283 (4.51)
371 (4.06),
279 (4.26)
7l
6.90
8
20.05
20.28
16.72
17.06
18.90
19.00
20.25
20.28
11a
11b
11c
C10H11N3O2S• 1563, 1539
•0.5H2O
C10H11N3O3
(C=N, C=C)
1592, 1537
(C=N, C=C)
1571, 1506
(С=N, С=С);
1516, 1336 (NO2)
1603, 1572,
1541 (C=N, C=C)
1579, 1539
(C=N, C=C)
1608, 1551, 1530
(С=N, С=С)
1759 (C=O);
1606, 1576, 1543
(С=N, С=С)
1542, 1505
C12H12N4O4
C13H15N3O3
11d
11e
11f
11g
230—234
(EtOH)
59.74
59.76
63.51
63.38
58.33
58.29
58.71
58.78
6.03
5.79
6.87
6.71
5.40
5.30
6.07
6.09
15.74
16.08
15.41
15.84
17.04
16.99
12.17
12.10
381 (3.55),
290 (4.50)
378 (3.67),
269 (4.52)
334 (3.32),
270 (3.90)
382 (3.61),
287 (4.53)
196—200
(AcOEt)
211—216
(AcOEt)
186—189
(AcOEt)
C14H17N3O2•
•1/3H2O
C12H13N3O3
C17H21N3O5
C6H9N3O2
11h
170 (decomp.)
(EtOH)
46.53
46.45
6.03
5.85
26.82
27.08
353 (3.88),
229 (3.93)
(C=N, C=C);
3161 (С—Н, nitrone)
(to be continued)

Synthesis of 4Hꢀimidazoleꢀ5ꢀcarbonitrile 3ꢀoxides
Table 2 (continued)
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
1521
Comꢀ
pound
M.p./°C
(solvent)
Found
Calculated
Molecular
formula
IR, ν/cm–1
UV,
max/nm (logε)
(%)
λ
С
Н
N
11i
11j
11k
11l
12
205—210
(AcOEt)
49.87
49.70
6.77
6.55
25.09
24.84
C7H11N3O2
C13H22N4O4
C11H12N4O2
C15H19N3O5
C42H47N7O4
1566, 1521
(C=N, C=C)
361 (3.97),
259 (4.01)
167—169
(AcOEt)
52.07
52.34
7.61
7.43
18.76
18.78
1562 (C=N, C=C);
1535, 1374 (NO2)
367 (3.85),
277 (3.45)
210—214
(AcOEt)
56.85
56.89
5.53
5.21
23.96
24.12
1596, 1574,
1534 (C=N, C=C)
377 (3.55),
286 (4.16)
155—157
(AcOEt)
56.33
56.07
6.05
5.96
12.96
13.08
1601, 1546,
1532 (C=N, C=C)
377 (3.55),
286 (4.16)
217—221
(AcOEt)
70.28
70.66
6.57
6.64
13.43
13.73
1524 br
(С=N, С=С)
519 (4.30),
491 (4.33),
379 (4.05),
361 (4.04)
(CHCl3)
13
230—234
(AcOEt)
70.33
70.02
7.29
6.92
12.76
12.70
C43H49N7O4• 1521 br
482 (4.28),
370 (4.05),
352 (4.03),
280 (4.67)
•0.5AcOEt
(С=N, С=С)
18
19
180—184
(AcOEt)
52.61
52.34
7.69
7.43
18.91
18.78
C13H22N4O4
C13H21N5O5
1566 (C=N, C=C);
1545, 1344 (NO2)
329 (3.72),
243 (4.05)
201—203
(AcOEt)
47.77
47.70
6.57
6.47
21.28
21.39
1530, 1507
(C=N, C=C);
1536, 1348 (NO2)
369 (3.70),
261 (4.30)
Note. The elemental analysis data for S, found/calculated (%): 14.30/14.62 (1a), 15.00/15.25 (2a), 15.06/15.18 (4),
15.40/15.40 (7a), 13.00/13.02 (11a).
to the proton of the ethylene fragment is observed instead
of the singlet for the protons of the methyl group at position
5 of the heterocycle.
was performed in the presence of triethylamine. Oximes 11
are yellow, brown, or orange crystalline compounds.
The nitrosation of compound 7g in the presence of
sodium isopropoxide is accompanied by the attachment
of propanꢀ2ꢀol at the nitrile group. As a result, isopropyl
ester of the corresponding carboxylic acid 11g was
isolated after the treatment of the reaction mixture
(see Scheme 5).
The reaction of compound 7e with isopropyl nitrite in
the presence of sodium isopropoxide produced a mixꢀ
ture, from which brightꢀred crystalline compound 12 was
isolated in 15% yield along with oxime 11e (Scheme 6).
The 1H and 13C NMR spectra of compound 12 have
a triple set of signals of the 5,5ꢀdiethylꢀ2ꢀphenylꢀ4Hꢀ
imidazole 3ꢀoxide fragment. In addition, the NMR specꢀ
tra have signals of the ketoxime group and the trisubstiꢀ
tuted ethylene fragment. The UV spectrum has longꢀwaveꢀ
length absorption maxima at 519 and 491 nm correspondꢀ
ing to the bathochromic shift by 120—140 nm compared
to the spectrum of oxime 11e. These maxima are indicaꢀ
tive of the presence of an extended conjugated system.
Based on these data and the results of elemental analysis,
we assigned the structure of 1,2,3ꢀtris(4,4ꢀdiethylꢀ2ꢀpheꢀ
nylꢀ4Hꢀimidazolꢀ5ꢀyl 3ꢀoxide)propenone oxime to comꢀ
It is known16 that the oxidation of 4Hꢀimidazole
3ꢀoxides containing the ethoxycarbonylmethyl or benzoylꢀ
methyl fragment at position 5 of the heterocycle and
existing in equilibrium with the ene hydroxylamine tauꢀ
tomeric form can afford vinyl imino nitroxide radicals,
which are transformed into ethaneꢀ or ethyleneꢀtype
dimers. Apparently, the oxidation of compounds 7
can also be accompanied by these transformations
(Scheme 4).
The successive conjugation of the imino and nitrone
groups in 5ꢀmethylꢀ4Hꢀimidazole 3ꢀoxides 7 leads to an
increase in the acidity of the methyl group at position 5 of
the heterocycle and is responsible for the ease of enolizaꢀ
tion and reactions with electrophilic reagents. 4HꢀImiꢀ
dazole 3ꢀoxides 7a—f,k,l were nitrosated with isopropyl
nitrite in the presence of bases (Scheme 5). In most cases,
the best yield and the satisfactory reaction rate were
achieved in the reactions with the use of sodium isoꢀ
propoxide in propanꢀ2ꢀol as the base. Poorly soluble
compound 7c was nitrosated with a solution of sodium
methoxide in methanol. The nitrosation of compound 7f

1522
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
Kirilyuk et al.

Synthesis of 4Hꢀimidazoleꢀ5ꢀcarbonitrile 3ꢀoxides
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
1523

1524
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
Kirilyuk et al.

Synthesis of 4Hꢀimidazoleꢀ5ꢀcarbonitrile 3ꢀoxides
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
1525

1526
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
Kirilyuk et al.

Synthesis of 4Hꢀimidazoleꢀ5ꢀcarbonitrile 3ꢀoxides
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
1527

1528
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
Kirilyuk et al.
Scheme 5
Under the conditions of nitrosation, both the nucleoꢀ
philic attack of carbanion 14 on the nitrogen atom of
isopropyl nitrite giving rise to oxime 11 and the oneꢀ
electron oxidation of carbanion 14 with isopropyl nitrite
resulting in the formation of radical 9 and evolution of
nitrogen oxide NO would be expected to proceed. Furꢀ
ther transformations of this radical can afford trimeric
radical 15 stabilized by delocalization of the unpaired
electron in the common conjugated system of the alꢀ
lylic fragment and the 4Hꢀimidazole 3ꢀoxide moieties
(see Scheme 7). The formation of compound 12 is apparꢀ
ently attributed to the reaction of this radical with a NO
molecule.
Since compounds 7h (R = Me, R´ = H) and 7i
(R = R´ = Me) were not isolated in the pure form, the
corresponding oximes were synthesized according to anꢀ
other procedure. The synthesis of 4,4ꢀdimethylꢀ4Hꢀ
imidazoleꢀ5ꢀcarbaldoxime 3ꢀoxide (11h) by the reaction
of 1ꢀhydroxyꢀ5,5ꢀdimethylꢀ2,5ꢀdihydroimidazole 3ꢀoxꢀ
ide (16) with amyl nitrite in liquid ammonia in the presꢀ
ence of sodium amide was documented.17 We failed to
reproduce this procedure (which is apparently erroneꢀ
ous); under these conditions, compound 2h is transꢀ
formed into oxime 11h in high yield. Further investigaꢀ
tions showed that it is not necessary to use strong bases,
such as sodium amide, for this transformation. The reacꢀ
tion proceeds in the presence of sodium ethoxide or triꢀ
ethylamine. In the latter case, the reaction can be perꢀ
formed at room temperature, and it is convenient to use
isopropyl nitrite as the nitrosating agent. The treatment
of compounds 2h—j with a threeꢀ to fourfold excess of
isopropyl nitrite in the presence of a catalytic amount of
triethylamine by analogy with the synthesis of 2ꢀethylꢀ5ꢀ
methylꢀ4Hꢀimidazole 3ꢀoxides6,7 gives rise to the correꢀ
sponding oximes 11h—j (Scheme 8). Isopropyl nitrite
acts as a mild oxidizing agent and a nitrosating agent.
Initially, the reaction produces nitroxide radical 17,
which undergoes disproportionation characteristic of
nitroxide radicals containing the βꢀhydrogen atoms, reꢀ
sulting in accumulation of 4Hꢀimidazole 3ꢀoxides 7h—j
in the reaction mixture (see Scheme 8). The oxidation of
compounds 2h—j to the corresponding 4Hꢀimidazole
3ꢀoxides is accompanied by vigorous evolution of nitroꢀ
gen oxide and warming of the reaction mixture, the reꢀ
agent (isopropyl nitrite) being partially removed with the
gas that is evolved. To decrease losses of the reagent,
isopropyl nitrite was initially added portionwise, and
1 equiv. of isopropyl nitrite was added after evolution of
NO ceased.
11: R = Ме (a—d, f, k, l), Et (e); R´ = 2ꢀthienyl (a), 2ꢀfuryl (b),
4ꢀО2NC6H4 (c), 4ꢀМеОС6Н4 (d), Ph (e), 2ꢀHOC6H4 (f),
3ꢀpyridyl (k), 2,3,4ꢀ(MeO)3C6H2 (l)
pound 12. The structure of compound 12 was confirmed
by the Xꢀray diffraction data for compound 13 (Fig. 1).
The latter was prepared by alkylation of oxime 12
with methyl iodide (see Scheme 6). It should be noted
that the Xꢀray diffraction data are of low quality. They
confirmed the molecular structure but did not allow us to
discuss the geometric details.
The formation of compound 12 can be represented by
Scheme 7.
Scheme 6
Earlier,6 we have reported that the reaction of isoproꢀ
pyl nitrite in the presence of triethylamine is not accomꢀ
panied by nitrosation of the methylene fragment of the
ethyl group at position 2 of the imidazole ring. The synꢀ
thesis of compound 11i is also not accompanied by the
formation of large amounts of byꢀproducts. On the conꢀ

Synthesis of 4Hꢀimidazoleꢀ5ꢀcarbonitrile 3ꢀoxides
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
1529
Scheme 7
Im =
trary, the treatment of imidazoline 2j with isopropyl niꢀ
trite in the presence of triethylamine affords a mixture of
oximes 11j, 18, and 19. The presence of the oxime group in
the alkyl chain at position 2 of the heterocycle in comꢀ
pounds 18 and 19 was confirmed by 13C NMR specꢀ
troscopic data (see Table 6). It is known18,19 that an inꢀ
crease in the electronꢀwithdrawing character of the subꢀ
stituent at the carbon atom of the nitrone group causes
the upfield shift of the signal of this atom. Actually, the
signal for the carbon atom of the nitrone group in the
Scheme 8
B is a base
11: R = Me (h, i), Et (j); R´ = H (h), Me (i), CH2CH2C(Me)2NO2 (j)

1530
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
Kirilyuk et al.
C(19)
C(18)
C(31)
C(32)
O(2)
N(7)
C(16)
C(8)
O(3)
C(33)
C(23)
C(24)
C(2)
C(17)
C(15)
C(6)
N(22)
C(34)
C(9)
C(14)
C(13)
C(1)
C(3)
O(1)
N(20)
C(45)
C(10)
C(11)
C(26)
C(21)
C(44)
N(5)
N(35)
C(25)
C(4)
C(27)
C(30)
C(40)
N(1)
C(39)
C(36)
C(38)
C(12)
C(43)
C(42)
C(28)
C(41)
C(46)
C(29)
C(49)
N(37)
O(4)
C(32)
C(48)
Fig. 1. Xꢀray diffraction structure of compound 13.
Scheme 9
spectra of compounds 18 and 19 is shifted upfield by
9—10 ppm compared to the spectra of compound 11j
and 2ꢀethylꢀ4,4ꢀdimethylꢀ4Hꢀimidazoleꢀ5ꢀcarbaldꢀ
oxime 3ꢀoxide6 (δ 155.19) containing the methylene fragꢀ
ment at the αꢀcarbon atom of the nitrone group. The
signal for the tertiary carbon atom at the nitro group in
compounds 18 and 19 undergoes only a slight downfield
shift (by 1—1.7 ppm compared to the corresponding sigꢀ
nal in the spectrum of compound 11j). It should be noted
that the yield of oxime 11j increases to 50%, whereas the
yields of compounds 18 and 19 decrease with decreasing
temperature of the reaction mixture from 30 to 10 °C.
The difference in the reactivity of the methylene fragꢀ
ments in 2ꢀethylꢀ and 2ꢀ(3ꢀmethylꢀ3ꢀnitrobutyl)ꢀ4Hꢀ
imidazole 3ꢀoxides is apparently attributed to the elecꢀ
tronic effect of the nitro group.
The treatment of oximes 11a—l with pꢀtoluenesulꢀ
fonyl chloride in the presence of triethylamine readily
affords nitriles 1a—l (Scheme 9). Interestingly, the presꢀ
ence of the 2ꢀhydroxyphenyl substituent in compound
11f does not complicate this transformation, and the reꢀ
action proceeds only at the oxime group. Nitriles 1 are
stable yellowish (1a—e,g—l) or red (1f) crystalline comꢀ
pounds. The spectroscopic feature of compounds 1 (comꢀ
pared to other derivatives of 4Hꢀimidazole 3ꢀoxide)
is that the signal for the imine carbon atom C(5) in
the 13C NMR spectra is substantially shifted
upfield (see Table 6). Earlier,15 we have observed the
corresponding influence of electronꢀwithdrawing subꢀ
stituents in the series of 4Hꢀimidazole 3ꢀoxide deꢀ
rivatives.aa
1: R = Me (a—d, f—i, k, l), Et (e, j); R´ = 2ꢀthienyl (a), 2ꢀfuryl (b),
4ꢀO2NC6H4 (c), 4ꢀMeOC6H4 (d), Ph (e), 2ꢀHOC6H4 (f),
4ꢀ(NCCH2O)C6H4 (g), H (h), Me (i), CH2CH2C(Me)2NO2 (j),
3ꢀpyridyl (k), 2,3,4ꢀ(MeO)3C6H2 (l)
To summarize, we synthesized new 4Hꢀimidazole
3ꢀoxide derivatives and developed procedures for the synꢀ
thesis of 4Hꢀimidazoleꢀ5ꢀcarbonitrile 3ꢀoxides containing
various substituents at positions 2 and 4 of the heteroꢀ
cycle. The byꢀproducts that are formed in the different
steps of the synthesis were isolated for the first time.
Experimental
The IR spectra were measured on a Bruker Vector 22 FTꢀIR
spectrometer in KBr pellets at a concentration of 1 : 150 or in a thin
layer. The UV spectra were recorded on an HP Agilent 8453
instrument in EtOH (10–4 M solutions). The 1H NMR spectra were
measured on Bruker AC 200 (200.132 MHz), Bruker AV 300
(300.132 MHz), and Bruker AM 400 (400.132 MHz) spectromꢀ
eters in 5—10% CDCl3, DMSOꢀd6, and CD3OD solutions using
the signal of the solvent as the standard. The assignment of the signals
for the protons of compound 11j was made based on the spectra
measured with partial spin decoupling. The 13C NMR spectra were

Synthesis of 4Hꢀimidazoleꢀ5ꢀcarbonitrile 3ꢀoxides
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
1531
recorded on Bruker AM 400 (100.614 MHz), Bruker AV 300 (75.476
MHz), and Bruker AC 200 (50.323 MHz) spectrometers at 300 K.
concentrated under reduced pressure. The residue was recrystalꢀ
lized from hexane.
The assignment of the signals was made based on the known data.6—
1ꢀHydroxyꢀ2,4,5,5ꢀtetramethylꢀ2,5ꢀdihydroimidazole (2i) was
synthesized analogously with the use of a solution of an equimolar
amount of acetaldehyde, which was prepared by purging gaseous
acetaldehyde through methanol (10 mL). Within 3 h after mixing of
the reagents, methanol was evaporated under reduced pressure.
Compound 2i was extracted with chloroform, and the extract was
dried with MgSO4. Chloroform was evaporated under reduced
pressure, and the residue was recrystallized from hexane.
To isolate 2,2,3,5,5,6ꢀhexamethylꢀ2,5ꢀdihydropyrazine 1,4ꢀdiꢀ
oxide (5), an aqueous solution, which was obtained after extraction
of compound 2i, was concentrated to dryness under reduced presꢀ
sure, the residue was triturated with a 10 : 1 chloroform—methanol
mixture, and the precipitate was filtered off. The solution was dried
with MgSO4 and concentrated under reduced pressure. The residue
was recrystallized from chloroform. The spectroscopic characterisꢀ
tics of compound 5 are identical to those of the authentic sample.14
5ꢀMethylꢀ4Hꢀimidazole 3ꢀoxides 7a—g (general procedure).
Lead oxide PbO2 (9.5 g, 40 mmol) was added portionwise with
magnetic stirring to solutions or suspensions of the corresponding
imidazolines 2a—g (10 mmol) in chloroform (30 mL) until the
starting compound was completely consumed (TLC data; diethyl
ether as the eluent) for 0.5—5 h. The oxidizing agent was filtered off,
the solvent was evaporated under reduced pressure, and compounds
7a—g were recrystallized.
4,4,5ꢀTrimethylꢀ4Hꢀimidazole 3ꢀoxides 7k,l. The reaction mixꢀ
ture, which was prepared by condensation of αꢀhydroxyamino
ketone 3a with 3ꢀpyridinecarbaldehyde or 2,3,4ꢀtrimethoxybenzꢀ
aldehyde according to the method A, was concentrated to dryness
under reduced pressure, and the residue was oxidized with PbO2 in
chloroform as described above. Compounds 7k,l were isolated by
silica gel column chromatography using chloroform as the eluent.
1,2ꢀBis(2,4,4ꢀtrimethylꢀ4Hꢀimidazolꢀ5ꢀyl 3ꢀoxide)ethylene
(8). Lead oxide PbO2 (10 g, 42 mmol) was added to a solution of
compound 2i (1 g, 7 mmol) in chloroform (15 mL), and the reaction
mixture was stirred for 5 h. The oxidizing agent was filtered off and
washed with chloroform. The solution was concentrated under
reduced pressure. The residue was triturated with diethyl ether. The
precipitate was filtered off and chromatographed on a silica gel
column using chloroform as the eluent. The yield was 0.32 g (32%),
red crystals having a metallic luster.
8,15,18
The melting points were determined on a Kofler hotꢀstage
microscope. The course of the reactions was monitored by TLC on
Sorbfil UVꢀ254 plates. The chromatographic purification was carꢀ
ried out by column chromatography using Kieselgel 60 silica gel
(Merck). αꢀHydroxyamino ketones 3a (see Ref. 20) and 3b
(see Ref. 7) were synthesized according to known procedures.
2,3,4ꢀTrimethoxybenzaldehyde was provided by V. M. Tormyshev
(N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry,
Siberian Branch of the Russian Academy of Sciences); 4ꢀmethylꢀ4ꢀ
nitropentanal, by V. A. Reznikov (the same Institute). The melting
points and spectroscopic characteristics of all compounds are given
in Tables 2—6.
1ꢀHydroxyꢀ4,5,5ꢀtrimethylꢀ2,5ꢀdihydroimidazoles 2a—d,f,j
(general procedure A). A 25% aqueous ammonia solution (2.5 mL)
and aldehyde (100 mmol) were added with stirring to a solution of
αꢀhydroxyamino ketone hydrochloride 3a,b (100 mmol) in meꢀ
thanol (10 mL). The resulting suspension was stirred for 5 h. Then
the reaction mixture was kept in a refrigerator (0 °C) for 10—12 h.
The precipitate of compounds 2a—d,f,j that formed was filtered off,
washed with water and 50% methanol, and recrystallized.
To isolate 3ꢀmethylꢀ3ꢀ[(2ꢀthienylmethylene)amino]butanꢀ2ꢀ
one Nꢀoxide (4), which was prepared by condensation of compound
3a with 2ꢀthiophenecarbaldehyde, the precipitate of 2a was sepaꢀ
rated, the filtrate was concentrated, the residue was triturated with
diethyl ether, and the precipitate was filtered off, washed with diethyl
ether, and recrystallized from a 1 : 1 AcOEt—hexane mixture. The
yield was 15%, colorless crystals, m.p. 98—102 °C (from hexane).
1H NMR (400 MHz, CD3OD—CDCl3), δ: 1.69 (s, 6 H, CMe2);
2.15 (s, 3 H, Me); 7.16, 7.47, and 7.51 (all m, 1 H each, thienyl);
8.07 (s, 1 H, HC=N). 13C NMR (100 MHz, CD3OD—CDCl3), δ:
22.6 (CMe2); 23.6 (Me); 78.9 (CMe2); 127.4 (HC=N); 203.7
(C=O); 126.6 (C(2)); 129.4 (C(3)); 132.2 (Ci); 130.2 (C(4)).
General procedure B. Ammonium acetate (3 g) and aldehyde
(100 mmol) were added with stirring to a solution of αꢀhydꢀ
roxyamino ketone hydrochloride 3a,b (100 mmol) in methanol
(10 mL). After 5—7 h, the reaction mixture was twice diluted with
water and kept in a refrigerator for 10—12 h. The precipitate that
formed was filtered off and recrystallized.
General procedure C. A solution of αꢀhydroxyamino ketone
hydrochloride 3a (100 mmol) in methanol (5 mL) was saturated
with gaseous ammonia. A solution of aldehyde (100 mmol) in
methanol (5 mL) was saturated with ammonia separately. The
solutions were mixed, and ammonia continued to be passed for
15 min. After 3 h, the precipitate that formed was filtered off, washed
with water and 50% methanol, and recrystallized from ethanol.
1ꢀHydroxyꢀ4,5,5ꢀtrimethylꢀ2,5ꢀdihydroimidazole (2h). A 38%
aqueous formaldehyde solution (10 mL, 130 mmol) and a 25%
aqueous ammonia solution (15 mL) were added with stirring and
cooling to a solution of αꢀhydroxyamino ketone 3a (10 g, 65 mmol)
in methanol (20 mL) cooled to 10 °C (the reaction mixture warmed
up). After cooling to ~20 °C, the mixture was allowed to stand for
2.5 h and then concentrated under reduced pressure. The viscous
residue was triturated with propanꢀ2ꢀol (50 mL), the precipitate
was filtered off, and the solution was concentrated under reduced
pressure. These steps were repeated 2—3 times. Then the mixture
was kept in vacuo to remove residual water and the solvent and
dissolved in ethyl acetate. The solution was dried with MgSO4 and
4,4ꢀDimethylꢀ4Hꢀimidazoleꢀ5ꢀcarbaldoxime
3ꢀoxides
11a,b,d,g,k,l (general procedure). Sodium metal (1 g, 43 mmol) was
added to propanꢀ2ꢀol (30 mL). The reaction mixture was carefully
heated with stirring until sodium was completely dissolved. The
solution was cooled to 5 °C. Then isopropyl nitrite (3.5 mL,
39 mmol) and a solution of compound 7 (16 mmol) in isopropanol
(20 mL) were added with stirring to a suspension of sodium
isopropoxide. The reaction mixture was allowed to stand for 1—8 h.
The course of the reaction was monitored by TLC using ethyl acetate
as the eluent, samples of the reaction mixture being neutralized with
acetic acid before the analysis. After the consumption of the starting
compound, the reaction mixture was neutralized with acetic acid to
pH 5—6, and propanꢀ2ꢀol was distilled off under reduced pressure.
A saturated NaCl solution (30 mL) was added to the residue, and
the precipitate was filtered off, dried in air, and recrystallized.
Under the same conditions, the nitrosation of compound 7e
afforded a mixture of compounds 11e and 12, which were sepaꢀ
rated by silica gel column chromatography using chloroform as
the eluent.

1532
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
Kirilyuk et al.
4,4ꢀDimethylꢀ2ꢀ(4ꢀnitrophenyl)ꢀ4Hꢀimidazoleꢀ5ꢀcarbaldoꢀ
xime 3ꢀoxide (11c). Isopropyl nitrite (8 mL, 76.4 mmol) was added
with stirring to a cold solution of compound 7c (6.22 g, 25.2 mmol)
in a 0.1 M sodium methoxide solution in methanol (500 mL). The
reaction mixture was allowed to stand for 4 h. The course of the
reaction was monitored by TLC using ethyl acetate as the eluent,
samples of the reaction mixture being neutralized with acetic acid
before the analysis. After the consumption of the starting compound,
the reaction mixture was neutralized with acetic acid to pH 5—6,
and methanol was distilled off under reduced pressure. A saturated
NaCl solution (30 mL) was added to the residue, and the precipitate
of oxime 11c was filtered off and dried in air.
2ꢀ(2ꢀHydroxyphenyl)ꢀ4,4ꢀdimethylꢀ4Hꢀimidazoleꢀ5ꢀcarbaldꢀ
oxime 3ꢀoxide (11f). Triethylamine (2 mL, 15 mmol) and isopropyl
nitrite (3 mL, 34 mmol) were successively added to a solution of
compound 7f (2.2 g, 9 mmol) in dichloromethane (5 mL).
The reaction mixture was kept at 22 °C for 24 h. The precipitate that
formed was filtered off, washed with a small amount of a 2 : 1
mixture of tertꢀbutylmethyl ether and propanꢀ2ꢀol, and dried.
1,2,3ꢀTris(4,4ꢀdiethylꢀ2ꢀphenylꢀ4Hꢀimidazolꢀ5ꢀyl 3ꢀoxide)ꢀ
propenone oxime Oꢀmethyl ether (13). Methyl iodide (0.15 mL,
1.6 mmol) was added with stirring to a solution of compound 12
(0.3 g, 0.42 mmol) in a 0.1 M sodium isopropoxide solution in
propanꢀ2ꢀol (10 mL). The reaction mixture was allowed to stand for
24 h and then acidified with acetic acid to pH 6. The solvent was
evaporated under reduced pressure, and the residue was chroꢀ
matographed on a silica gel column using chloroform as the eluent.
Compound 13 was recrystallized from ethyl acetate.
water). After completion of evolution of NO, isopropyl nitrite (1 mL,
9.55 mmol) was added to the reaction mixture. After 24 h,
the precipitate of oxime 11h was filtered off and washed with
tertꢀbutylmethyl ether. The yield was 0.9 g (75%).
2,4,4ꢀTrimethylꢀ4Hꢀimidazoleꢀ5ꢀcarbaldoxime 3ꢀoxide (11i)
was synthesized analogously by nitrosation of compound 2i. The
course of the reaction was monitored by TLC using ethyl acetate as
the eluent. After completion of the reaction, the solvent was evapoꢀ
rated under reduced pressure. Water and tertꢀbutymethyl ether were
added to the residue, and the reaction mixture was shaken until
complete dissolution. The organic phase was extracted with water.
The combined aqueous solutions were saturated with NaCl and
extracted with chloroform. The extract was dried with MgSO4,
chloroform was evaporated under reduced pressure, the residue was
triturated with ethyl acetate, and the precipitate of oxime 11i was
filtered off.
Under the same conditions, the nitrosation of imidazoline 2j
afforded a mixture of compounds 11j, 18, and 19, which were
separated by silica gel column chromatography using chloroform as
the eluent. The yields were 34% (11j), 15% (18), and 7% (19). The
nitrosation at 5—10 °C afforded compounds 11j, 18, and 19 in 50,
3, and 7% yields, respectively.
4,4ꢀDimethylꢀ4Hꢀimidazoleꢀ5ꢀcarbonitrile 3ꢀoxides 1a—g,i—l
(general procedure). Triethylamine (16 mL, 110 mmol) was added to
a suspension of the corresponding oxime 11a—l (50 mmol) in
chloroform (75 mL). The reaction mixture was stirred until comꢀ
plete dissolution. Then pꢀtoluenesulfonyl chloride (9.5 g, 50 mmol)
was added portionwise. The course of the reaction was monitored
by TLC using chloroform as the eluent. After the starting compound
was completely consumed, the reaction mixture was washed with
a saturated aqueous NaCl solution and dried with MgSO4. The
drying agent was filtered off, and the solvent was evaporated under
reduced pressure. The residue was chromatographed on a silica gel
column using chloroform as the eluent.
4,4ꢀDimethylꢀ4Hꢀimidazoleꢀ5ꢀcarbonitrile 3ꢀoxide (1h) was
prepared analogously, but after the completion of the reaction,
chloroform was evaporated under reduced pressure, the residue was
triturated with diethyl ether, the precipitate of triethylammonium
salts was filtered off, diethyl ether was evaporated, and the residue
was sublimed in vacuo (4 Torr) at 100 °C.
4,4ꢀDimethylꢀ4Hꢀimidazoleꢀ5ꢀcarbaldoxime 3ꢀoxide (11h). A.
Imidazoline 2h (2 g, 16 mmol) was added to a solution of sodium
amide in liquid ammonia, which was prepared from sodium (0.54 g,
23 mmol) and liquid ammonia (100 mL). The reaction mixture was
cooled to –60 °C, and isopropyl nitrite (4 mL, 40 mmol) was added
dropwise. The resulting brickꢀred mixture was stirred for 1 h, and
ammonia was evaporated. The residue was dissolved in methanol
(20 mL) and acidified with acetic acid to pH 6. Methanol was
evaporated under reduced pressure and triturated with H2O (20 mL).
The precipitate that formed was filtered off and recrystallized from
ethanol. The yield was 0.68 g (29%).
B. Isopropyl nitrite (20 mL, 195 mmol) was added dropwise to
a solution of imidazoline 2h (10 g, 78 mmol) in a 1.3 M sodium
methoxide solution (90 mL) cooled to –25 °C. The reaction mixꢀ
ture was stirred for 1 h, the temperature being gradually raised to
~20 °C. Then the mixture was neutralized by adding a solution of
AcOH (6.7 mL) in propanꢀ2ꢀol (20 mL), which was accompanied
by a change in the color of the solution from blackꢀgreen to orangeꢀ
red. The precipitate of sodium acetate was filtered off, and the
solution was concentrated to dryness under reduced pressure. Water
(50 mL) was added to the residue, and the mixture was heated to
80 °C (until complete dissolution). The resulting solution was kept
in a refrigerator for 24 h, and the precipitate of oxime 11h was filtered
off and recrystallized from ethanol. The yield was 2.85 g (23%).
C. Triethylamine (0.1 mL) was added to a solution of compound
2h (1.0 g, 7.8 mmol) in THF (3.5 mL; or in a minimum amount of
a 1 : 1 CHCl3—CCl4 mixture). To prevent nitric acid, which was
formed on the walls of the vessel as a result of oxidation of NO that
was evolved in air, from being passed to the reaction mixture, the
reaction vessel was sealed with a cap. Isopropyl nitrite (3 mL,
28.7 mmol) was added portionwise to the reaction solution so as to
prevent warmingꢀup, vigorous evolution of NO, and boilingꢀup of
the reaction mixture (if necessary, the mixture was cooled with cold
Xꢀray diffraction study of compound 13 was carried out on
a Smart APEX diffractometer (Bruker AXS) according to a standard
procedure (MoꢀKα radiation, 2θ < 47°). The crystals were of low
quality. Hence, the Xꢀray diffraction data confirmed the molecular
structure, but the details of the geometry cannot be discussed. The
structure was solved by direct methods using the SIR2002 program
and refined by the leastꢀsquares method with anisotropic displaceꢀ
ment parameters for all nonhydrogen atoms (with isotropic disꢀ
placement parameters for H atoms) with the use of the SHELXLꢀ97
program package. The hydrogen atoms were positioned geometriꢀ
cally and refined using a riding model. The ethanol solvent molecule
is disordered over two positions with equal occupancies. The crysꢀ
tallographic data are as follows: C43H49N7O4•0.5(C2H6O),
M = 750.93, monoclinic system, space group C2/c, a = 38.767(8)
Å, b = 11.339(2) Å, c = 19.805(4) Å, β = 90.164(5)°, V = 8706(3)
Å3, Z = 8, dcalc = 1.167 g cm–3, μ = 0.077 mm–1, R = 0.1558
for 2989 reflections with I > 2σ(I), 545 refined parameters,
wR2 = 0.3311, GOF = 1.191 for all 6333 independent reflections.
This study was financially supported by the Russian
Foundation for Basic Research (Project No. 04ꢀ03ꢀ32299)

Synthesis of 4Hꢀimidazoleꢀ5ꢀcarbonitrile 3ꢀoxides
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
1533
10. P. Genix, A. Villier, PflanzenschutzꢀNachrichten Bayer (Gerꢀ
man Edition), 2003, 56, 444.
11. M.ꢀW. Ding, G.ꢀP. Zeng, Z.ꢀL. Liu, Phosphorus, Sulfur, Siliꢀ
con, Rel. Elem., 2002, 177, 1315.
12. I. A. Kirilyuk, I. A. Grigor´ev, L. B. Volodarskii, Izv. Sib. Otd.
Akad. Nauk SSSR, Ser. Khim., 1989, 4, 99 [Bull. Sib. Branch
Acad. Sci. USSR, Ser. Khim. Nauk, 1989, 4 (Engl. Transl.)].
13. V. A. Reznikov, L. B. Volodarsky, Tetrahedron, 1993,
49, 10669.
and the US Civilian Research and Development Foundaꢀ
tion (CRDF, Grant RUCꢀ1 2635ꢀNOꢀ05).
References
1. L. B. Volodarskii, L. A. Fust, V. S. Kobrin, Khim. Geterotsikl.
Soedin., 1972, 1246 [Chem. Heterocycl. Compd., 1972, 8, 1126
(Engl. Transl.)].
14. V. A. Reznikov, L. B. Volodarskii, Khim. Geterotsikl. Soeꢀ
din., 1990, 772 [Chem. Heterocycl. Compd., 1990, 26, 643
(Engl. Transl.)].
15. I. A. Grigor´ev, I. A. Kirilyuk, L. B. Volodarskii, Khim.
Geterotsikl. Soedin., 1988, 1640 [Chem. Heterocycl. Compd.,
1988, 24, 1355 (Engl. Transl.)].
16. V. A. Reznikov, L. B. Volodarskii, Izv. Akad. Nauk, Ser. Khim.,
1996, 1789 [Russ. Chem. Bull., 1996, 45, 1699 (Engl. Transl.)].
17. I. K. Korobeinicheva, M. M. Mitasov, V. S. Kobrin, L. B.
Volodarskii, Izv. Sib. Otd. Akad. Nauk SSSR, Ser. Khim., 1976,
2, 96 [Bull. Sib. Branch Acad. Sci. USSR, Ser. Khim. Nauk,
1976, 2 (Engl. Transl.)]; Chem. Abstrs, 1976, 85, 26913.
18. I. A. Grigor´ev, V. V. Martin, G. I. Shchukin, V. I. Mamatyuk,
L. B. Volodarskii, Khim. Geterotsikl. Soedin., 1985, 247 [Chem.
Heterocycl. Compd., 1985, 21, 205 (Engl. Transl.)].
19. I. A. Grigor´ev, G. I. Shchukin, V. V. Martin, V. I. Mamatyuk,
Khim. Geterotsikl. Soedin., 985, 252 [Chem. Heterocycl. Compd.,
1985, 21, 210 (Engl. Transl.)].
2. V. A. Reznikov, O. N. Burchak, L. A. Vishnivetskaya, L. B.
Volodarskii, T. V. Rybalova, Yu. V. Gatilov, Zh. Org. Khim.,
1997, 1377 [Russ. J. Org. Chem., 1997, 33, 1302 (Engl. Transl.)].
3. I. A. Grigor´ev, G. I. Shchukin, B. B. Khramtsov, L. M. Vainer,
V. F. Starichenko, L. B. Volodarskii, Izv. Akad. Nauk SSSR,
Ser. Khim., 1985, 2342 [Bull. Acad. Sci. USSR, Div. Chem. Sci.,
1985, 34, 2169 (Engl. Transl.)].
4. I. A. Grigor´ev, I. A. Kirilyuk, V. F. Starichenko, L. B.
Volodarskii, Izv. Akad. Nauk SSSR, Ser. Khim., 1989, 1624
[Bull. Acad. Sci. USSR, Div. Chem. Sci., 1989, 38, 1488
(Engl. Transl.)].
5. I. G. Kursakina, V. F. Starichenko, I. A. Grigor´ev, I. A.
Kirilyuk, L. B. Volodarskii, Izv. Akad. Nauk SSSR, Ser. Khim.,
1991, 2009 [Bull. Acad. Sci. USSR, Div. Chem. Sci., 1991, 40,
1774 (Engl. Transl.)].
6. I. A. Kirilyuk, T. G. Shevelev, D. A. Morozov, E. L.
Khromovskih, N. G. Skuridin, V. V. Khramtsov, I. A. Grigor´ev,
Synthesis, 2003, 871.
20. L. B. Volodarskii, I. A. Grigor´ev, S. A. Dikanov, Imidazolinovye
nitroksil´nye radikaly [Imidazoline Nitroxides], Nauka, Novoꢀ
sibirsk, 1988, p. 29 (in Russian).
7. I. A. Kirilyuk, A. A. Bobko, I. A. Grigor´ev, V. V. Khramtsov,
Org. Biomol. Chem., 2004, 2, 1025.
8. I. A. Kirilyuk, A. A. Bobko, V. V. Khramtsov, I. A. Grigor´ev,
Org. Biomol. Chem., 2005, 3, 1269.
9. D. I. Potapenko, M. A. Foster, D. J. Lurie, I. A. Kirilyuk,
J. M. S. Hutchison, I. A. Grigor´ev, E. G. Bagryanskaya, V. V.
Khramtsov, J. Magn. Reson., 2006, 182, 1.
Received October 25, 2007;
in revised form February 27, 2008