Synthesis and properties of monoimines of α-diketones, derivatives of 3-imidazoline nitroxides

Article abstract of DOI:10.1023/A:1011319528481

The reaction of 4-(2R-1-chloro-2-oxoethylidene)-substituted imidazolidine-1-oxyl with sodium azide gives monoimines of α-diketones, derivatives of 3-imidazoline nitroxides. Reactions of these products with nitrogen binucleophiles were used to prepare various heterocyclic compounds containing an imidazoline nitroxide moiety.

Full text of DOI:10.1023/A:1011319528481

874
Russian Chemical Bulletin, International Edition, Vol. 50, No. 5, pp. 874—881, May, 2001
Synthesis and properties of monoimines of α-diketones,
derivatives of 3-imidazoline nitroxides
V. A. Reznikov,a« G. I. Roshchupkina,b T. V. Ribalova,a and Yu. V. Gatilova
aNovosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences,
9 prosp. Akad. Lavrent´eva, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383 2) 33 4752. E-mail: mslf@nioch.nsc.ru
bNovosibirsk State University,
2 ul. Pirogova, 630090 Novosibirsk-90, Russian Federation
The reaction of 4-(2R-1-chloro-2-oxoethylidene)-substituted imidazolidine-1-oxyl with
sodium azide gives monoimines of α-diketones, derivatives of 3-imidazoline nitroxides.
Reactions of these products with nitrogen binucleophiles were used to prepare various
heterocyclic compounds containing an imidazoline nitroxide moiety.
Key words: enamino ketones, azides, monoimines of α-diketones nitroxides, 3-imidazoline,
imidazole, quinoxaline, pyrazine, triazine, oxazole.
Previously,1 we showed that the reaction of chloro-
Scheme 1
substituted enamino ketones (1) with sodium cyanide
affords cyano-substituted derivatives. This reaction, which
is formally nucleophilic substitution, proceeds in reality
via the formation of epoxides. The nitriles thus pro-
duced can be used as paramagnetic chelating reagents2
and ðH-sensitive spin probes. Probably, azide-substi-
tuted enamino ketones would also be of interest as
paramagnetic ligands because the azido group, which is
geometrically similar to the nitrile group, can be in-
volved in the coordination with a metal. To continue
research into the properties of chloro-substituted enamino
ketones and to prepare new chelating reagents, in this
work, we studied the reactions of chloro-substituted
enamino ketones 1a—e with sodium azide (Scheme 1).
R
O
N
Cl
NaN3
H
N
•
O
1a—e
R
–
+
O
N
N2
N
O
R
N3
H
H
N
–N2
N
N
Results and Discussion
•
•
O
O
3a—e
In view of the previously established possibility of
replacement of the chlorine atom in enamino ketones 1
by the cyano group, it could be expected that the
reaction with sodium azide will give the corresponding
azido derivatives, although according to published data,
the substitution of an azide group for chlorine at the
C=C bond can proceed only in the presence of an
electron-withdrawing substituent in the β-position.3
However, the reaction of enamino ketone 1a with NaN3
in DMSO gave compound 2a instead of the expected
azide (see Scheme 1). The structure of this product as
an α-diketone monoimine, a derivative of 3-imidazoline,
was confirmed by X-ray diffraction data and by the IR
spectrum of this compound, which exhibits absorption
O
•
N
R
O
N
HO
N
N
N
NH
R = Me
N
OH
N
•
O
N
•
O
2a—e
4e
R = Ph (a), EtO (b), Prn (c), 4-pyridyl (d), Me (e)
The molecule of 2a is generally nonplanar (Fig. 1).
–1
bands for the carbonyl group at 1666 cm , for C=C
The dihedral angle between the imino group and the
imidazoline ring is equal to 17.10(8)°, and the angle
between the imino group and the benzoyl fragment
reaches 89.89(6)°. The ÐÌ3 calculations for molecule
–1
and C=N bonds at 1622, 1600, and 1580 cm , and an
intense band corresponding to NH-bond vibrations at
–1
3219 cm .
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 837—844, May, 2001.
1066-5285/01/5005-874 $25.00 © 2001 Plenum Publishing Corporation

Synthesis of monoimines of α-diketones
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 5, May, 2001
875
tion of enamino ester 1b with NaN3 gives, apart from
imine 2b, intermediate azide 3b, which is easily con-
verted into imine 2b on recrystallization. Conversely, in
the case of ketone 1å, the corresponding imine cannot
be isolated, dimer 4 being produced as the reaction
product. The dimeric structure of 4 is confirmed by the
double molecular mass found by ebullioscopy and by
the ESR spectrum, which is a quintet with the HFC
constant aN = 14.3 Gs (CHCl3). The transformation of
chloro-substituted enamino ketones into imino ketones
is apparently a fairly general process. In particular,
biradical 5 is converted into imine 6 under similar
conditions (Scheme 2).
C(13)
C(14)
C(15)
C(12)
C(11)
C(10)
C(7)
C(6)
O(9)
N(8)
Scheme 2
C(16)
N(3)
C(4)
C(19)
•
•
O N
O N
N
N
C(5)
C(2)
O
N
O
N
N(1)
O(20)
Fig. 1. Structure of molecule 2a in the crystal.
NaN3
HN
Cl
C(17)
H
C(18)
N
N
•
•
O
O
5
6
2a predict a similar nonplanar structure. A search
through the Cambridge Structural Database4 for a
N=C—C(=N)—C=O fragment not incorporated in cy-
clic systems resulted in three nonplanar structures. How-
ever, the ketoimine fragment in these three compounds
is planar, unlike that in molecule 2a. The bond lengths
in 2a are close to the statistical mean values5 and to
those in 4-(1-methoxyiminoethyl)-2,2,5,5-tetramethyl-
3-imidazoline 1-oxide.6
It is known that imines can be formed on treatment
of azides with strong acids. Under these conditions, the
azido group is protonated and a nitrogen molecule is
cleaved. Since the reaction of chloro-substituted enamino
ketones 1 with NaN3 was carried out in a nearly alkaline
medium, the instability of azides 3 could be explained
by migration of a proton from the ring heteroatom to
the azido group. The ease of this migration might be due
to the fact that it occurs as an intramolecular process.
Yet another possibility is deprotonation of the ring
nitrogen atom induced by the azide ion followed by
elimination of a nitrogen molecule and protonation of
the resulting imine anion (cf. Ref. 8). In order to verify
the possibility of participation of the hydrogen atom in
position 3 of the heterocycle in the formation of imines,
enamino ketone 7, whose molecule contains no N—H
bond, was involved in the reaction with NaN3. How-
ever, it was found that this compound does not react
with NaN3 under similar conditions (∼20 °C), and only
slow reduction of the nitroxide group to the hydroxyl-
amine group takes place on heating (70 °C). This reac-
tion route seems unusual if one recalls that DMSO is an
oxidant. However, the absence of nucleophilic substitu-
tion in this case confirms the substitution mechanism
proposed in our previous study,1 according to which
nucleophilic addition at the carbonyl carbon atom is the
first step. This step is evidently followed by migration of
the double bond into the ring, stimulated by the absence
of conjugation. As a result, the chlorine atom becomes
attached to an sp3 carbon atom, which ensures the
Bond
d/Å
Bond
d/Å
N(1)—O(20)
N(3)—C(4)
C(4)—C(6)
C(6)—N(8)
1.267(2)
1.279(2)
1.480(2)
1.263(2)
C(6)—C(7)
C(7)—O(9)
C(7)—C(10) 1.473(2)
1.522(2)
1.215(2)
Attention is attracted by the length of the C(6)—C(7)
bond (1.522(2) Å) between the carbonyl and imino
groups, which is longer than the statistical mean value for
the nonconjugated C=C—C=O fragment (1.484(17) Å)5
and than, for example, the length of this bond in
(E,E)-hexane-2,3,4,5-tetraone 3,4-dioxime, which is
1.494 Å.7 The length of this bond found by PM3
calculations is 1.52 Å. In the crystal, the molecules of
2a are connected in chains stretched along the a axis
through N—H...O type interactions.
Interaction
N(8)—H
H...O(20)
N(8)...O(20)
d/Å
Angle
ω/deg
0.96(3)
2.32(3)
3.270(2)
N(8)—H...O(20) 171(2)
Enamino ketones 1b—e react with NaN3 in a similar
way (see Scheme 1). It should be noted that the reac-

876
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 5, May, 2001
Reznikov et al.
Scheme 4
possibility of intramolecular nucleophilic substitution to
give an epoxide. The subsequent opening of the epoxide
ring induced by a second equivalent of the nucleophile
furnishes the reaction product (Scheme 3).
Ph
Cl
OR´
–
N
N3
–
N3
R´ = H
R´ = Me
Scheme 3
O
8a,b
R
R Nu
O
–
O
N
–
Nu
O
Ph
N3
OH
Ph
Cl
Cl
H
H
N
N
N
HN
R
O
O
R Nu
O
O
–
Nu
9a
–
+Nu
R´ = H (a), Me (b)
Cl
–
–Nu
N
N
An indirect piece of evidence for the involvement of
the N—H-bond proton in the decomposition of azides
is the reaction of compound 10 with NaN3, giving rise
to stable azide 11 as the only product (Scheme 5).
R
O
N
Nu
H
Scheme 5
Ph
Ph
N3
Ph
Ph
O
N
O
N
–
N3
Cl
O
N
O
NaN3
–
Cl
Cl
N3
N
N
N
•
•
N
N
O
O
•
•
O
O
10
11
7
The reaction of dichloro derivative 12 with NaN3
follows a more complicated route. In addition to the
expected diazide 13, it affords dichloro 3-imidazoline
14 and benzoyl azide. This composition of the reaction
products is consistent with the assumption that the
reaction of chloro-substituted enamino ketones with
When there is no proton at the enamine nitrogen
atom, as in compound 7, the double bond migration is
impossible and no substitution takes place. Similarly,
the reaction of pyrroline 8a with sodium azide gives rise
to imine 9, while the methoxy derivative 8b does not
react under these conditions (Scheme 4).
Scheme 6
Ph
Ph
N3
O
O
N
N3
N3
Cl
N
N3
Ph
Ph
–
–
O
N
O
–Cl
N
N
Cl
Cl
Cl
Cl
•
•
O
O
NaN3
N
13
N
N
–
–PhCON3
Cl2C
•
•
Cl2HC
O
O
N
N
H+
12
N
•
N
•
O
O
14

Synthesis of monoimines of α-diketones
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 5, May, 2001
877
Scheme 8
nucleophiles starts with the addition to the carbonyl
group (cf. Ref. 1) (Scheme 6).
As was to be expected, the reaction of the chlori-
nated β-oxo nitrone 15 with NaN3 follows a similar
route and yields imine 16. Apparently, the nitroxide group
does not influence the reaction pathway (Scheme 7).
Ph
Ph
Ph
O
N
O
N
O
N
O
HN
O
H3O+
NaBH4
N
N
N
•
•
Scheme 7
O
O
OH
18
17
2a
Ph
O
NH2OH
OH
Cl
NaN3
N
O
O
N
O
Ph
Ph
Ph
N
N
N
MnO2
+
O
HON
N
N
15
O N
O N
NOH
H
O
Ph
N H
O
N
19
20″
20´
O
O
O
Ph
N
N
N
ring. The subsequent recyclization and oximation give
rise to dioxime derived from pyrroline oxide 19 (cf.
Ref. 11). It should be noted that the properties of
compound 19, in particular, the melting point and
NMR chemical shifts, differ markedly from published
data, although they do not contradict the structure
ascribed. The data of elemental analysis also correspond
to structure 19.
N
16″
16´
An interesting feature of compound 16 is the double
set of signals in the NMR spectra in CDCl3, which can
be indicative of the existence of two isomers (16´ and
16″), differing in the position of the intramolecular
hydrogen bond. The presence of an intramolecular hy-
drogen bond in both forms is indicated by the fact that
the NH-proton signals are located in a very low field, at
10.4 and 13.5 ppm for isomers 16´ and 16″, respec-
tively. The signals were assigned proceeding from the
position of a more intense low-field signal correspond-
ing to C(4) in form 16´ in the 13C NMR spectrum (cf.
Ref. 9). According to NMR data, in DMSO, the com-
pound exists almost exclusively as isomer 16´.
According to published data, dioxime 19 is oxidized
by MnO2 to give furoxan derivative 20; judging by
NMR spectra, this product is mainly formed as one of
the two possible isomers, namely, 20´.11 Oxidation of
compound 19 under similar conditions also produces
two isomeric furoxans 20 but these are formed in ap-
proximately equal amounts, their ratio changing with
1
time toward isomer 20´. According to H NMR, the
20´ : 20″ ratio after 2 h at 20 °C in a CDCl3 solution
is 1.5 : 1.
Some properties of the monoimines synthesized were
studied taking compound 2a as an example. Thus imine
2a is hydrolyzed in dilute HCl to give α-diketone 17,
while the reaction of the same imine with an equivalent
amount of NaBH4 reduces the nitroxide group and is
accompanied by hydrolysis of the imino group giving
rise to diamagnetic diketone 18 (Scheme 8).
The nitroxide group is usually stable against NaBH4.
The reduction of the nitroxide group in this particular
case is due to a multistep process that includes prelimi-
nary hydrolysis of the imino group, its reduction with
sodium borohydride, and subsequent reduction of the
nitroxide group by the intermediate hydroxy ketone,
which affords diamagnetic diketone 18 (cf. Ref. 10).
The reaction of imine 2 with hydroxylamine is also
accompanied by reduction of the nitroxide group; this
results in the hydrolytic cleavage of the 3-imidazoline
The foregoing facts indicate that compound 19 is
actually a dioxime but it differs from the compound
reported in the literature in the configuration of the
oxime groups. The different positions of signals in the
NMR spectra suggest that in compound 19, the oxime
group in position 4 has a Z-configuration relative to the
methyl groups, whereas the compound described in the
literature is the E-isomer. This is quite consistent with
the fact that the conditions for the synthesis of dioxime
19 described in the literature,11 are much more rigorous
(refluxing in pyridine for 6 h) than those used in this
study.
The ease of formation of the heterocyclic system of
dihydropyrazine 4 from monoimine 2å stimulated us to
attempt to synthesize heterocyclic compounds from the
α-diketone monoimines prepared in this work. When
compound 2a is made to react with î-phenylenedi-

878
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 5, May, 2001
Reznikov et al.
Scheme 9
2a with formaldehyde and ammonia affords imidazole
24 (Scheme 9).
Quite unexpectedly, the reaction of α-diketone
monoimine 2a with benzamidine gives rise to two com-
pounds. According to elemental analysis and spectral
characteristics, one product can be identified as oxazole
derivative 25 and the other product is triazine derivative
26. However, it cannot be ruled out that these com-
pounds are derivatives of compounds 25´ and 26´,
respectively, with a different arrangement of heteroat-
oms. The formation of oxazole 25 cannot be explained
without the step of reduction, while the formation of
triazine 26 cannot be interpreted without oxidation.
Apparently, the first step of the reaction is the nucleo-
philic addition of the benzamidine amino group to
either the imino or the carbonyl group of the substrate
2a to give the corresponding intermediates, and at the
second step, these intermediates are reduced and oxi-
dized giving rise to the final products (Scheme 10).
The reaction of 2a with benzoylhydrazine, which
was performed in order to synthesize 26 via an alterna-
tive route yielded benzoylhydrazone 27, resulting from
nucleophilic attack at the imino group.
Ph
NH2
N
N
O
N
HN
NH2
Ph
N
N
N
•
•
O
O
21
2a
CH2O
NH
N
NH3
NH2
NH2
Ph
N
N
•
O
24
N
N
N
N
MnO2
Thus, it was demonstrated that imines 2 are useful
starting compounds in the synthesis of heterocyclic
compounds containing an imidazoline nitroxide-con-
taining fragment as a substituent and presenting interest
as paramagnetic chelate-forming compounds.12
Ph
Ph
N
N
N
N
•
•
O
O
23
22
Experimental
amine, quinoxaline derivative 21 is formed; the reaction
with ethylenediamine affords dihydropyrazine derivative
22, which readily undergoes aromatization on treatment
with MnO2 to give pyrazine 23. The reaction of imine
IR spectra were recorded on a Bruker IFS 66 spectrometer
as KBr pellets (concentration 0.25%, thickness of a pellet
Scheme 10
Ph
O
N
O
N
Ph
Ph
Ph
Ph
NH
N
O
[H]
Ph
N
N
N
N
•
N
•
N
•
NH
Ph
O
O
O
NH2
25´
25
2a
Ph
Ph
N
N N
N
N
Ph
NH
Ph
N
Ph
Ph
PhCONHNH2
N
[O]
NH
N
N
N
Ph
N
N
N
O
H
•
•
•
O
O
O
Ph
N
26´
26
N
N
O
N
•
O
27

Synthesis of monoimines of α-diketones
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 5, May, 2001
879
1 mm). UV spectra were measured on a Specord M-40 spectro-
photometer in EtOH. 1H and 13C NMR spectra were run on a
Bruker WP 200SY spectrometer for a 5% solution in CDCl3
using HMDS as the internal standard. High-resolution mass
spectra were recorded on a Finnigan MAT 8200 mass spec-
trometer with direct sample injection. The chloro-substituted
enamino ketones 1 were prepared by a procedure described
previously;1 dichloro derivative 12 was synthesized by a known
procedure;13 and oxonitrone 15 and pyrroline 8a were prepared
by a known procedure.14 Commercial-grade CHCl3 and CCl4
Table 1. Characteristics of the compounds synthesized
Com-
pounda
YieldM.p.
(%)
IR
(KBr),
ν/cm
UV
(EtOH), Found
Molecular
(%)
Calculatedformula
–1
/°C
λ
max/nm (logε)
C
H
N
2à
2b
2c
2d
2e
4
95
65
75
75
—
148—150
73—75
1666 (C=O); 1622, 1600,
1580 (Ñ=Ñ, C=N), 3219 (NH)
1743 (C=O), 1626, 1605 (C=N),
3198 (NH)
1710 (C=O), 1602 (C=N),
3216 (NH)
1696 (C=O), 1621, 1600 (C=N),
3140 (NH)
1720 (C=O), 1624, 1603 (C=N),
3184 (NH)
253 (4.28)
66.43 6.79 15.65
66.16 6.66 15.43
55.01 7.52 17.42
55.99 7.55 17.59
60.33 8.80 17.34
60.48 8.46 17.63
61.24 6.22 20.12
61.52 6.27 20.50
C15H18N3O2
C11H18N3O3
C12H20N3O2
C14H17N4O2
—
—
63—65
—
147—148
—
—
—
—
—
—
50
60
90
60
177—179
172—173
153—155
101—104
1636, 1608 (C=N); 3273,
3405 (OH)
1628, 1607 (C=N); 3261 (NH)
—
57.11 7.82 19.83
57.12 7.67 19.99
57.34 7.71 20.54
57.30 7.51 20.88
C20H32N6O4
C16H25N5O3
C16H20ClN2O2
C12H12N2O2
6
335 (3.09)
7
1620, 1597, 1576,
1530 (C=C—C=O)
1766 (Ñ=Î), 1616 (Ñ=N),
3224 (NH)
249 (4.16),
372 (4.0)
244 (3.57),
296.4 (3.82),
334.4 (3.37)
252 (4.07)
62.03 6.51
62.43 6.55
8.94
9.10
9
66.72 5.51 13.04
66.65 5.59 12.96
10
11
13
16
17
18
60
80
108—110
45—48
1697 (C=O), 1611, 1597,
1582 (C=N, C=C)
62.05 6.55
62.43 6.55
8.83
9.10
C16H20ClN2O2
C16H20N5O2
C15H17N8O2
C16H21N3O2
C15H17N2O3
C15H18N2O3
1697 (C=O), 1626, 1598,
1579 (C=N, C=C), 2109 (N3)b
1697 (C=O), 1622, 1598,
1582 (C=N, C=C), 2131 (N3)
1675 (C=O), 1599, 1580,
1548 (C=C, C=N), 3253 (NH)
1704, 1675 (C=O), 1638, 1597,
1581 (C=C, C=N)
250 (4.10)
256 (4.15)
60.01 6.51 22.91
61.13 6.41 23.28
52.82 5.14 33.10
52.79 5.02 32.82
66.92 7.31 14.63
66.88 7.37 14.62
65.73 6.23 10.13
65.92 6.27 10.25
65.43 6.60 10.30
65.68 6.61 10.21
25
79—81
∼100
80
120—122
135—136
128—130
253 (4.08),
289 (3.91)
251 (4.08)
60
1701, 1673 (C=O), 1626,
1596 (C=C, C=N), 3240 (OH);
3586 (OH)c
252 (4.02)
19
21
22
23
24
70
50
60
90
50
20
20
25
178—180
146—148
152—154
98—100
1650, 1607 (C=NOH),
1545 (C=N), 3220, 3145 (OH)
1634 (C=N)
235 (4.27),
297 (3.82)
246 (4.66),
333 (3.92)
262 (3.88),
283 (3.96)
232 (4.09),
281 (3.92)
281 (3.83)
57.93 5.01 17.00
58.29 5.30 17.00
73.15 6.14 16.18
73.02 6.13 16.22
68.42 6.96 18.81
68.66 7.12 18.84
69.13 6.38 19.03
69.13 6.48 18.97
67.54 6.81 19.54
67.82 6.76 19.77
C12H13N3O3
C21H21N4O
C17H21N4O
C17H19N4O
C16H19N4O
C22H22N3O2
C22H22N5O
C22H23N4O3
1621 (C=N)
1617 (C=N)
185—187
146—148
188—190
160—163
1608 (C=N), 3230 (NH)
1615, 1600, 1580 (C=N, C=C)
1621, 1661 (C=C, C=N)
d
25
233 (4.11),
286 (4.15)
273 (4.48)
—
—
—
26
27
70.54 5.89 18.69
70.95 5.95 18.80
67.12 5.78 14.47
67.50 5.92 14.31
1682, 1664 (C=O), 1603,
1581 (C=N), 3436 (NH)
258 (4.32)
a The compounds were recrystallized from a hexane—AcOEt mixture (2a,d, 4, 16, 18, 26, 27), hexane (2b,c, 9, 10, 13, 25),
CCl4 (7), AcOEt (6, 21, 22, 23), aqueous EtOH (11), or EtOH (19).
b The IR spectrum was recorded in CCl4.
c The IR spectrum was recorded in CHCl3.
d Found, m/z: 360.17045. C22H22N3O2. Calculated: M = 360.17119.

880
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 5, May, 2001
Reznikov et al.
were dried over CaCl2 and distilled, DMSO was dried with
NaOH and distilled in vacuo over NaOH, and "pure"
grade hexane and rectified EtOH were used as received;
N-chlorosuccinimide (NCS, Fluka) was used for chlorination.
Manganese(IV) oxide for catalysis (TU 6-09-01-718-87) was
used as the oxidant. Chromatographic purification of the syn-
thesized compounds was performed using KSK silica gel ground
at the pilot chemical plant of the Novosibirsk Institute of
Organic Chemistry of the Siberian Branch of the RAS and
activated by heating at 110—120 °C for 6 h and neutral Al2O3
with Brockman activity II. In all cases, evaporation was carried
out in the vacuum of a water aspirator pump. The yields and
characteristics of the compounds synthesized are presented in
Table 1.
by a known procedure,16 in CCl4, and the mixture was stirred
for 15 min at 20 °C. The succinimide precipitate was filtered off
and washed with CCl4 until the filtrates were colorless. The
solution was concentrated, the residue was washed with hexane,
and the precipitate of compound 7 was filtered off and also
washed with hexane.
2,2,5,5-Tetramethyl-4-(2-oxo-2-phenyl-1-chloroprop-1-yl)-
3-imidazoline-1-oxyl (10). A solution of 2,2,5,5-tetramethyl-
4-(1-methyl-2-oxo-2-phenylethylidene)imidazolidin-1-oxyl
(0.41 g, 1.5 mmol), prepared by a previously reported proce-
dure,17 and NCS 0.22 g (1.7 mmol) in CHCl3 was kept for
30 min at 20 °C and concentrated. Compound 10 was isolated
by chromatography on a column with silica gel using CHCl3 as
the eluent.
4-(1-Imino-2-oxo-2-phenylethyl)-2,2,5,5-tetramethyl-3-
imidazoline-1-oxyl (2a). Enamino ketone 1a (1.47 g, 5 mmol)
was added in portions with stirring to a solution of NaN3
(0.65 g, 10 mmol) in 25 mL of anhydrous DMSO. The reaction
mixture was stirred for 2 h at 20 °C, cooled to 0 °C, and diluted
with 40 mL of ice-cooled brine. The resulting precipitate of
imine 2a was filtered off, washed with brine and water and
dried. The precipitate was dissolved in 10 mL of CHCl3 and the
solution was filtered through a silica gel layer (10 cm) and
eluted with CHCl3. The solution was concentrated to give
imine 2a.
Similar procedures were used to prepare imines 2b—d and 6
from enamino ketones 1b—d and 5, imine 9 from pyrroline 8a,
and imine 16 from oxo nitrone 15. The 1H NMR spectrum of
compound 16 (DMSO-d6), δ: 1.28 (s, 6 H); 1.54 (s, 6 H,
2,5-Me2); 2.37 (s, 3 H, N—Me); 7.70 (m, 5 H, C6H5); 11.81
(s, 1 H, NH). 13C NMR (DMSO-d6), δ: 23.4 (2,5-Me2); 26.1
(N—Me); 62.4 (C(5)); 89.5 (C(2)); 127.8, 128.4, 133.1, 134.0
(C6H5); 140.8 (C(4)); 166.7 (C=NH); 190.1 (C=O). 1H NMR
(CDCl3), δ: 1.35 (s, 6 H); 1.59 (s, 6 H, 2,5-Me2, 16´); 1.30
(s, 6 H); 1.49 (s, 6 H, 2,5-Me2, 16″); 2.31 (s, 3 H, N—Me,
16´); 2.39 (s, 3 H, N—Me, 16″); 7.70 (m, 5 H, C6H5,
16´+16″); 10.41 (s, 1 H, NH, 16´); 13.50 (s, 1 H, NH, 16″).
Ratio of the isomers 16´ : 16″ = 4 : 1. 13C NMR (CDCl3),
δ: 23.9 (2,5-Me2, 16´); 24.2 (2,5-Me2, 16″); 26.3 (N—Me, 16″);
26.6 (N–Me, 16´); 63.2 (C(5), 16´); 90.3 (C(2), 16´);
91.3 (C(2), 16″); 128.4, 128.5, 130.3, 133.4, 133.8, 134.0
(C6H5, 16´+16″); 141.8 (C(4), 16´); 138.0 (C(4), 16″); 162.9
(C=NH, 16″); 168.8 (C=NH, 16´), 190.7 (C=O).
The sample of imine 2b prepared under the indicated
conditions contained, according to IR, an impurity of azide 3b,
which disappeared upon recrystallization.
In the case of reaction with enamino ketone 1å, the pre-
cipitate formed was a mixture of imine 2å and dimer 4; on
washing with hexane, imine 2å was dissolved and was converted
into dimer 4 upon recrystallization.
2,2,5,5-Tetramethyl-4-[2-oxo-2-(2,2,5,5-tetramethyl-1-
oxyl-3-imidazolin-4-yl)-1-chloroethylidene]imidazolidine-1-oxyl
(5). N-Chlorosuccinimide (0.27 g, 2 mmol) was added in
portions over a period of 10 min to a stirred solution of
2,2,5,5-tetramethyl-4-[2-oxo-2-(2,2,5,5-tetramethyl-1-oxyl-
3-imidazolin-4-yl)ethylidene]imidazolidin-1-oxyl (0.59 g,
1.8 mmol), prepared by a known procedure,15 in 20 mL of
CHCl3. The mixture was stirred for 10 min at 20 °C and
concentrated, the residue was washed with hexane, and the
precipitate of compound 5 containing a succinimide impurity
was filtered off, washed with hexane, and used in the reaction
with NaN3 without purification.
4-(2-Azido-3-oxo-3-phenylprop-2-yl)-2,2,5,5-tetramethyl-
3-imidazoline-1-oxyl (11). Compound 10 (0.24 g, 0.8 mmol)
was added to a solution of NaN3 (0.1 g, 1.6 mmol) in 10 mL of
anhydrous DMSO. The reaction mixture was stirred for 3 h at
20 °C, cooled to 0 °C, and diluted with 20 mL of ice-cooled
brine. The solution was extracted with CHCl3 (3½15 mL), and
the extract was washed with brine (3½15 mL) and water, dried
with MgSO4, and concentrated to give azide 11.
Reaction of enamino ketone 7 with NaN3. A suspension of
compound 5 (0.5 g, 1.6 mmol) and NaN3 (0.21 g, 3.3 mmol) in
10 mL of anhydrous DMSO was heated for 30 h at 70 °C,
cooled to 0 °C, and worked-up as described for azide 11. The
mixture obtained after the workup was chromatographed on a
column with silica gel using CHCl3 as the eluent; this gave
successively the starting enamino ketone 7 (0.1 g) and 1-hydr-
oxy-2,2,3,5,5-pentamethyl-4-(2-oxo-2-phenyl-1-chloroethyl-
idene)imidazolidine (0.1 g), whose structure was confirmed by
oxidation by MnO2 in enamino ketone 7. For this purpose, a
solution of 1-hydroxy-2,2,3,5,5-pentamethyl-4-(2-oxo-2-phe-
nyl-1-chloroethylidene)imidazolidine (0.1 g) in 10 mL of CHCl3
was stirred with MnO2 (1 g) for 15 min, filtered, and concen-
trated. The residue was enamino ketone 7, whose structure was
established by comparison of the IR spectrum with the spec-
trum of an authentic sample.
Reaction of dichloro derivative 12 with NaN3. Dichloro
derivative 12 (0.8 g, 2.4 mmol) was added with stirring to a
solution of NaN3 (0.47 g, 7.2 mmol) in 25 mL of anhydrous
DMSO. The mixture was stirred for an additional 2.5 h at
20 °C and worked-up as indicated for azide 11. The resulting
product mixture was chromatographed on a column with silica
gel (using a hexane—AcOEt mixture, 10 : 1, as the eluent); this
gave successively benzoyl azide (0.1 g), diazide 13 (0.2 g), and
dichloro derivative 14 (0.12 g)18.
2,2,5,5-Tetramethyl-4-(1,2-dioxo-2-phenylethyl)-3-imid-
azoline-1-oxyl (15). A 5% solution of HCl was added dropwise
to a stirred suspension of imine 2a (0.1 g) in 3 mL of MeOH to
ðH 1. The mixture was stirred for an additional 10 min and the
precipitate of diketone 17 was filtered off, washed with water,
and dried.
1-Hydroxy-2,2,5,5-tetramethyl-4-(1,2-dioxo-2-phenyl-
ethyl)-3-imidazoline (18). A mixture of imine 2a (0.3 g,
1.1 mmol) and NaBH4 (0.013 g, 0.33 mmol) in 10 mL of EtOH
was stirred for 1 h at 20 °C, then an additional NaBH4 (0.013 g,
0.33 mmol) was added, and stirring was continued for an
additional 2 h. The solution was concentrated, water (5 mL)
was added to the residue, and the product was extracted with
CHCl3. The extract was dried with MgSO4, the solution was
concentrated, and compound 18 was isolated by preparative
TLC on silica gel using a 30 : 1 CHCl3—MeOH mixture as the
eluent.
2,2,3,5,5-Pentamethyl-4-(2-oxo-2-phenyl-1-chloroethyl-
idene)imidazolidine-1-oxyl (7). N-Chlorosuccinimide (0.27 g,
2 mmol) was added to a solution of 2,2,3,5,5-pentamethyl-4-
phenacylideneimidazolidin-1-oxyl (0.55 g, 2 mmol), prepared
3,4-Dihydroximino-5,5-dimethyl-2-phenylpyrroline 1-oxide
(19). Sodium methoxide (0.53 g, 10 mmol) and then imine 2a

Synthesis of monoimines of α-diketones
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 5, May, 2001
881
(0.67 g, 2.5 mmol) were added to a solution of NH2OH•HCl
(1.05 g, 15 mmol). The resulting mixture was kept for 24 h at
20 °C and concentrated. Water (5 mL) was added to the
residue, the precipitate of dioxime 19 was filtered off, washed
with water, and dried. 1H NMR (DMSO-d6), δ: 1.53 (s, 6 H,
5,5-Me2); 7.50 (m, 5 H, C6H5); 12.14 (s, 2 H, NOH). 13C NMR
(DMSO-d6), δ: 24.8 (5,5-Me2); 72.3 (C(5)); 127.0, 128.8,
129.2, 129.9 (C6H5); 136.6 (C(2)); 140.85, 147.9 (C=N).
Dioxime 19 was oxidized to give a mixture of furoxans 20 by
treatment of 19 (0.2 g, 0.9 mmol) with MnO2 (1 g, 11.4 mmol)
in CHCl3 (stirring for 1 h at 20 °C). The reaction mixture was
filtered through a silica gel layer (10 cm) and the solution was
concentrated. The 13C NMR spectrum (CDCl3) corresponds to
published data.11 1H NMR (CDCl3), δ: 1.76 (s, 6 H, Me2,
20´); 1.82 (s, 6 H, Me2, 20″); 7.50 (m, 3 H, C6H5, 20´+20″);
8.40 (m, 2 H, C6H5, 20″); 8.60 (m, 2 H, C6H5, 20´); the ratio
20´ : 20″ = 1.5 : 1.
2-(2,2,5,5-Tetramethyl-1-oxyl-3-imidazolin-4-yl)-3-phenyl-
quinoxaline (21). A solution of imine 2a (0.3 g, 1 mmol),
î-phenylenediamine (0.12 g, 1 mmol), and a small amount of
TsOH•H2O (∼10 mg) in 5 mL of EtOH was refluxed for 2 h
and concentrated. Compound 21 was isolated by chromatogra-
phy on a column with Al2O3 using CHCl3 as the eluent.
The reaction of 2a with ethylenediamine under similar
conditions gave dihydropyrazine 22, which was purified by
chromatography on a column with silica gel using CHCl3 as the
eluent.
were applied over crystal faceting (transmission 0.97—0.99).
The structure was solved by the direct method using the
SHELXS-86 program and refined using the SHELXL-97 pro-
gram by the least-squares method in the full-matrix anisotropic
or isotropic (for H atoms) approximation to wR2 = 0.0994,
S = 1.042 for all reflections (R = 0.0352 for 1975 F0 > 4σ).
References
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2-(2,2,5,5-Tetramethyl-1-oxyl-3-imidazolin-4-yl)-3-phenyl-
pyrazine (23) was prepared by oxidation of dihydropyrazine 22
by MnO2 (10 mmol of the oxidant per mmol of the substrate)
in CHCl3 for 10 min and purified by chromatography on a
column with silica gel using CHCl3 as the eluent.
9. I. A. Grigor'ev, V. I. Mamatyuk, G. I. Shchukin, V. V.
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Synthetic Chemistry of Stable Nitroxides, CRC Press, Boca
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Izv. Sib. Otd. Akad. Nauk SSSR, Ser. Khim. Nauk [Bull.
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5-(2,2,5,5-Tetramethyl-1-oxyl-3-imidazolin-4-yl)-4-phenyl-
imidazole (24). A solution of imine 2a (0.1 g) and 0.2 mL of
formalin in 5 mL of MeOH saturated with ammonia at 20 °C
was refluxed for 2 h and concentrated. Water (1 mL) and a 1 : 3
ether—hexane mixture were added to the residue. On tritura-
tion, imidazole 24 crystallized and the precipitate was fil-
tered off.
4-(2,2,5,5-Tetramethyl-1-oxyl-3-imidazolin-4-yl)-2,5-di-
phenyloxazole (25) and 6-(2,2,5,5-tetramethyl-1-oxyl-3-imid-
azoline-4-yl)-3,5-diphenyl-1,2,4-triazine (26). A solution of
benzamidine hydrochloride (0.16 g, 1 mmol) in 5 mL of
MeOH was made alkaline to ðH 11 by sodium methoxide,
imine 2a (0.3 g, 1 mmol) was added, and the resulting mixture
was refluxed for 2 h. The solution was concentrated and the
residue was chromatographed on a column with silica gel using
CHCl3 as the eluent; this gave successively oxazole 25 and
triazine 26.
2,2,5,5-Tetramethyl-4-(1-benzoylhydrazono-2-oxo-2-phe-
nylethyl)-3-imidazoline-1-oxyl (27). A mixture of imine 2a
(0.5 g, 1.8 mmol) and benzoylhydrazine (0.24 g, 1.8 mmol) in
10 mL of EtOH was heated until the compounds dissolved and
the solution was kept for 30 h at 20 °C and concentrated.
Compound 27 was isolated by chromatography on a column
with silica gel using a 1 : 1 ether—hexane mixture as the eluent.
X-ray diffraction analysis of compound 2a was performed
on a Bruker P4 diffractometer with a graphite monochromator
(Mo-Kα radiation). The crystals of compound 2a are mono-
clinic: a = 8.6964(8), b = 15.423(2), c = 11.621(1) Å,
β = 109.862(6)°, V = 1465.9(3) Å3, space group P21/s,
–1
C15H18N3O2, Z = 4, dcalc = 1.234 g cm–3, µ = 0.084 mm
,
sample dimensions 0.22½0.25½0.88 mm. The intensities of
2488 independent reflections were measured using θ/2θ scan
mode in the region of 2θ < 50°. The absorption corrections
Received July 11, 2000;
in revised form December 9, 2000