Heterocyclization Reaction of α-Imino Carbonyl Compounds - Derivatives of 2,5-Dihydro-1H-imidazole Nitroxides

Article abstract of DOI:10.1002/ejoc.200300212

α-Imino carbonyl compounds - derivatives of 3-imidazoline nitroxides - were found to undergo heterocyclization reactions, yielding oxazole and 1,3,5-triazine derivatives. The most probable course of the reaction was suggested by the radioactive label meth

Full text of DOI:10.1002/ejoc.200300212

FULL PAPER
Heterocyclization Reaction of α-Imino Carbonyl Compounds ؊ Derivatives of
2,5-Dihydro-1H-imidazole Nitroxides
Galina A. Roshchupkina,*[a] Natalie V. Pervukhina,[b] Tatjana V. Rybalova,[c]
Yuri V. Gatilov,[c] Alexey B. Burdukov,[b] and Vladimir A. Reznikov[c]
Keywords: Heterocycles / Ketones / Luminescence / Nitroxides / Radiochemistry
α-Imino carbonyl compounds − derivatives of 3-imidazoline
synthesized were verified by X-ray analysis of the mixed-
nitroxides − were found to undergo heterocyclization reac- ligand complexes with copper hexafluoroacetylacetonate.
tions, yielding oxazole and 1,3,5-triazine derivatives. The
most probable course of the reaction was suggested by the
radioactive label method. The structures of the heterocycles
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Stable nitroxides have been the subject of intense investi- nitroxide molecules can be generalized to other classes of
gation during the last four decades. The reason for this organic compounds and so is of general interest.
interest was initially the singularity of this class of com-
pounds, connected to their paramagnetism.[1] Very soon,
though, chemists found out that the majority of organic
reactions involving nitroxides as substrates proceed to a
great extent just the same as with diamagnetic com-
pounds.[2] In such a transformation, a nitroxyl group is sim-
ply one more functional group in a molecule, often not tak-
ing part in the transformations and very rarely (but not
always[3]) even affecting them. The next phase of the devel-
opment of nitroxide chemistry was, and currently is, dic-
tated by very wide possibilities of application of nitroxides
for solving different scientific problems that in fact are out-
side the field of synthetic organic chemistry. The main ap-
plications of nitroxides lie in the fields of biochemistry, bio-
physics, and molecular biology (spin labels and probes
etc.).[4] Another very important field is the use of nitroxides
as paramagnetic ligands for coordination chemistry. In this
connection the synthesis of nitroxides of different topolog-
ies, and also differing in the presence of various functional
groups in the molecule, is an active field of study. It also
should be noted that information obtained from investi-
gation of the chemical properties of functional groups in
Previously we had found that treatment of imino ketone
1a with benzamidine results in the formation of compounds
2a and 3a. The structures of oxazole 2a and triazine 3a
were not determined unambiguously Ϫ the positions of the
heteroatoms in the heterocycles formed were attributed ar-
bitrarily, based only on the scheme, which is speculative in
nature. The formation of compounds 2a and 3a was attri-
buted to the reduction or oxidation of corresponding inter-
mediates, formed as a result of nucleophilic attack of the
amidine nitrogen atom at the carbonyl atoms of the imino
or carbonyl groups in the molecule of 1a (Scheme 1).[5]
Scheme 1
[a]
Novosibirsk State University,
Pirogova str. 2, 630090 Novosibirsk, Russian Federation
[b]
Institute of Inorganic Chemistry, Siberian division of the
Russian Academy of Sciences,
Akad. Lavrent’ev ave. 3, 630090 Novosibirsk, Russian
Federation
In the context of some current work the investigation of
a transformation as described above was extended, and
compound 3a was in fact shown to be a 1,3,5-triazine de-
rivative. The structure of triazine 3a was determined by X-
ray diffraction analysis of the mixed-ligand complex of 3a
[c]
N. N. Vorozhtsov Institute of Organic Chemistry, Siberian
Division of the Russian Academy of Sciences,
Akad. Lavrent’ev ave. 9, 630090 Novosibirsk, Russian
Federation,
E-mail: mslf@nioch.nsc.ru
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DOI: 10.1002/ejoc.200300212
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Heterocyclization of α-Imino Carbonyl Compounds
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Scheme 2
Figure 1. Crystal structure of the copper complex 4 of 4-(4,6-di-
phenyl-1,3,5-triazin-2-yl)-2,2,5,5-tetramethyl-2,5-dihydroimidazol-
1-oxyl (3a) and hfac
and copper hexafluoroacetylacetonate [Cu(hfac)2] (4), the
structure of which is shown in Figure 1.
It should be noted that 1,3,5-triazine formation could
only be the result of a skeleton transformation of the start-
ing molecule 1a and, consequently, that the previously pos-
tulated reaction scheme for 1a and benzamidine could not
be entirely valid.
The methyl-substituted α-imino ketone 1b, unlike imine
1a, exists as a dimer in both its solution and its crystalline
forms, and both diastereomeric forms are present in equilib-
rium in solution.[5] Thus, one could suppose that the chemi-
cal behavior of 1b should be similar to that of 1a. In spite
of this, treatment of 1b with benzamidine was found to pro-
ceed with formation of oxazole 2b, which does not have a
phenyl group attached to the oxazole cycle, and amide 5.
Moreover, treatment of 1b with different nucleophiles Ϫ
ethylenediamine, o-phenylenediamine, triethylamine, am-
monium acetate Ϫ resulted in the formation of the same set
of products: oxazole 2b and amide 5 (cf. ref.[5]). Thus, the
nucleophile in this transformation seems to act simply as a
base (Scheme 2). The structure of oxazole 2b was deter-
mined by single-crystal X-ray diffraction analysis of the
mixed-ligand complex 6 of 2b and Cu(hfac)2, the structure
being shown in Figure 2. It should be noted that the IR and
UV spectra of compounds 2a and 2b are very similar, which
could indicate that these compounds possess similar struc-
tures Ϫ imidazoline substituent in both cases being at-
tached to the 4-position of the oxazole ring Ϫ and, hence,
despite the incorrect interpretation of the reaction pathway
of 1a with benzamidine, that the structure of 2a in ref.[5]
was determined correctly.
Figure 2. Crystal structure of the copper complex 6 of 4-(2,5-di-
methyloxazol-4-yl)-2,5,5-trimethyl-2,5-dihydroimidazol-1-oxyl (2b)
and hfac (fluorine atoms omitted)
The first step of the reaction is apparently a depro-
tonation of the hydroxy group, which results in dihydro-
pyrazine heterocycle cleavage. Subsequent hydrolysis of in-
termediate nitrile 8 results in the formation of an amide 5
(cf. ref.[6]), and cyclization of intermediate 7 results in the
oxazole heterocycle closure.
Imine 1c, on being heated in the presence of triethylamine
in ethanol solution, is transformed into nitrile 8 and ester
9. Heating of imine 1a in ethanol in the presence of triethyl-
amine results in the formation of oxazole 2a and amide 5
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G. A. Roshchupkina et al.
FULL PAPER
idine the only isolated product was the corresponding tri-
azine 3c (Scheme 4).
Scheme 4
It might thus be assumed that amidine participates at le-
ast in the formation of the triazine heterocycle, but it is
not obvious whether, in the reaction between imine 1a and
benzamidine, both, one, or neither of the phenyl groups in
the oxazole cycle originate from the benzamidine molecule,
or whether some of them come from the starting material
Scheme 3
along with some quantities of compound 2c (Scheme 3). 1a. The formation of the triazine 3 could proceed either as
The IR and UV spectra of 2c are similar to those of ox- a result of the reaction of an intermediate nitrile 8 with
azoles 2a and 2b, and its EPR spectrum is a quintuplet with 2 equiv. of amidine (path A), or from the intermediate 7,
hfsc aN ϭ 14.6 G (in CHCl3).
postulated for the explanation of the formation of oxazole
These data show that, although imine 1a exists mainly in 2 (path B) (cf. Scheme 2). It could also not be ruled out
the monomeric form, some concentration of corresponding that both routes might take place concurrently (Scheme 5).
dimer 1b is also present in solution. This concentration is
The lack of formation of the triazine 3a in the reaction
obviously low (EPR spectra of 1a correspond to a monor- between the nitrile 8 and benzamidine is an indirect argu-
adical),[5] but its sufficiently high reactivity provides the ment against the existence of route A. At the same time, it
possibility for its transformation into oxazole 1a and amide should be noted that the ratio of the oxazole 2a and the
5, similarly to the case of the dimeric imine 1b. In this con- triazine 3a formed in the reaction between imine 1a and
nection the question that arises is whether the formation of benzamidine depends on the ratio of reagents Ϫ an increase
oxazole 2a and triazine 3a is a result of reaction of benzam- in the excess of benzamidine results in an increase in the
idine with 1a as a nucleophile, or whether benzamidine acts comparative proportion of the triazine 3a. At an equimolar
as a base and the products form without its direct partici- ratio of reagents, the yields of the oxazole 2a and the tri-
pation.
azine 3a are almost equal (18 and 17%, respectively). If the
The reaction between imine 1a and acetamidine was ratio of imine 1a to benzamidine is 1:1.5, the yields of the
shown to proceed to give rise to diphenyl-substituted ox- oxazole 2a and triazine 3a are 5 and 20%, respectively. This
azole 2a along with the expected monophenyl-substituted could be interpreted as a result of two competitive pro-
triazine 3b. On treatment of imine 1a with p-bromobenzam- cesses: intermediate 7 being able to react with amidine to
Scheme 5
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Heterocyclization of α-Imino Carbonyl Compounds
FULL PAPER
give the triazine 3a or to undergo intramolecular cyclization
with formation of the oxazole 2a.
To clarify the question of the origins of the phenyl groups
in the molecules of the oxazole 2a and the triazine 3a, a
sample of benzamidine labeled with 14C at the amidine
group was synthesized and used for study of the reaction
with the imine 1a.
Direct measurement of the β-activities of the synthesized
radioactive oxazole 2a* and triazine 3a* {Beckman β-mate
scintillation counter with employment of a liquid scintil-
lator [composition: dioxane, naphthalene, 2,5-diphenylox-
azol (POP) and 1,4-bis(5-phenyloxazol-2-yl)benzene (PO-
POP)], concentration of 2a* and 3a* was ca. 10Ϫ2 )} failed
due to effective scintillation quenching. This phenomena
could be explained by two factors: the first being the ab-
sorption of light by the nitroxyl group in the range in which
scintillator photoemission takes place.[7] The second, that
nitroxides are well known as quenchers of excited states,[8]
also could be a reason for the diminution of measurable
scintillation.
Figure 3. Fluorescence spectra (methanol, 10Ϫ4 ): 1 Ϫ back-
ground; left: 2 Ϫ methoxy-substituted triazine 3d; center: 2 Ϫ tria-
zine 3a; right: 2 Ϫ oxazole 2a, 3 Ϫ oxazole 2a after addition of
hydrazine hydrate (3 equiv.)
However, the addition of a nitroxide Ϫ 2,2,5,5-tetra-
methyl-4-phenyl-2,5-dihydroimidazol-1-oxyl (2Ϫ5 ϫ 10Ϫ2 radiation, with a maximum peak of emission at λem
ϭ
) Ϫ, that does not contain the oxazole or triazine frag- 428 nm, excitation being at λex ϭ 380 nm. In contrast to
ment, to the scintillator solution causes only a slight de- this, neither the paramagnetic triazine 3a nor the oxazole
crease in scintillator efficacy.
2a display fluorescence ability. It should be noted that the
This implies that in the case of oxazole 2a* and triazine fluorescence value of a sample of oxazole 2a changes insig-
3a* samples, some other Ϫ more efficient Ϫ mechanism of nificantly on addition of excess hydrazine hydrate (Fig-
quenching is operative. The high efficiency of quenching ure 3), indicating that even trace amounts of the radical
hints that the radical may intervene at some ‘‘bottleneck’’ provide effective quenching. Thus, it is reasonable to sup-
of scintillator emission, as the concentration of the radical pose that 2a and 3a suppress the scintillation of the solu-
(ca. 4 mmol/L) is much less then that of the primary (naph- tions through effective intramolecular quenching of scintil-
thalene, ca. 1.3 ) and secondary (POP, ca. 30 mmol/L) lation by the nitroxyl group.
scintillators. This ‘‘bottleneck’’ may be the transmission of
In this connection, samples of β-active benzamidine hy-
light from POP to wavelength shifter POPOP, the concen- drochloride monohydrate, oxazole 2a*, and triazine 3a*
trations of the latter being noticeably smaller than the con- were converted into sodium carbonate by combustion and
centrations of 2a* and 3a* in the measured solutions (ca. their activities were measured by use of the scintillation
0.8 mmol/L). The compounds 2a* and 3a* could interfere counter. The activity of the sample obtained from 2.104 mg
with the scintillation if their heterocyclic substituents were (5.65 µmol) triazine 3a was 10.7 Ϯ 1.2 counts/min, from
to possess photoluminescent properties similar to those of 2.116 mg (5.87 µmol) oxazole 2a 3.6 Ϯ 1.8 counts/min, and
POPOP. This looks quite reasonable, at least in the case of from benzamidine (2.178 mg, 12.5 µmol) 30.0 Ϯ 1.4 counts/
2a, which contains a diphenyloxazole function Ϫ exactly min. The activities of the oxazole 2a* and triazine 3a*
the same as in POPOP. We undertook a special study on samples in the case of involvement of one phenyl group
this point and tried to prepare diamagnetic analogues of 2a from benzamidine would be expected to be 14.3 Ϯ 1.8 and
and 3a by treatment of the methoxy-substituted diamag- 13.7 Ϯ 1.8 counts/min, respectively. Thus, oxazole 2a arises
netic imine 1d with benzamidine (Scheme 6).
mainly without direct participation of benzamidine accord-
ing to the mechanism shown in Scheme 2, although the
pathway shown in Scheme 1 also takes place to some extent.
As to triazine 3a formation, the most probable seems to be
pathway B, as shown in Scheme 5. In order to exclude the
possibility of exchange of phenyl substituents in oxazole 2a
and triazine 3a molecules as the result of subsequent reac-
tion of these heterocycles with benzamidine, 2a and 3a were
treated with p-methoxybenzamidine under the conditions
of their formation. Analysis of the products obtained by
Scheme 6
Unfortunately, the only product isolated was the corre- high-resolution mass spectrometry shows no exchange in
sponding 1-methoxy-substituted triazine 3d.
both cases.
Measurement of the fluorescence spectra of triazine 3d
Thus, the reaction between imine 1a and benzamidine
shows emission in a wide range of excitatory UV ir- has been shown to proceed mainly through the formation
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G. A. Roshchupkina et al.
FULL PAPER
Reaction between 1a and Benzamidine: Imine 1a (0.5 g, 1.8 mmol)
was added to a solution of benzamidine hydrochloride monohydr-
ate (0.48 g, 2.8 mmol) in methanol (15 mL). The system was alkal-
ized to pH ϭ 11 with sodium methoxide, and the resulting solution
was kept at 20 °C for 24 h. The solvent was removed in vacuo, and
the residue was dissolved in water (10 mL) and extracted with
CHCl3 (3 ϫ 20 mL). The combined extracts were dried with
MgSO4, the solution was concentrated in vacuo, and a mixture of
products 2a and 3a was separated on alumina, with a hexane/ethyl
acetate mixture (5:1) as eluent (cf. ref.[5]).
of intermediate 7, which then either undergoes cyclization,
giving rise to oxazole 2a, or reacts with amidine to give
triazine 3a (Scheme 7). Other routes of formation of prod-
ucts 2, 3 are inconsequential.
4-(2,5-Diphenyloxazol-4-yl)-2,2,5,5-tetramethyl-2,5-dihydroimid-
azol-1-oxyl (2a): The yield was 18%, m.p. 146Ϫ148 °C (from hex-
ane). IR (KBr): ν˜ ϭ 1615, 1600, 1580 (CϭN, CϭC) cmϪ1. UV
(ethanol): λmax (lg ε) ϭ 233 (4.11), 286 nm (4.15). MS: calcd. for
C22H22N3O2 m/z ϭ 360.17119, found 360.17045.
4-(4,6-Diphenyl-1,3,5-triazin-2-yl)-2,2,5,5-tetramethyl-2,5-di-
hydroimidazol-1-oxyl (3a): The yield was 17%, m.p. 188Ϫ190 °C
(from hexane/ethyl acetate). IR (KBr): ν˜ ϭ 1621, 1661 (CϭC, Cϭ
N) cmϪ1. UV (ethanol): λmax (lg ε) ϭ 273 nm (4.48). C22H22N5O
(372.2): calcd. C 70.9, H 5.9, N 18.8; found C 70.5, H 5.9, N 18.7.
Scheme 7
Treatment of imine 1a with radioactive benzamidine was carried
out under identical conditions and with the same quantities of re-
agents.
Experimental Section
General: IR spectra were recorded with a Bruker IFS 66 spec-
trometer as KBr pellets (concentration 0.25%, thickness of a pellet
1 mm). UV spectra were measured with a Specord M-40 spectro-
photometer in EtOH. 1H NMR spectra were run with a Bruker
WP 200 SY spectrometer with 5% solutions in CDCl3 and HMDS
as the internal standard. High-resolution mass spectra were re-
corded with a Finnigan MAT 8200 mass spectrometer with direct
sample injection with resolution 10000. Melting points were meas-
ured with a ‘‘Boetius’’ plate and are uncorrected. DMSO was dried
with NaOH and distilled in vacuo from BaO. Measurement of the
β-activity was carried out with a Beckman β-mate II scintillation
counter in a dioxane solutions containing naphthalene (100 g/L),
2,5-diphenyloxazole (7 g/L), and 1,4-bis(4-methyl-5-phenyloxazol-
2-yl)benzene (0.3 g/L). Dioxane for measurements was dried with
NaOH and distilled from sodium wire before use. Fluorescence
spectra were measured with a Shimadzu RF-520 spectrophoto-
meter in ethanol. The synthesis of imines 1a, 1b, 1c, and 1e was
published in ref.[5] Benzamidine enriched with 14C at the amidine
group carbon atom was synthesized from Ph14CO2H benzoic acid
according to the standard procedure shown in Scheme 8). Benzoyl
chloride was synthesized by use of an aqueous solution containing
radioactive benzoic acid. A mixture of aqueous radioactive benzoic
acid (5 mL), benzoic acid (10 g, 82 mmol), and benzene (100 mL)
2-(1-Methoxy-2,2,5,5-tetramethyl-2,5-dihydro-1HϪimidazol-4-yl)-
4,6-diphenyl-1,3,5-triazine (3d): Similarly, treatment of imine 1d
(1 g, 3.5 mmol) with benzamidine hydrochloride monohydrate (1 g,
5.7 mmol) resulted in the formation of 3d in 35% yield, m.p.
160Ϫ161 °C (from hexane). IR (KBr): ν˜ ϭ 2810 (OCH3), 1518
(CϭC, CϭN) cmϪ1. UV (ethanol): λmax (lg ε) ϭ 274 nm (4.30).
C23H25N5O (387.2): calcd. C 71.3, H 6.5, N 18.1; found C 71.0, H
6.4, N 18.0.
X-ray Crystallography of Compounds 4 and 6: Atomic coordinates,
thermal parameters, bond lengths and bond angles have been de-
posited at the Cambridge Crystallographic Data Center. CCDC-
207326 and -207327 contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; Fax: (internat.)
ϩ 44-1223/336-033; E-mail:
deposit@ccdc.cam.ac.uk]. It may be noted that according to CSD[9]
[10]
˚
the CuϪO distance to axial oxygen O(5) is shorter than 2.232 A,
the minimum value in analogous Cu(HFA)2 complexes with similar
five-membered metallacycles.
was heated at reflux in a DeanϪStark apparatus for 12 h. SOCl2 2-Imino-2-(1-methoxy-2,2,5,5-tetramethyl-2,5-dihydro-1H-imidazol-
(12 mL, 164 mmol) was added to the resulting solution after cool-
ing, and the mixture was heated at reflux for 8 h. The benzene was
distilled off, and the residue was distilled in vacuo to give benzoyl
chloride (9.5 g, 80%), b. p. 105Ϫ107 °C (25 Torr). The synthesis
of benzamidine hydrochloride monohydrate was carried out in a
standard manner.
4-yl)-1-phenyl-ethanone (1d): Enaminone 10 (1.3 g, 4.2 mmol) was
added to a solution of NaN3 (0.55 g, 8.4 mmol) in DMSO (10 mL).
The reaction mixture was stirred at 20 °C for 2.5 h, then cooled to
0 °C and poured into cold brine (40 mL). The resulting mixture
was extracted with CHCl3 (3 ϫ 20 mL), and the combined extracts
were washed with brine and water and dried with MgSO4. The
solution was concentrated to give imine 1d (1.26 g, almost 100%),
m.p. 73Ϫ74 °C (from hexane). IR (KBr): ν˜ ϭ 3206 (NH), 2811
(OϪCH3), 1669 (CϭO) 1608, 1597, 1580 (CϭC, CϭN) cmϪ1. UV
(ethanol): λmax (lg ε) ϭ 253 nm (4.06). C16H21N3O2 (287.2): calcd.
C 66.9, H 7.4, N 14.6; found C 66.8, H 7.5, N 14.7.
2-Chloro-2-(1-methoxy-2,2,5,5-tetramethylimidazolidin-4-ylidene)-1-
phenylethanone (10): NCS (0.64 g, 4.7 mmol) was added to a solu-
tion of 2-(1-methoxy-2,2,5,5-tetramethylimidazolidin-4-ylidene)-1-
phenylethanone[11] (1.3 g, 4.7 mmol) in CCl4 (20 mL), and the re-
Scheme 8
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Heterocyclization of α-Imino Carbonyl Compounds
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sulting mixture was stirred at 20 °C for 30 min. Precipitated suc-
cinimide was filtered off, the filtrate was concentrated to dryness
(0.25 g, 90%) and amide 5 (0.13 g, 65%). 2b: M.p. 136Ϫ139 °C
(from hexane). IR (KBr): ν˜ ϭ 1614 (CϭCϪCϭN) cmϪ1. UV (etha-
nolϭ: λmax (lg ε) ϭ 252 (4.14), 372 nm (4.00). C12H18N3O2 (236.1):
in vacuo, and the residue was recrystallized from hexane to give 10
1
(1.45 g, almost 100%). M.p. 127Ϫ129 °C (from hexane). H NMR calcd. C 61.0, H 7.6, N 17.8; found C 60.6, H 7.9, N 17.8. MS:
(200 MHz, CDCl3): δ ϭ 1.48 (s, 6 H), 1.62 [br. s, 6 H, 2,5-(CH3)2],
3.70 (s, 3 H, OCH3), 7.37 (m, 3 H), 7.57 (m, 2 H, C6H5) ppm. IR
(KBr): ν˜ ϭ 3210 (NH), 1594, 1538 (OϭCϪCϭCϪN, CϭC, Cϭ
N) cmϪ1. UV (ethanol): λmax (lg ε) ϭ 243 (3.58), 343 nm (4.69).
C16H21ClN2O2 (308.8): calcd. C 62.24, H 6.81, N 9.08; found C
62.53, H 6.85, N 9.07.
calcd. for C12H18N3O2 m/z ϭ 236.13989, found 236.13942.
4-[4-(4-Bromophenyl)-6-phenyl-1,3,5-triazin-2-yl]-2,2,5,5-tetra-
methyl-2,5-dihydro-imidazol-1-oxyl (3c): Imine 1a (0.5 g, 1.8 mmol)
was added to a solution of 4-bromobenzamidine hydrochloride
(0.42 g, 1.8 mmol) in methanol (10 mL). This was alkalized to
pH ϭ 11 with sodium methoxide, and the reaction mixture was
kept at 20 °C for 24 h, and then concentrated. CHCl3 (20 mL) was
added to the residue, and the chloroform solution was washed with
0.5% HCl solution and dried with MgSO4. The solution was con-
centrated and triazine 3c was purified by chromatography on silica
gel with CHCl3 as eluent. The yield was 0.16 g (20%), m.p.
187Ϫ192 °C (from ethanol). IR (KBr): ν˜ ϭ 1590, 1578, 1515 (Cϭ
C, CϭN) cmϪ1. UV (ethanol): λmax (lg ε) ϭ 284 nm (4.24).
C22H21BrN5O (450.1): calcd. C 58.5, H 4.7, N 15.5; found C 58.1,
H 4.5, N 15.1.
Treatment of Imine 1a with Triethylamine: A solution of imine 1a
(0.2 g, 0.74 mmol), triethylamine (0.1 mL, 0.72 mmol), and p-tolu-
enesulfonic acid (5 mg) in ethanol (20 mL) was heated at reflux
for 12 h and then concentrated to dryness. Reaction products were
isolated by preparative thin layer chromatography on silica gel with
CHCl3/methanol (30:1) as eluent. The yield of oxazole 2a was
0.06 g (45%), of oxazole 2c 0.01 g (6%), and of amide 5 0.006 g
(8%).
Compound 2c: M.p. 223Ϫ225 °C (from hexane/ethyl acetate), IR
(KB): ν˜ ϭ 1610, 1578 (CϭCϪCϭN) cmϪ1. UV (ethanol): λmax (lg
ε) ϭ 305 nm (4.05). C23H29N5O3 (423.2): calcd. C 65.2, H 6.9, N
16.5; found C 65.2, H6.7, N16.3.
[1]
[1a] A. R. Forrester, J. M. Hay, R. H. Thomson, Organic Chem-
istry of Stable Free Radicals, Academic Press, New York, 1968.
[1b] E. G. Rozantsev, Free Nitroxyl Radicals, Plenum Press, New
[1c]
York, 1970.
A. L. Buchachenko, Stable Radicals. Electron
On heating of a solution of imine 1c (0.2 g, 0.73 mmol), triethyl-
amine (0.1 mL, 0.7 mmol), and p-toluenesulfonic acid (5 mg) in
ethanol (20 mL) for 1 h, a mixture of nitrile 8 and ester 9 was ob-
tained. It was separated by preparative thin-layer chromatography
on silica gel with CHCl3/methanol (30:1) as eluent. The yield of 8
was 0.013 g (10%) and of 9 0.015 g (10%) The structures of 8 and
9 were confirmed by comparison with authentic samples.[7]
Structure, Reactivity and Applications, Khimia, Moscow, 1973
(in Russian).
[2]
[3]
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B. Volodarsky), CRC Press, Boca Raton, FL, 1989, chapter 5.
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Treatment of Imine 1a with Acetamidine. 2,2,5,5-Tetramethyl-4-(4-
methyl-6-phenyl-1,3,5-triazin-2-yl)-2,5-dihydroimidazol-1-oxyl (3b):
Imine 1a (0.5 g, 1.8 mmol) was added to a solution of acetamidine
hydrochloride in ethanol (10 mL). This was alkalized to pH ϭ 11
with sodium methoxide and the resulting mixture was kept at 20
°C for 24 h and then heated at 70 °C for 5 h. The solution was
concentrated, water (5 mL) was added to the residue, and the re-
sulting mixture was extracted with CHCl3 (3 ϫ 10 mL). The com-
bined extracts were dried with MgSO4, the solution was concen-
trated, and the reaction products were isolated by chromatography
on silica gel with CHCl3/methanol (30:1) as eluent, with oxazole
2a (0.17 g 50%) and 3b (0.085 g, 15%) being eluted sequentially. 3b:
M.p. 125Ϫ128 °C (aqueous ethanol). IR (KBr): ν˜ ϭ 1600, 1586,
1536, 1518 (CϭC, CϭN) cmϪ1. UV (ethanol): λmax (lg ε) ϭ 237
(3.89), 263 nm (3.96). C17H20N5O (310.2): calcd. C 63.9, H 6.5, N
21.9; found C 64.1, H 6.3, N 22.0.
J. F. W. Keana, Nitroxide spin labels in Spin Labeling in
Pharmacology (Ed.: J. L. Holtzmann), Academic Press, Or-
[4b]
lando, FL, 1984.
L. J. Berliner, J. Reuben (Eds.), Spin labe-
ling: Theory and Applications, vol. 1, 2, 8 and 14, Plenum Press,
New York, 1976, 1979, 1989 and 1998; L. B. Volodarsky (Ed.),
Imidazoline Nitroxides, V, II (‘‘Applications’’), CRC Press, Boca
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V. A. Reznikov, G. I. Roshchupkina, T. V. Rybalova, Yu. V.
Gatilov, Russ. Chem. Bull., Int. Ed. 2001, 50, 874.
L. B. Volodarskii, G. A. Kutikova, V. S. Kobrin, R. Z. Sagdeev,
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Properties of Heterocyclic Nitroxides, in Imidazoline Nitroxides,
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11, 493.
[7]
[8]
[9]
Treatment of Imine 1b with Triethylamine. 4-(2,5-Dimethyloxazol-
4-yl)-2,5,5-trimethyl-2,5-dihydroimidazol-1-oxyl (2b): A solution of
imine 1b (0.5 g, 2.4 mmol), triethylamine (0.3 mL, 2.4 mmol), and
p-toluenesulfonic acid (10 mg) in ethanol (20 mL) was heated at
reflux for 2 h and then concentrated. A mixture of oxazole 2b and
amide 5 was separated by preparative thin-layer chromatography
on silica gel with CHCl3/methanol (30:1) as eluent to give 2b
[10]
[11]
V. A. Reznikov, L. B. Volodarsky, Khim. Geterosikl. Soedin.
1990, 921; Chem. Heterocycl. Compd. 1973 (Engl. Transl.).
Received April 2, 2003
Eur. J. Org. Chem. 2003, 4432Ϫ4437
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