N-vinyl-nitroimidazole cycloadditions: Potential routes to nucleoside analogues

Article abstract of DOI:10.1055/s-2005-872083

Cycloaddition reactions of 4-nitro- and 5-nitro-1-vinylimidazoles have been investigated. The cycloadducts obtained are potential intermediates for synthesis of purine nucleoside analogues via reduction to the corresponding aminoimidazoles. A byproduct obtained using benzonitrile oxide as 1,3-dipolarophile has been identified as a novel tricyclic isomer 12 of the cycloadduct 11. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-872083

PAPER
2695
N-Vinyl-Nitroimidazole Cycloadditions: Potential Routes to Nucleoside
Analogues
N
-Vinyl-Nitroimi
u
dazole Cyclo
s
a
dditionssell Clayton, Christopher A. Ramsden*
Lennard-Jones Laboratories, School of Chemistry and Physics, Keele University, Keele, Staffordshire ST5 5BG, UK
Fax +44(1782)712378; E-mail: c.a.ramsden@chem.keele.ac.uk
Received 20 April 2005
NH2
Abstract: Cycloaddition reactions of 4-nitro- and 5-nitro-1-vi-
N
N
N
N
nylimidazoles have been investigated. The cycloadducts obtained
are potential intermediates for synthesis of purine nucleoside ana-
logues via reduction to the corresponding aminoimidazoles. A
byproduct obtained using benzonitrile oxide as 1,3-dipolarophile
has been identified as a novel tricyclic isomer 12 of the cycloadduct
11.
N
H
N
O2N
HO
O
OH
OH
3
4
Key word: nitroimidazole, vinylimidazole, 1,3-dipolar cycloaddi-
tions, isoxazoline, nucleoside analogues
N
N
A
N
B
C
O2N
N
4-Unsubstituted-5-aminoimidazoles 11 are useful synthet-
ic intermediates. Early workers claimed that these simple
amines are very unstable2 and, although they were impli-
cated in the anaerobic antibacterial activity of 5-nitroimi-
N
X
X
Y
Y
Z
Z
5
6
dazoles such as metronidazole (2)(R1 = Me, R2
=
CH2CH2OH),3 their chemistry remained largely unex-
plored. We have subsequently shown that 5-nitroimida-
zoles 2 are readily reduced to 5-aminoimidazoles 1
(Figure 1), which can be isolated4,5 or trapped by soft
electrophiles6 giving convenient precursors to purine nu-
cleosides and their analogues. Using this approach we
have reported the preparation of a variety of purine deriv-
atives and related heterocycles.6,7 We now report the re-
sults of an investigation of cycloaddition reactions of N-
vinyl-nitroimidazoles that are potential routes to nucleo-
side analogues.
Scheme 1
of selected N-vinyl derivatives of both 4- and 5-nitroimi-
dazoles and now report our findings.
Because of the ready availability of metronidazole 2 (R1 =
Me, R2 = CH2CH2OH) we initiated our studies by investi-
gating cycloadditions of the 2-methyl-1-vinyl derivative 9
(Scheme 2). This was prepared by treatment of the tosyl
derivative 7 with base using the procedure of Ross and co-
workers.8 Since 5-nitroimidazoles are electron-deficient
heterocycles and the nitrogen lone pair is in conjugation
with the nitro group, we made no assumptions about the
nature of the C=C bond and investigated potential reac-
tions with a range of dienes and 1,3-dipolarophiles. No
formation of the cycloadduct 8 occurred when the alkene
9 was reacted with freshly prepared cyclopentadiene, even
in the presence of acid catalysts (AlCl3, TiCl4, aq HCl).
Similarly, no cycloaddition products were identified using
phenyl azide or the four 1,3-dipoles RHC=(Me)N+X–
(X = O or CH2, R = H or Ph) under various conditions.
These negative results suggested that the imidazole 9 con-
tains an electron-rich vinyl substituent and we therefore
directed our attention to reactions with nitrile oxides (low
LUMO).
N
N
R1
R1
N
R2
N
R2
O2N
H2N
2
1
Figure 1
Inspection of Scheme 1 shows that the N-vinyl-5-nitro-
imidazole molecule 3 has the same molecular skeleton as
a central portion of purine nucleosides such as adenosine
(4). 1,3-Dipolar cycloaddition of the N-vinyl substituent
in principle gives sugar mimics 5 which can be further
elaborated, via the corresponding 5-aminoimidazoles, to
purine nucleoside analogues of general structure 6. We
have therefore investigated the preparation and chemistry
When compound 9 was reacted with propanenitrile oxide
(EtC≡N+O–), generated in situ by treatment of a mixture
of 1-nitropropane and phenyl isocyanate with a catalytic
amount of Et3N,9 a small amount of cycloadduct 10 was
isolated using column chromatography. The yield of this
product (< 3%) was too low for full characterization but
SYNTHESIS 2005, No. 16, pp 2695–2700
Advanced online publication: 20.07.2005
DOI: 10.1055/s-2005-872083; Art ID: P05405SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
5
1
the H NMR spectrum supported the structural assign-

2696
R. Clayton, C. A. Ramsden
PAPER
N
N
N
N
gen, and the anomeric CH signal at higher field. All other
aspects of the 13C spectrum were consistent with structure
11. The mass spectrum of the product 11 showed a weak
molecular ion [m/z (%) = 272 (1)] together with fragment
ions, corresponding to cleavage of the C(1¢)N bond, at
m/z (%) = 146 (26) and m/z (%) = 127 (100). The consti-
tution C13H12N4O3 was confirmed by microanalysis. The
similarity between the spectra of the products 10 and 11
strongly supports the structural assignment 10.
Me
Me
O2N
O2N
OTs
7
8
N
N
N
Me
Me
In an attempt to reduce dimerisation the preparation was
repeated using only a catalytic amount of Et3N with stir-
ring over excess solid NaHCO3. The yield slightly in-
creased but in this case the cycloadduct 11 was
accompanied by a second product (ca 9:1) that was sepa-
rated by chromatography. Initially we thought that this
minor product (mp 113 °C) was the regioisomer. Subse-
O2N
N
O2N
O
N
Et
9
10
1
quently, a more critical analysis of the H and 13C NMR
N
N
Me
spectra eliminated the regioisomer and suggested the un-
expected tricyclic structure 12. The 1H NMR spectrum of
this minor product shows a three proton doublet (J = 1 Hz)
at d = 1.35. This is at too high field to be a simple 2-meth-
yl-5-nitroimidazole signal (ca d = 2.5) and suggests a
methyl group attached to a saturated carbon atom. A sin-
glet at d = 8.30, which superficially appears to be an imi-
dazole 4-H signal, is not coupled with this methyl signal.
The product is clearly not an aromatic 5-nitroimidazole
and this is confirmed by the 13C NMR spectrum which
does not show a signal at ca 138 ppm, highly characteris-
tic of the C-5 carbon atoms of 5-nitroimidazoles.12 In ad-
dition to the phenyl protons, three other protons are
observed at d = 2.16 (ddd, J = 14, 4, 1 Hz), d = 3.70 (dd,
J = 14, 6 Hz) and d = 7.71 (dd, J = 6, 4 Hz). A DEPT spec-
trum confirmed that the protons at d = 2.16 and d = 3.70
are associated with a methylene group (JAB = 14 Hz,
CHAHB). One of these protons (d = 2.16) is weakly cou-
pled (J = 1 Hz) to the methyl substituent suggesting bond
Me
O2N
Ph
N
O2N
N
O
+
O
H
N
N
Ph
12
11
Scheme 2
ment 10. In particular the isoxazoline ring protons were
observed at d = 3.53 (J = 5, 18.5 Hz, CHCH2(trans)], 4.08
(J = 10, 18.5 Hz, CHCH2(cis)] and 7.33 (J = 5, 10 Hz,
CHCH2]. A regioisomer was not detected and the only
other reaction products were diphenylurea and nitrile ox-
ide dimer. Dimerisation of the 1,3-dipole appeared to be
the preferred reaction pathway,10 even in the presence of
a large excess of alkene 9. We therefore investigated a
more sterically hindered derivative (i.e. PhC≡N+O–) hop-
ing that this might reduce the relative rate of dimerisation.
Benzonitrile oxide was generated in situ in the presence of formation between the vinyl 2¢-carbon and the imidazole
the alkene 9 by treatment of benzylhydroximinoyl chlo- 2-carbon of the precursor 9. The only structure that satis-
ride with Et3N.11 Again, dimerisation competed with cy- factorily accounts for all aspects of the NMR spectra is
cloaddition but a cycloadduct (mp 118 °C) was isolated in structure 12. The proton singlet at d = 8.30 is the imine
31% yield and assigned structure 11. The 1H NMR spec- proton. In the 13C spectrum the two imine carbons appear
trum of the product 11 showed the mutually coupled (J = at 153.5 (t) and 152.5 (q) ppm and there are three other
18 Hz) methylene protons of the 2-isoxazoline ring at d = quaternary carbons at d = 135.5, 121.6 and 98.7 ppm. The
3.53 and 4.08. These signals are further split by coupling mass spectrum showed a protonated molecular ion [MH+]
to the proton at position 1¢ [J = 10 (cis), 5 (trans) Hz, re- at m/z = 273 with the constitution C13H13N4O3. Formation
spectively]. As expected the anomeric proton (1¢) appears of the product 12 is repeatable but attempts to increase the
at low field (d = 7.33) as a doublet of doublets (J = 5, 10 yield by varying the conditions were unsuccessful. The
cycloadduct 11 does not appear to be a precursor of the
isomer 12.
Hz). The imidazole proton at position 4 and the methyl
substituent at position 2 appear as singlets at d = 7.91 and
d = 2.49. All these features are entirely consistent with the
cycloadduct having structure 11. The regioisomeric struc-
ture can be eliminated since the 2-isoxazoline methylene
protons, being adjacent to an oxygen, would be signifi-
cantly shifted to lower field. The 13C NMR spectrum con-
firms these conclusions. The 2¢-CH2 and 1¢-CH
isoxazoline carbons are observed (DEPT) at 43.7 and 87.5
ppm, respectively. In the regioisomer the OCH2 signal
would be expected at lower field, due to the adjacent oxy-
Although only a minor side-product, the unusual structure
12 merits some mechanistic justification. We suggest that
addition of the nitrile oxide (or the anion of its oxime pre-
cursor) to the vinyl group (13) produces an anionic spe-
cies (e.g. 14) in which negative charge is resonance
stabilised. Intramolecular cyclisation then gives the prod-
uct 12. This mechanistic pathway (Scheme 3) shows that
there is a structural and mechanistic relationship between
the products 11 and 12.
Synthesis 2005, No. 16, 2695–2700 © Thieme Stuttgart · New York

PAPER
N-Vinyl-Nitroimidazole Cycloadditions
2697
N
When 4-nitro-1-vinylimidazole (21) was reacted with
benzonitrile oxide and N-methyl benzaldehyde nitrone
under the same conditions as for the 5-nitro derivative 17,
the corresponding adducts 20 and 22 were obtained in
similar yields (Scheme 5). The position of the nitro sub-
stituent appears to have little influence on these cycload-
dition reactions.
N
N
Me
Me
12
O2N
N
–
–
O2N
C
H
+
N
O
Ph
Ph
C
N
O
14
13
Scheme 3
N
O2N
At this stage we turned our attention to 5-nitro-1-vinyl-
imidazole (17), which is a potential precursor to purine
nucleoside analogues as shown in Scheme 1. The tosylate
15 was prepared from the alcohol. Elimination of p-tolu-
enesulfonic acid using EtOH–EtONa was achieved in 51%
yield provided that the EtOH was anhydrous and all traces
of water were removed from the apparatus. Alternatively
the vinyl derivative 17 can be prepared from the chloride
using a procedure that we have described elsewhere.13 For
a comparative study we have also investigated 4-nitro-1-
vinylimidazole (21), which is readily prepared from 4-ni-
troimidazole (19).13
N
N
O2N
O
N
H
N
Ph
20
19
N
N
O2N
O
O2N
N
N
MeN
Ph
Reaction of the alkene 17 with benzonitrile oxide gave the
cycloadduct 16 (36%) as a pale yellow solid (Scheme 4).
All spectroscopic properties of the adduct 16 were similar
to those of the 2-methyl derivative 11. We then investigat-
ed other 1,3-dipoles. N-Methyl benzaldehyde nitrone was
prepared in toluene solution using the method of De
Shong and Leginus.14 When the N-vinylimidazole 17 was
added and the solution heated under reflux (72 h) a single
product was formed. After isolation by column chroma-
21
22
N
N
O2N
O
N
N
O2N
O
N
RN
1
tography this was identified as the adduct 18 (21%). H
OR
NMR showed that the 5-nitroimidazole fragment was
present (d = 8.0, 8.3) together with a phenyl group (d =
7.2–7.4) and an N-methyl singlet (d = 2.7). The methylene
group of the isoxazolidine ring appears as coupled (J = 14
Hz) non-equivalent protons at d = 2.4 and d = 3.5. These
chemical shifts eliminate the regioisomeric structure in
which the chemical shifts of the OCH2 protons would be
at significantly lower field. The anomeric proton is ob-
served at d = 6.6 and the PhCH proton is at d = 3.8.
25 R = THP
26 R = H
23 R = THP
24 R = H
Scheme 5
The presence of a phenyl substituent in the cycloadducts
described above is undesirable in nucleoside precursors
and we next investigated the in situ use of unstabilised ni-
trile oxides and nitrones. (Tetrahydropyran-2-yl)oxyace-
tonitrile oxide [THP-OCH2CNO]15 was formed by
reaction of 2-(2-nitroethoxy)tetrahydropyran with
PhNCO–Et3N and reacted with 4-nitro-1-vinylimidazole
(21) at room temperature (24 h). Column chromatography
and acid workup (to deprotect the initial product 23) gave
the adduct 24 (61%) as yellow crystals.
N
N
O2N
N
O2N
N
O
N
OTs
15
Ph
The spectroscopic features of product 24 were analogous
to the adducts previously described and fully support the
assigned structure 24. The CH2OH substituent was ob-
served as a two proton multiplet at d = 4.39 and a triplet
(OH) at d = 5.6. When this procedure was repeated using
5-nitro-1-vinylimidazole (17) 1H NMR analysis of the re-
action mixture suggested that cycloaddition had occurred
but the only product isolated after workup was 4-nitro-
imidazole (19). Repetition and chromatography of the re-
action mixture before acid work-up gave a yellow oil that
was identified as the crude THP protected adduct 27.
Deprotection under mild conditions (MeOH–HCO2H)
16
N
N
N
N
O2N
O2N
O
MeN
Ph
17
18
Scheme 4
Synthesis 2005, No. 16, 2695–2700 © Thieme Stuttgart · New York

2698
R. Clayton, C. A. Ramsden
PAPER
IR (KBr): 650, 661, 823, 896, 1179, 1366, 1469, 1524, 1596, 1772,
2924 cm–1.
followed by chromatography gave a low yield (7%) of a
yellow oil. This was identified as the product 28 by H
1
NMR and mass spectrometry but a pure sample could not 1H NMR (CDCl3–TMS): d = 2.39 (s, 3 H, CH3), 4.31 (t, 2 H, NCH2),
4.54 (t, 2 H, OCH2), 7.23 (d, J = 8.3 Hz, 2 H, arom-H), 7.53 (d, J =
be obtained. We have previously encountered high insta-
8.3 Hz, 2 H, arom-H), 7.57 [s, 1 H, imidazole C(4)H], 7.81 [s, 1 H,
bility of sugar derivatives of 5-nitroimidazoles to acid
imidazole C(2)H].
conditions under which the 4-nitro isomers are stable.7b
This is attributed to protonation of the imidazole and 4-ni-
13C NMR (CDCl3–TMS): d = 21.66 (ArCH3), 46.99 (NCH2), 66.87
(OCH2), 127.69 (arom-CH), 130.13 (arom-CH), 131.84 (arom-C),
troimidazole acting as a very good leaving group assisted
133.88 [C(4)H], 137.99 [C(5)], 142.59 [C(2)H], 145.68 (arom-C).
by the ring oxygen atom.
MS (EI): m/z (%) = 311 (62) [M+], 310, 155, 140, 139, 92, 91 (100),
Finally, we investigated the reaction of N-(tetrahydropy-
90, 65, 53.
ran-2-yl)formaldehyde nitrone [H2C=(THP)N+O–] gener-
Anal. Calcd for C12H13N3O5S (311.31): C, 46.30; H, 4.21; N, 13.50.
ated in situ from N-(tetrahydropyran-2-yl)hydroxylamine
Found: C, 46.64; H, 4.26; N, 13.28.
and para-formaldehyde.16 Reaction of this reagent with
the 4-nitro dipolarophile 21 in hot THF gave the adduct 25
(62%), which was isolated by column chromatography as
a crystalline solid (mp 98 °C) and identified by 1H NMR.
Deprotection (MeOH–concd HCl) of this product and
chromatographic purification gave the isoxazoline 26
(71%) as a colourless oil. The structure was confirmed by
NMR spectroscopy and mass spectrometry. Attempts to
repeat this procedure with the 5-nitro isomer 17 were un-
satisfactory. Although the adduct 29 was formed in rea-
2-Methyl-5-nitro-1-(2-tosyloxyethyl)imidazole (7)
Following the method described for compound 15, the title com-
pound was obtained from metronidazole (15.0 g, 82.5 mmol); yield:
22.67 g (85%); pale cream needles from EtOH; mp 151 °C (Lit.8
153 °C).
IR (KBr): 898, 1174, 1366, 1430, 1460, 1526, 1596 cm–1.
1H NMR (CDCl3–TMS): d = 2.45 (s, 3 H, CH3), 2.52 (s, 3 H, CH3),
4.37 (t, 2 H, NCH2), 4.54 (t, 2 H, OCH2), 7.30 (d, J = 8.3 Hz, 2 H,
arom-H), 7.60 (d, J = 8.3 Hz, 2 H, arom-H), 7.79 [s, 1 H, imidazole
C(4)H].
13C NMR (CDCl3–TMS): d = 13.91 (Ar-CH3), 21.01 [C(2)CH3],
44.61 (NCH2), 68.38 (OCH2), 127.21 (arom-CH), 129.24 (arom-
CH), 131.50 (arom-C), 133.04 [C(4)H], 138.03 [C(5)], 145.22
(arom-C), 151.57 [C(2)].
1
sonable yield and identified by H NMR it could not be
isolated in pure form. Deprotection of the crude mixture
(MeOH–HCO2H) gave mainly 4-nitroimidazole (19) and
a low yield (ca. 3%) of material tentatively identified as
the desired product 30 (Figure 2). Like adduct 27, the
product 29 is extremely sensitive to acid.7b
MS (EI): m/z (%) = 325 (11) [M+], 199, 170 (100), 155, 91, 65, 53.
Anal. Calcd for C13H15N3O5S (325.34): C, 47.99; H, 4.65; N, 12.92.
Found: C, 47.99; H, 4.59; N, 12.63.
N
N
5-Nitro-1-vinylimidazole (17)
O2N
O
N
O2N
O
N
NaOEt (1.10 g, 16 mmol) was added to a solution of 1-(2-tosyloxy-
ethyl)-5-nitroimidazole (15; 5.00 g, 16 mmol) in anhyd EtOH (100
mL) heated under reflux. Heating of the resulting orange solution
was maintained (30 min), before cooling to r.t. and stirring over-
night. The precipitate was removed and the volume was reduced
(ca. 10 mL). The concentrated solution was diluted with H2O (200
mL) and Et2O (200 mL). The organic phase was separated, dried
(MgSO4) and evaporated to give a yellow oil. Column chromatog-
raphy (silica gel; Et2O as eluent) gave the vinylimidazole 17 (1.15
g, 51%); yellow crystals; mp 24 °C.
N
RN
OR
29 R = THP
30 R = H
27 R = THP
28 R = H
Figure 2
1
The H and 13C NMR spectra were recorded on a Bruker Avance
DPX300 NMR spectrometer at 300 MHz and 50 MHz, respectively,
in CDCl3 (TMS as internal standard). IR spectra were recorded on a
Perkin-Elmer Paragon 1000 FT-IR spectrophotometer, and mi-
croanalyses on a Perkin-Elmer 240 Elemental Analyser. Unless oth-
erwise stated, IR spectra were measured as thin films (liquids) or
KBr discs (solids). Only significant bands for the IR spectra are
quoted. Melting points were determined on a Reichert–Kofler block
apparatus and are uncorrected. Chromatotron chromatography was
performed on plates prepared using silica gel 60 PF254 containing
CaSO4.
IR (film): 643, 826, 1119, 1526, 1376, 1473, 1530, 1641, 3127 cm–1.
1H NMR (CDCl3–TMS): d = 5.36 [dd, J = 1.8, 8.4 Hz, 1 H,
CH=CH2(cis)], 5.57 [dd, J = 1.8, 15.5 Hz, 1 H, CH=CH2(trans)],
7.44 (dd, J = 8.4, 15.5 Hz, 1 H, NCH=CH2), 7.85 [d, J = 0.8 Hz, 1
H, imidazole C(4)H], 8.00 [d, J = 0.8 Hz, 1 H, imidazole C(2)H].
13C NMR (DMSO-d6–TMS): d = 110.09 (C=CH2), 128.82 (C=CH),
133.20 [C(4)H], 137.95 [C(5)], 140.23 [C(2)H].
MS (EI): m/z (%) = 139 (48) [M+], 94, 82, 67, 66, 55, 54, 40, 39
(100), 28, 27.
Anal. Calcd for C5H5N3O2 (139.11): C, 43.17; H, 3.62; N, 30.21.
Found: C, 43.44; H, 3.50; N, 30.19.
5-Nitro-1-(2-tosyloxyethyl)imidazole (15)
p-TsCl (11.4 g, 60 mmol) was added to 1-(2-hydroxyethyl)-5-
nitroimidazole17 (8.0 g, 50 mmol) in anhyd pyridine (75 mL) and
the mixture was stirred (7 h). A further portion of p-TsCl (2.85 g, 15
mmol) was then added and stirring was maintained overnight. The
precipitate was collected, recrystallised from MeOH and identified
as the 5-nitroimidazole 15 (13.1 g, 84%); colourless rectangular
crystals; mp 129 °C.
2-Methyl-5-nitro-1-vinylimidazole (9)
Following the method described for compound 17, the title com-
pound was obtained from the 5-nitroimidazole 7 (20.0 g, 61.5
mmol) and NaOEt (4.60 g, 65.0 mmol). After reduction of the vol-
ume (ca. 60–70 mL) and dilution with H2O (200 mL), the solution
was extracted with Et2O (3 × 100 mL). The combined organic ex-
tracts were dried and concentrated (40 mL). Careful trituration with
Synthesis 2005, No. 16, 2695–2700 © Thieme Stuttgart · New York

PAPER
N-Vinyl-Nitroimidazole Cycloadditions
2699
n-hexane gave a red oil which was discarded. Further dilution with
n-hexane yielded the vinylimidazole 9 (5.32 g, 55%); pale yellow
needles; mp 48 °C (Lit.8 49–50 °C).
IR (KBr): 962, 1204, 1260, 1369, 1472, 1525, 1636, 3119 cm–1.
MS (EI): m/z (%) = 272 (1) [M+], 226, 184, 160, 149, 119, 103, 86,
84, 76, 51, 49 (100).
HRMS: m/z calcd for C13H13N4O3 [M + H]: 273.0982; found:
273.0983.
1H NMR (CDCl3–TMS): d = 2.51 (s, 3 H, CH3), 5.41 [dd, J = 1.3,
15.6 Hz, 1 H, CH=CH2(trans)], 5.64 [dd, J = 1.3, 8.2 Hz, 1 H,
CH=CH2(cis)], 7.06 (dd, J = 8.2, 15.6 Hz, 1 H, NCH=CH2), 7.93 [s,
1 H, imidazole C(4)H].
13C NMR (CDCl3–TMS): d = 15.13 (2-CH3), 116.40 (C=CH2),
129.59 (C=CH), 131.80 [C(4)H], 138.98 [C(5)], 149.52 [C(2)].
5-(5-Nitroimidazol-1-yl)-3-phenyl-4,5-dihydroisoxazole (16)
Following the method described for compound 11, the title com-
pound was obtained from 5-nitro-1-vinylimidazole (17; 100 mg,
0.72 mmol); yield: 66 mg (36%); pale yellow solid; mp 119 °C.
IR (KBr): 690, 772, 858, 954, 1120, 1214, 1257, 1370, 1467, 1535,
3077 cm–1.
MS (EI): m/z = 153 (61) [M+], 67, 54, 43, 42, 39 (100), 27.
1H NMR (CDCl3–TMS): d = 3.55 [dd, J = 2.1, 18.2 Hz, 1 H,
CHCH2(trans)], 4.14 [dd, J = 8.1, 18.2 Hz, 1 H, CHCH2(cis)], 7.09
(dd, J = 2.1, 8.1 Hz, 1 H, NCHCH2), 7.26–7.51 (m, 3 H, arom-H),
7.64–7.69 (m, 2 H, arom-H), 7.88 [s, 1 H, imidazole C(4)H], 8.01
[s, 1 H, imidazole C(2)H].
MS (EI): m/z (%) = 258 (7) [M+], 163, 146, 145 (100), 144, 118,
117, 105, 103 (75), 91, 77, 51, 40, 39.
Anal. Calcd for C6H7N3O2 (153.14): C, 47.06; H, 4.61; N, 27.44.
Found: C, 47.00; H, 4.49; N, 27.17.
1,3-Dipolar Cycloaddition Reactions of 4- and 5-Nitro-1-vinyl-
imidazoles
(a) With Benzonitrile Oxide
5-(2-Methyl-5-nitroimidazol-1-yl)-3-phenyl-4,5-dihydroisox-
azole (11)
2-Methyl-5-nitro-1-vinylimidazole (9; 1.00 g, 6.3 mmol) was dis-
solved in anhyd THF (50 mL) at 0 °C and benzohydroximinoyl
chloride (1.00 g, 6.4 mmol) was added. The solution was stirred rap-
idly and Et3N (0.65 g, 6.4 mmol) was added. Stirring was main-
tained at r.t. (20 h), after which time TLC showed that starting
material was still present. Further portions of benzohydroximinoyl
chloride (0.50 g, 3.22 mmol) and Et3N (0.33 g, 3.22 mmol) were
added and stirring was continued (24 h). The precipitate was re-
moved and the filtrate was concentrated (ca. 10 mL). Column chro-
matography (silica gel; EtOAc as eluent) gave cycloadduct 11 (500
mg, 31%); light yellow solid; mp 118 °C.
Anal. Calcd for C12H10N4O3 (258.24): C, 55.81; H, 3.90; N, 21.70.
Found: C, 55.76; H, 3.88; N, 21.93.
5-(4-Nitroimidazol-1-yl)-3-phenyl-4,5-dihydroisoxazole (20)
Following the method described for compound 11, the title com-
pound was obtained from 4-nitro-1-vinylimidazole (21; 1.00 g, 7.19
mmol); yield: 766 mg, (41%); flat almost colourless crystals from
toluene; mp 136 °C.
IR (KBr): 692, 794, 938, 1286, 1346, 1507, 1539, 1653, 3093 cm–1.
1H NMR (CDCl3–TMS): d = 3.57 [dd, J = 2.5, 17.9 Hz, 1 H,
CHCH2(trans)], 4.00 [dd, J = 9.0, 17.9 Hz, 1 H, CHCH2(cis)], 6.51
(dd, J = 2.5, 8.9 Hz, 1 H, NCHCH2), 7.39–7.50 (m, 3 H, arom-H),
7.58 [d, J = 1.5 Hz, 1 H, imidazole C(5)H], 7.64–7.67 (m, 2 H,
arom-H), 7.76 [d, J = 1.5 Hz, 1 H, imidazole C(2)H].
13C NMR (DMSO-d6–TMS): d = 40.99 [C(4¢)H2], 86.33 [C(5¢)H],
119.03 (arom-CH), 127.27 (arom-CH), 127.84 (arom-C), 128.77
(arom-CH), 130.83 [C(5)H], 135.94 [C(2)H], 147.67 [C(4)], 157.69
[C(3)].
IR (KBr): 693, 762, 860, 1045, 1140, 1166, 1203, 1245, 1362, 1412,
1480, 1535, 1732, 2983 cm–1.
1H NMR (CDCl3–TMS): d = 2.49 (s, 3 H, CH3), 3.53 [dd, J = 4.8,
18.4 Hz, 1 H, CHCH2(trans)], 4.08 [J = 10.1, 18.4 Hz, 1 H,
CHCH2(cis)], 7.33 (dd, J = 4.8, 10.1 Hz, 1 H, NCHCH2), 7.37–7.66
(m, 5 H, arom-H), 7.91 [s, 1 H, imidazole C(4)H].
13C NMR (CDCl3–TMS): d = 16.51 [C(2¢)CH3], 43.74 [C(4)H2],
87.47 [C(5)H], 127.02 (arom-CH), 127.40 (arom-C), 129.10 (arom-
CH), 131.37 (arom-CH), 133.43 [C(4¢)H], 138.76 [C(5¢)], 150.44
[C(2¢)], 157.50 [C(3)].
MS (EI): m/z (%) = 258 (4) [M], 146 (100), 145, 144, 118, 91, 77,
51, 40, 28.
Anal. Calcd for C12H10N4O3 (258.24): C, 55.81; H, 3.90; N, 21.70.
Found: C, 55.72; H, 3.86; N, 21.45.
MS (EI): m/z (%) = 272 (1) [M+], 146, 145, 127 (100), 81, 77, 54,
53, 52, 43, 42, 40, 27, 26.
(b) With N-Methylbenzaldehyde Nitrone
Anal. Calcd for C13H12N4O3 (272.26): C, 57.35; H, 4.44; N, 20.58.
Found: C, 57.34; H, 4.51; N, 20.31.
2-Methyl-5-(5-nitroimidazol-1-yl)-3-phenylisoxazolidine (18)
N-Methylbenzaldehyde nitrone was prepared from benzaldehyde
(0.5 g, 4.7 mmol) and kept as the crude product in toluene solution.
5-Nitro-1-vinylimidazole (17; 100 mg, 0.7 mmol) was added to the
filtered nitrone solution and the mixture was heated under reflux
and a N2 atmosphere until TLC showed that no starting imidazole
remained (72 h). Evaporation and column chromatography (silica
gel; Et2O as eluent) yielded the isoxazolidine 18 (42 mg, 21%).
In a separate experiment the solution was stirred rapidly and Et3N
(2 drops) and NaHCO3 (2.0 g) were added. Stirring was then main-
tained at r.t. for 20 h. The precipitate was removed and the filtrate
concentrated (ca. 10 mL). Column chromatography (silica gel;
EtOAc as eluent) gave the adduct 11 (27%) together with a second
product that was identified as 12 (50 mg, 3%); light yellow solid;
mp 113 °C.
IR (film): 649, 699, 826, 1064, 1119, 1209, 1371, 1466, 1526, 2875
cm–1.
IR (KBr): 659, 699, 775, 804, 879, 1026, 1051, 1098, 1261, 1298,
1365, 1413, 1448, 1509, 1571, 1601 cm–1.
1H NMR (CDCl3–TMS): d = 1.36 (d, J = 1.0 Hz, 3 H, CH3), 2.20
[dd, J = 4.0, 14.1 Hz, 1 H, CHCH2(trans)], 3.70 [dd, J = 5.9, 14.1
Hz, 1 H, CHCH2(cis)], 7.51–7.63 (m, 5 H, arom-H), 7.71 (dd, J =
4.1, 5.8 Hz, 1 H, NCHCH2), 8.30 [s, 1 H, imidazole C(4)H].
13C NMR (CDCl3–TMS): d = 27.67 [C(2¢)CH3], 45.34 [C(4)H2],
87.47 [C(5)H], 98.68 (arom-C), 119.94 (arom-CH), 121.58 [C(5¢)],
128.75 (arom-CH), 129.89 (arom-CH), 132.56 [C(4¢)H], 135.83
[C(2¢)], 152.55 [C(3)], 153.51 [C(4)H].
1H NMR (CDCl3–TMS): d = 2.42 (ddd, J = 3.3, 9.6, 13.7 Hz, 1 H,
ArCH), 2.74 (s, 3 H, NCH3), 3.54 (dt, J = 7.7, 14.1 Hz, 1 H,
CHCH2CH), 3.77 (dd, J = 9.6, 8.2 Hz, 1 H, CHCH2CH), 6.59 (dd,
J = 7.3, 3.3 Hz, 1 H, OCH), 7.21–7.35 (m, 5 H, arom-H), 8.02 [d,
J = 1.0 Hz, 1 H, imidazole C(4)H], 8.30 [s, 1 H, imidazole C(2)H].
MS (EI): m/z (%) = 274 (22) [M+], 135, 134 (100), 118, 115, 105,
104, 103, 91, 78, 77, 52, 42, 28.
HRMS: m/z calcd for C13H14N4O3: 274.1066; found: 274.1061.
Synthesis 2005, No. 16, 2695–2700 © Thieme Stuttgart · New York

2700
R. Clayton, C. A. Ramsden
PAPER
2-Methyl-5-(4-nitroimidazol-1-yl)-3-phenylisoxazolidine (22)
Following the method described for compound 18, the title com-
pound was obtained from 4-nitro-1-vinylimidazole (100 mg, 0.719
mmol); yield: 53 mg (27%).
1H NMR (CDCl3–TMS): d = 2.58 (ddd, J = 3.7, 9.7, 13.7 Hz, 1 H,
CHCH2CH)), 2.69 (s, 3 H, NCH3), 3.41 (dt, J = 7.9, 13.8 Hz, 1 H,
CHCH2CH), 3.74 (dd, J = 9.7, 7.9 Hz, 1 H, NCHPh), 6.03 (dd, J =
3.7, 7.9 Hz, 1 H, OCH), 7.32–7.41 (m, 5 H, arom-H), 7.79 [d, J =
1.5 Hz, 1 H, imidazole C(5)H], 8.16 [d, J = 1.5 Hz, 1 H, imidazole
C(2)H].
as eluent) gave an oil that was identified as the isoxazolidine 26
(0.13 g, 71%); colourless oil.
1H NMR (DMSO-d6–TMS): d = 2.57 (m, 1 H, 4-CH), 2.74 (br s, 1
H, 4-CH), 3.07 (br s, 1 H, 3-CH), 3.37 (br s, 1 H, 3-CH), 6.22 (dd,
J = 6.9, 3.2 Hz, 1 H, 5-CH), 7.08 (br s, 1 H, 2-NH), 8.08 [s, 1 H,
imidazole C(5)H], 8.62 [s, 1 H, imidazole C(2)H].
13C NMR (DMSO-d6–TMS): d = 37.05 [C(4¢)H2], 47.31 [C(3¢)H2],
87.10 [C(5¢)H], 119.65 [imidazole C(5)H], 136.40 [imidazole
C(2)H], 147.50 [imidazole C(4)].
MS (EI): m/z (%) = 184 (9) [M+], 113, 69 (100), 43, 31.
HRMS: m/z [M+] calcd for C6H8N4O3: 184.0597; found: 184.0592
HRMS: m/z calcd for C13H14N4O3: 274.1066; found: 274.1054
(c) With O-(Tetrahydropyran-2-yl)oxyacetonitrile
3-Hydroxymethyl-5-(4-nitroimidazo-1-yl)isoxazoline (24)
2-(2-Nitroethoxy)tetrahydropyran (0.52 g, 3 mmol), phenyl isocy-
anate (1.0 g, 8 mmol) and Et3N (2 drops) were placed in benzene (15
mL) and stirred (1 h). 4-Nitro-1-vinylimidazole (21; 0.28 g, 2
mmol) was dissolved in THF (15 mL) and this solution was added
to the reaction mixture and the resultant solution was stirred (24 h).
Column chromatography (silica gel: EtOAc–hexane 1:1 as eluent)
separated the fraction below the 4-nitro-1-vinylimidazole as an or-
ange oil that was dissolved in MeOH (30 mL) and concd HCl (1
mL) and stirred (1 h). The acidity was adjusted to pH 7 using aq
NaHCO3 and the solvent was removed. Column chromatography
(silica gel: EtOAc as eluent) yielded a yellow oil which crystallised
overnight at 0 °C and was identified as the isoxazoline 24 (0.26 g,
61%); yellow crystals; mp 119 °C.
Acknowledgment
We thank Scotia Pharmaceuticals for financial support and the
EPSRC National Mass Spectrometry Service for mass spectra.
References
(1) Lythgoe, D. J.; Ramsden, C. A. In Advances in Heterocyclic
Chemistry, Vol. 61; Katritzky, A. R., Ed.; Academic Press:
San Diego, 1994, 1.
(2) Boyer, J. H. Organic Nitro Chemistry Series 1: Nitroazoles.
The C-Nitro Derivatives of Five Membered N- and N,O-
Heterocycles; VCH Publishers: Deerfield Beach, Florida,
1986, 147.
(3) McFadzean, J. A. Flagyl: The Story of a Pharmaceutical
Discovery; Parthenon Publishing Group Ltd.: Lancaster,
1986.
(4) Al-Shaar, A. H. M.; Gilmour, D. W.; Lythgoe, D. J.;
McClenaghan, I.; Ramsden, C. A. J. Chem. Soc., Perkin
Trans. 1 1992, 2779.
(5) Jones, R. H.; Lothian, A. P.; Ramsden, C. A. Acta
Crystallogr., Sect. C 1996, 52, 982.
(6) Al-Shaar, A. H. M.; Chamber, R. K.; Gilmour, D. W.;
Lythgoe, D. J.; McClenaghan, I.; Ramsden, C. A. J. Chem.
Soc., Perkin Trans. 1 1992, 2789.
(7) (a) Clayton, R.; Davis, M. L.; Fraser, W.; Li, W.; Ramsden,
C. A. Synlett 2002, 1483. (b) Curtis, A. D. M.; Humphries,
M. J.; Ramsden, C. A. Arkivoc 2000, iii, 218.
(c) Humphries, M. J.; Ramsden, C. A. Synthesis 1999, 985.
(d) Humphries, M. J.; Ramsden, C. A. Synlett 1995, 203.
(e) Ramsden, C. A. Chem. Heterocycl. Compd. (Engl.
Transl.) 1995, 1323. (f) Al-Shaar, A. H. M.; Gilmour, D.
W.; Lythgoe, D. J.; McClenaghan, I.; Ramsden, C. A. J.
Chem. Soc., Chem. Commun. 1989, 551.
IR (KBr): 3331, 3155, 3124, 1553, 1503, 1294, 1034, 8489, 676
cm–1.
1H NMR (DMSO-d6–TMS): d = 3.57 (dd, J = 18.9, 2.6 Hz, 1 H, 4-
CH), 3.82 (dd, J = 18.9, 9.1 Hz, 1 H, 4-CH), 4.39 (m, 2 H, CH2OH),
5.56 (t, J = 5.9, 6.3 Hz, 1 H, OH), 6.75 (dd, J = 9.1, 2.7 Hz, 1 H, 5-
CH), 8.05 [d, J = 1.4 Hz, 1 H, imidazole C(5)H], 8.47 [d, J = 1.4 Hz,
1 H, imidazole C(2)H].
13C NMR (DMSO-d6–TMS): d = 41.90 [C(4¢)H2], 55.72 (CH2OH),
85.36 [C(5¢)H], 118.82 [imidazole C(5)H], 135.91 [imidazole
C(2)H], 147.65 [imidazole C(4)], 160.77 [C(3¢)].
MS (EI): m/z (%) = 212 (3) [M+], 113, 99, 69, 43, 31 (100).
HRMS: m/z [M+] calcd for C7H8N4O4: 212.0546; found: 212.0548
(c) With N-(tetrahydropyran-2-yl)formaldehyde Nitrone
5-(4-Nitroimidazo-1-yl)isoxazolidine (26)
1-Vinyl-4-nitroimidazole (21; 0.28 g, 2 mmol), 5-hydroxypentanal
oxime (0.35 g, 3 mmol) and p-formaldehyde (0.12 g, 4 mmol) were
placed in THF (25 mL) and the mixture was stirred under reflux (24
h). Column chromatography (silica gel, EtOAc–hexane, 1:2 as elu-
ent) separated the fraction just above the 1-vinyl-4-nitroimidazole
starting material. This was identified as the isoxazolidine 25 (0.33
g, 62%; mp 98 °C), which was used without further characteriza-
tion.
1H NMR (DMSO-d6–TMS): d = 1.31–1.78 (m, 6 H, 3 × THP-CH2),
2.57 (m, 1 H, 4-CH), 2.77 (m, 1 H, 4-CH), 3.15 [m, 1 H, THP(2)-
CH], 3.25–3.46 [m, 2 H, THP(6)-CH2], 3.86 (m, 1 H, 3-CH), 4.10–
4.28 (dd, J = 8.8, 2.6 Hz, 1 H, 3-CH), 6.22 (ddd, J = 10.0, 7.7, 2.8
Hz, 1 H, 5-CH), 8.03 [t, J = 1.2 Hz, 1 H, imidazole C(5)H], 8.48 [t,
J = 1.6 Hz, 1 H, imidazole C(2)H].
(8) Ross, W. J.; Jamieson, W. B.; McCowen, M. C. J. Med.
Chem. 1972, 15, 1035.
(9) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82,
5339.
(10) Barrow, S. J.; Easton, C. J.; Savage, G. P.; Simpson, G. W.
Tetrahedron Lett. 1997, 38, 2175.
(11) Liu, K.-C.; Shelton, B. R.; Howe, R. K. J. Org. Chem. 1980,
45, 3916.
(12) McKillop, A.; Wright, D. E.; Podmore, M. L.; Chambers, R.
K. Tetrahedron 1983, 39, 3797.
(13) Clayton, R.; Ramsden, C. A. J. Heterocycl. Chem. 2004, 41,
701.
(14) DeShong, P.; Leginus, J. M. J. Org. Chem. 1984, 49, 3421.
(15) Xiang, Y.; Chen, J.; Schinazi, R. F.; Zhao, K. Bioorg. Med.
Chem. Lett. 1996, 6, 1051.
(16) Mzengeza, S.; Whitney, R. A. J. Chem. Soc., Chem.
Commun. 1984, 606.
The isoxazolidine 25 (0.27 g, 1 mmol) was dissolved in MeOH (20
mL). To the solution was added concd HCl (2 drops) and the result-
ant solution was stirred under a N2 atmosphere (1 h). The pH was
adjusted to 7 using 1 M aq K2CO3 and the solvent was removed un-
der reduced pressure. Column chromatography (silica gel: EtOAc
(17) Rhone-Poulenc, S. Eur. Patent, 0324691A1, 1989.
Synthesis 2005, No. 16, 2695–2700 © Thieme Stuttgart · New York