One-pot, three-component synthesis of five-membered cyclic nitrones by addition/cyclization/condensation domino reaction

Article abstract of DOI:10.1016/j.tet.2010.01.040

A new approach to five-membered cyclic nitrones connected with the incorporation of a planar aromatic ring system into the structure is described. This procedure is based on an allenyloxime one-pot domino transformation under simple base catalysis in alcoholic and aqueous solvents. The structure of obtained nitrones was studied by X-ray analysis and the reactivity of products in 1,3-dipolar cycloadditions was tested.

Full text of DOI:10.1016/j.tet.2010.01.040

Tetrahedron 66 (2010) 1821–1826
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One-pot, three-component synthesis of five-membered cyclic nitrones
by addition/cyclization/condensation domino reaction
a
b
c
a,
*
ˇ a
´ ˇ
Marian Buchlovic , Stanislav Man , Konstantin Kislitso˜n , Charlotte Mathot , Milan Potacek
a
ˇ
´
´
Department of Organic Chemistry, Masaryk University, Kotlarska 2, 611 37 Brno, Czech Republic
b Institute of Chemistry, Tallinn University of Technology, Ehitajate tee 5, 19086 Tallinn, Estonia
c
´
´
ˆ
Departement de Chimie, Universite Catholique de Louvain, Batiment Lavoisier, Place Louis Pasteur 1, B-1348 Louvain-la-Neuve, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
A new approach to five-membered cyclic nitrones connected with the incorporation of a planar aromatic
ring system into the structure is described. This procedure is based on an allenyloxime one-pot domino
transformation under simple base catalysis in alcoholic and aqueous solvents. The structure of obtained
nitrones was studied by X-ray analysis and the reactivity of products in 1,3-dipolar cycloadditions was
tested.
Received 2 September 2009
Received in revised form 2 December 2009
Accepted 11 January 2010
Available online 18 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Allenyloximes
Allenes
Nitrones
Cyclization reaction
Heterocyclization
Condensation
Domino reactions
1. Introduction
R3
N
N
OH
N
O
The consistent interest of our research group in allene chemistry
has been recently documented by a published results.1,2 We
described the ability of 2,2-dimethylpenta-3,4-dienal oxime 1 to
undergo heterocyclizations under various conditions leading to
stable functionalized five-membered cyclic nitrones (Scheme 1).
These presented methods provide easy access to completely new
nitrone-type building blocks. In most cases, each process involves
only one reaction step, where cyclization together with
introduction of a functional group takes place.2
•
R2
H
N
H
N
O
N
O
N
OH
1
Nitrones enjoy great popularity among chemists due to their
numerous applications as building blocks in organic synthesis3 or
as spin traps.4 Furthermore, in the last decade they have shown
widespread biological activities (e.g., antitumour, neuroprotective,
anti-stroke, suppression of age-associated degeneration), even
though they possess simple structure (Scheme 2) and the struc-
ture–activity relationship has not been determined.5,7
3
4
5
2
O
OH
N
1
O
N
O
R1
Scheme 1.
Interestingly, syntheses of planar aromatic ring systems con-
taining polar side functionalities and in particular, the in-
corporation of fused polyaromatic rings into the structure of
N
O
N
O
N
O
N
O
PBN
DMPO
2-PhDMPO
MDL
* Corresponding author. Tel.: þ420 549496615; fax: þ420 549492688.
Scheme 2. Examples of biologically active nitrones.
´ ˇ
E-mail address: potacek@chemi.muni.cz (M. Potacek).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.040

ˇ
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M. Buchlovic et al. / Tetrahedron 66 (2010) 1821–1826
Table 1
nitrones was found to be useful in the design of new antitumour
DNA intercalating agents.6
Summary of one-pot synthesis of nitrones 3–5 from 1
With this background in mind, combined with the actual ap-
plication of nitrones as therapeutics,7 we want to report a new one-
pot transformation of allenyloxime 1. The 5-methyl substitution is
present in the structure of all our previously reported cyclic
nitrones (see Scheme 1). This paper applies the reactivity of the 5-
methyl group for the incorporation of planar aromatic system at the
nitrone structure.
H
•
R
3a-d (R = Me)
Ar
+
+ ROH
O
4a-d
(R = Et)
Ar
O
N
O
N
OH
5
(R = H)
1
Entry Ar
Solvent Temp.
(ROH)
Reaction Nitrone Yield
time (h)
(%)
1
2
3
4
5
6
7
8
9
Phenyl
MeOH
MeOH
MeOH
Reflux
Reflux
Reflux
Reflux
3
3
3
3
3a
3b
3c
3d
4a
4b
4c
4d
5
78
73
66
72
51
50
54
50
29
1-Naphthyl
9-Anthryl
9-Phenanthryl MeOH
2. Results and discussion
Phenyl
EtOH
EtOH
EtOH
Reflux/ambident 8.5
Reflux/ambident 8.5
Reflux/ambident 8.5
Reflux/ambident 8.5
Methyl groups located at nitrone C]Nþ carbon atom are well-
knownto undergo deprotonation in the presence of a strong base and
then to react with electrophiles.8 To test the reactivity of structurally
different substrates, we chose nitrone 2 for initial experiments. As we
had shown earlier, nitrone 2 is available from oxime 1 via a base
catalyzed cyclization in methanol (1/2, Scheme 3).2
1-Naphthyl
9-Anthryl
9-Phenanthryl EtOH
Phenyl Water
70 ꢀC
24
According with the previously published procedures,9 we have
successfully performed the condensation of nitrone 2 in methanolic
solution in the presence of potassium hydroxide (4 equiv) and
benzaldehyde (2/3a, Scheme 3). The reaction offered aryl-modi-
fied cyclic nitrone 3a in 46% overall yield (path A).
3
4
•
i, 70 %
Path A
5
2
O
N
1
N
OH
O
1
2
Figure 1. ORTEP representation14 of compound 3c.
ii, 78%
ii, 65%
46% overall
one-pot
Path B
Additionally, we found that this procedure is limited to non-
enolizable aldehydes. All attempts to incorporate aldehydes bear-
ing -hydrogens into the structure of final product, even under
a
milder conditions (lower temperature) failed.
O
Interestingly, a simple exchange of methanol for a higher alco-
holic solvent under analogous conditions, does not lead exclusively
to expected 2-alkoxy substituted products. Thus, a 2-hydroxy
substituted product was observed as a detectable product of a side
process in the reaction where methanol was replaced by ethanol.
The isolated nitrone 5 in 15% yield illustrates situation (Scheme 5,
Fig. 2).15 Moreover, secondary and tertiary alcohols were found not
to be reactive to yield single products (only complex reaction
mixtures were obtained).
N
O
3a
Scheme 3. Preparation of nitrone 3a: (i) KOH (0.1 equiv),
D,
4 h, 70%; (ii) KOH
(4 equiv), benzaldehyde, MeOH,
4 h, yield 78%.
D. Path A overall time 8 h, overall yield 46%; Path B
Because the reaction conditions for both the reaction steps (i, ii) are
similar, we have subsequently exercised one-pot modification for this
reaction transformation. Simple mixing of allenyloxime 1, potassium
hydroxide andbenzaldehyde in boiling methanolledto desired product
in this effective manner and high yield (1/3a, Scheme 3, path B).
At first, we tried to explore limitations of this reaction protocol in
respect to an aldehyde component inthe reactionmixture. Increasing
sterical demands of fused aromatic aldehydes, i.e., switching from
benzaldehyde to anthracene carbaldehyde or phenanthrene carbal-
dehyde, does not lead to significant decrease inyields under identical
reaction conditions. Isolated yields of corresponding nitrones were
found within 10% interval (Scheme 4; Table 1, entries 1–4).
O
N
4a (40%)a
O
•
i
+
N
OH
OH
5 (15%)a
1
N
O
The structure of selected nitrone 3c was studied by X-ray anal-
ysis15 that fully confirmed the expected structure (Fig. 1).
Side product
Scheme 5. One-pot domino reaction of allenyloxime 1 in ethanol: (i) KOH (4 equiv),
EtOH,
, benzaldehyde; aisolated yields.10
D
H
•
i
Ar
To explain the formation of compound 5, the formulation of
a new reaction pathway is necessary (Scheme 6). In previous work
we established that reaction starts by a nucleophilic attack of the
alkoxide anion at the carbon atom of the C]N bond of allenyloxime
1. The attack is followed by a cyclization in the second step,
resulting in alkoxy-substituted nitrone.2 A further step then
+
+
MeOH
O
Ar
O
N
OH
N
O
1
Ar = Phenyl (a), 1-Naphthyl (b), 9-Anthryl (c), 9-Phenanthryl (d)
3a-d (68-78%)
Scheme 4. One-pot domino reaction of allenyloxime 1 in methanol: (i) KOH (4 equiv),
D
, aromatic aldehyde.

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M. Buchlovic et al. / Tetrahedron 66 (2010) 1821–1826
1823
•
N
O
OH
1
i
ii
OH
N
OH
5 (29%)
N
O
O
6 (70%)
Main product
Figure 2. Ortep representation14 of compound 5.
Scheme 7. Transformation of oxime 1 in aqueous solutions: (i) KOH (4 equiv), H2O,
70 ꢀC; (ii) KOH (4 equiv), H2O, 60 ꢀC.
observation is probably due to the increased sterical demand of the
nucleophile (ethoxide anion), since no desired products with alk-
oxy substitution in position 2 were observed with better nucleo-
philes (reactions with secondary and tertiary alcohols).
Furthermore, methanol is more acidic than ethanol and therefore
formation of the reagent (ethoxide) will also be harder. On the
other hand, cyclization under same conditions in methanol leads
exclusively to desired nitrone with no detectable formation of the
side product 5.
Therefore to eliminate the side reaction pathway in ethanol, we
had to decrease the concentration of base to a catalytic amount
(0.1 equiv). However, more than one equivalent of base was nec-
essary for the condensation reaction step, where four equivalents of
potassium hydroxide in methanol were found to be the most effi-
cient choice.
For that reason in the case of reaction in ethanolwehavetodivide
the reaction procedure into two steps: (i) allenyloxime cyclization at
reflux in the presence of catalytic amount of base (formation of 2-
alkoxy-substituted nitrone), (ii) subsequent condensation with al-
dehydes at elevated concentration of base at room temperature.
Both procedure parts were again arranged as one-pot modifi-
cation. This reaction set-up leads exclusively to nitrones 4a–d to-
gether with no detectable hydroxy-substituted products (Scheme 8,
Table 1, entries 5–8).
•
•
+
RO
R
N
OH
N
OH
O
Cyclization
Addition
1
ROH - RO
OH
H
R
O
N
O
O
Ar
HO
H
H
R
Ar
O
N
O
Condensation
- H2O
R
Ar
O
N
O
Scheme 6. Domino reaction pathway of allenyloxime 1; arrows at the structure of the
final product show positions where in this reaction carried out in CD3OD (instead of
methanol) incorporation of deuterium was observed.
involves 5-methyl deprotonation with participation of the base
present and consequent condensation with aldehyde with forma-
tion of the dehydrated final product.
H
•
i,ii
Ar
+
+
EtOH
O
Ar
O
N
OH
N
O
It should be noted that during cyclization step, protonation of
former allenyloxime at positions 3 and 5 is possible. Although one
could think about more straight process connected with a direct
attack of the intermediate formed by the nucleophilic attack of
alkoxide anion at the present aldehyde. But such a mechanism may
be excluded, according with results obtained in the case of the
reaction in CD3OD. Besides expected CD3O group instead CH3O in
position 2 and deuterium at position 4, the final reaction product
showed incorporation of deuterium at carbon atom of the C]C
double bond (shown in Scheme 6). This way the participation of the
solvent in the reaction pathway was clearly documented.
1
Ar = Phenyl (a), 1-Naphthyl (b), 9-Anthryl (c), 9-Phenanthryl (d) 4a-d (50-54%)
Scheme 8. One-pot two-step transformation of allenyloxime 1 in ethanol: (i) KOH
(0.1 equiv),
D; (ii) KOH (3.9 equiv), aromatic aldehyde, room temperature.
Ability of prepared nitrones to undergo 1,3-dipolar cycloaddtions
and form corresponding isoxazoles was tested on selected nitrone
3d with dimethylacetylenedicarboxylateas a reactivedipolarophile.
Expected compound 7 was isolated in high yield (Scheme 9).
It is obvious, that first addition reaction step determines the
type of substitution in position 2 of the final nitrone. Accordingly,
compound 5 must result from hydroxide attack rather than alk-
oxide anion attack at the beginning of the reaction cascade. We
have already shown that the addition of the hydroxide anion can be
effectively used for the preparation of 2-hydroxy nitrones (shown
as the left part of Scheme 7).2 When analogous conditions11 were
tested in the presence of benzaldehyde, nitrone 5 was isolated in
low yield as the main product (Scheme 7).
i
O
N
O
O
MeO2C
MeO2C
N
O
3d
7 (87%)
Scheme 9. 1,3-Dipolar cycloaddition of nitrone 3d: (i) dimethyl acetylenedicarbox-
ylate, toluene,
D.
This supports the fact that the formation of side product 5, in the
previously shown procedure (Scheme 5), is probably affected by
a high concentration of hydroxide promoter (4 equiv). Under such
conditions, we can assume that in ethanol, the elevated hydroxide
concentration initiates a competitive reaction. The reason for this
Compound 7 was found as a single diastereomer (racemate).12
The relative stereochemistry was confirmed by X-ray analysis15
(Fig. 3). Similar diastereoselectivity for 1,3-dipolar cycloaddition
was observed for nitrone 2 and its structural analogs.2

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M. Buchlovic et al. / Tetrahedron 66 (2010) 1821–1826
1824
dried over MgSO4 and the solvent evaporated. The residual oil was
purified by column chromatography (Et2O/EtOAc), and the re-
sidual content of solvent was evaporated under high vacuum
(10ꢂ2 mbar).
4.2.1. (E)-2-Methoxy-3,3-dimethyl-5-(2-phenylethenyl)-3,4-dihydro-
2H-pyrrole 1-oxide (3a). Crude product was sonificated in hexane
until a slightly yellow precipitate was formed. The suspension was
then cooled to ꢂ15 ꢀC for 30 min. Formed solid was separated by
filtration, washed with hexane and dried under vacuum to give 3a
as white solid (229 mg, 78%), mp 109–110 ꢀC. dH (CDCl3): 1.15 (s,
3H, C–CH3), 1.22 (s, 3H, C–CH3), 2.55 (d, 2JH,H 16.3, 1H, CH2), 2.73 (d,
2JH,H 16.3, 1H, CH2), 3.87 (s, 3H, O–CH3), 4.52 (s, 1H, CH–O), 6.91 (d,
3JH,H 16.5, 1H, CAr–CH]CH), 7.28–7.55 (m, 6H, CAr–CH]CHþCHAr);
dC (CDCl3): 22.0 (C–CH3), 27.3 (C–CH3), 37.1 (C–CH3), 41.0 (CH2),
61.0 (O–CH3), 108.2 (CH–O), 116.2 (CH), 127.5 (CH), 129.0 (CH),
129.3 (CH), 136.2 (CAr), 136.9 (CH), 142.9 (C]N); IR (KBr): 694, 754,
962, 1117, 1142, 1196, 1215, 1275, 1541, 2870, 2953, 2970, 3035; MS
m/z (%): 245 (Mþ, 20), 215 (25), 198 (100), 128 (60), 115 (20), 77
(35), 71 (50). Calcd for C15H20NO2 (MHþ) 246.1494, HRMS found
246.1492.
Figure 3. ORTEP representation14 of compound 7.
3. Conclusion
4.2.2. (E)-2-Methoxy-3,3-dimethyl-5-(2-naphthalene-1-ylethenyl)-
3,4-dihydro-2H-pyrrole 1-oxide (3b). Et2O/EtOAc¼3:1, Rf 0.17, yel-
low solid (258 mg, 73%), mp 121–123 ꢀC. dH (CDCl3): 1.18 (s, 3H, C–
CH3), 1.25 (s, 3H, C–CH3), 2.65 (d, 2JH,H 16.3, 1H, CH2), 2.84 (d, 2JH,H
16.3, 1H, CH2), 3.89 (s, 3H, O–CH3), 4.55 (s, 1H, CH–O), 7.43–7.56
(m, 4H), 7.77–7.88 (m, 4H), 8.12 (d, JH,H 7.9, 1H); dC (CDCl3): 21.9 (C–
CH3), 27.2 (C–CH3), 37.0 (C–CH3), 41.1 (CH2), 61.0 (O–CH3), 108.1
(CH–O), 118.3 (CH), 123.0 (CH), 124.4 (CH), 125.7 (CH), 126.0 (CH),
126.5 (CH), 128.8 (CH), 129.6 (CH), 131.1 (CAr), 133.1 (CH), 133.8
(CAr), 142.6 (C]N); IR (KBr): 777, 798, 966, 1117, 1138, 1200, 1261,
1288, 1362, 1404, 1533, 2872, 2927, 2958, 3045; MS m/z (%): 295
(Mþ, 100), 248 (75), 178 (100), 165 (30), 152 (90), 86 (30), 71 (65),
41 (45). Calcd for C19H22NO2 (MHþ) 296.1651, HRMS found
296.1648.
A new approach to functionalized five-membered cyclic nitro-
nes bearing diverse-size fused polyaromatic structural motifs is
presented. The developed method is based on a one-pot reaction of
allenyloxime under mild, base catalyzed conditions. The reaction
mixtures consist of three components: 2,2-dimethyl-3,4-dienal
oxime, aromatic aldehyde and alcohol (or water) serving as the
reagent/solvent. Nine selected derivatives of target nitrones were
prepared to explore and indicate the possible limitations of the
presented method (Table 1). The reaction in methanol offers high
yields and fulfils the definition of domino arrangement.16
4. Experimental section
4.1. Instrumentation and materials
4.2.3. (E)-5-(2-Anthracene-9-ylethenyl)-2-methoxy-3,3-dimethyl-
3,4-dihydro-2H-pyrrole 1-oxide (3c). Et2O, Rf 0.17, yellow solid
(275 mg, 66%), mp 148–150 ꢀC. dH (CDCl3): 1.23 (s, 3H, C–CH3), 1.33
All chemicals were used as purchased. For preparation of com-
pounds 1, 2 see Ref. 2. Solvents (methanol, ethanol) were frac-
tionally distilled before use. Toluene was dried over sodium and
stored over molecular sieves. Column chromatography was per-
formed on Horizon HPFC system (Biotage), with FLASH Si 25þM
cartridge. Melting points are uncorrected. FTIR spectra were
recorded on a Genesis ATI (Unicam) apparatus. NMR spectra were
2
2
(s, 3H, C–CH3), 2.94 (d, JH,H 16.4, 1H, CH2), 2.77 (d, JH,H 16.4, 1H,
CH2), 3.93 (s, 3H, O–CH3), 4.62 (s, 1H, CH–O), 7.30 (d,, 3JH,H 16.8, 1H,
CAr–CH]CH), 7.33–7.52 (m, 4H, CHAr), 7.91–8.01 (m, 3H, CAr
–
CH]CHþCHAr), 8.25–8.28 (m, 2H, CHAr), 8.40 (s, 1H, CHAr); dC
(CDCl3): 22.3 (C–CH3), 27.5 (C–CH3), 37.3 (C–CH3), 41.4 (CH2), 61.4
(O–CH3), 108.5 (CH–O), 124.8 (CH), 125.5 (CH), 125.6 (CH), 126.3
(CH),128.0 (CH), 129.0 (CH),129.6 (CAr), 131.0 (CAr), 131.6 (CAr), 133.6
(CH), 142.1 (C]N); IR (KBr): 733, 906, 987, 1109, 1188, 1205, 1269,
1286, 1400, 1462, 1535, 2816, 2854, 2868, 2910, 2927, 2958, 2985,
3045; MS m/z (%): 345 (Mþ, 100), 328 (40), 298 (90), 228 (90), 215
(40), 202 (100), 126 (30), 86 (40), 71 (60), 41 (50). Calcd for
C23H24NO2 (MHþ) 346.1807, HRMS found 346.1805. Compound was
subjected to X-ray diffraction.
collected on a Bruker Avance 300 spectrometer. TMS (
d¼0.00 ppm)
or CHCl3
(
d
¼7.27 ppm) for 1H and CDCl3 (77.23 ppm) for 13C NMR
were used as internal standards, interaction constants are in Hertz.
MS data were obtained with MS TRIO 1000 (Fisons) apparatus at
70 eV in the electron impact mode, HRMS with Waters-Micromas
Q-TOF (ESSI positive mode). Diffraction data were collected on
a Kuma KM-4 four-circle CCD diffractometer and corrected for
Lorentz and polarization effects. The structures were solved by
direct methods and refined using the SHELXTL program package.13
The hydrogen atoms were placed in calculated idealized positions
and refined as riding.
4.2.4. (E)-2-Methoxy-3,3-dimethyl-5-(2-phenanthrene-9-ylethenyl)-
3,4-dihydro-2H-pyrrole 1-oxide (3d). Et2O/EtOAc¼2:1, Rf 0.13, yel-
low solid (300 mg, 72%), mp 170–172 ꢀC. dH (CDCl3): 1.20 (s, 3H,
C–CH3), 1.28 (s, 3H, C–CH3), 2.69 (d, 2JH,H 16.3,1H, CH2), 2.87 (d, 2JH,H
16.3, 1H, CH2), 3.91 (s, 3H, O–CH3), 4.58 (s, 1H, CH–O), 7.53–7.92 (m,
7H), 8.13–8.17 (m, 2H), 8.63–8.74 (m, 2H); dC (CDCl3): 22.1 (C–CH3),
27.4 (C–CH3), 37.3 (C–CH3), 41.3 (CH2), 61.1 (O–CH3), 108.4 (CH–O),
118.9 (CH),122.7 (CH),123.4 (CH),124.0 (CH),126.0 (CH),126.9 (CH),
127.0 (CH), 127.2 (CH), 127.5 (CH), 129.3 (CH), 130.2 (CAr),130.7 (CAr),
130.9 (CAr), 131.6 (CAr), 132.1 (CAr), 133.8 (CH), 142.8 (C]N); IR
(KBr): 723, 739, 984, 1001, 1115, 1144, 1196, 1271, 1286, 1367, 1404,
1537, 2866, 2926, 2954, 3016, 3047; MS m/z (%): 345 (Mþ, 25), 328
4.2. General procedure for nitrones 3a–d preparation
Potassium hydroxide (269 mg, 4.79 mmol,) was dissolved in
methanol (5 mL), then allenyloxime 1 (150 mg, 1.20 mmol) and
aromatic aldehyde (1.32 mmol) were added. The mixture was
heated at reflux for 3 h. The solution was concentrated under
reduced pressure; water (3 mL) was added and mixture was
extracted to dichloromethane (8ꢁ5 mL). Combined extracts were

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M. Buchlovic et al. / Tetrahedron 66 (2010) 1821–1826
1825
(35), 298 (30), 228 (100), 215 (25), 202 (40), 126 (30), 85 (20), 71
(20). Calcd for C23H24NO2 (MHþ) 346.1807, HRMS found 346.1807.
202 (30), 71 (20), 43 (30). Calcd for C24H26NO2 (MHþ) 360.1964,
HRMS found 360.1960.
4.3. General procedure for nitrones 4a–d preparation
4.3.4. (E)-2-Ethoxy-3,3-dimethyl-5-(2-phenanthrene-9-ylethenyl)-
3,4-dihydro-2H-pyrrole 1-oxide (4d). Et2O/Et2O/EtOAc¼1:2, Rf 0.14
(Et2O), yellow oil (215 mg, 50%). dH (CDCl3): 1.21 (s, 3H, C–CH3), 1.27
Potassium hydroxide (7 mg, 0.12 mmol) was dissolved in
methanol (5 mL), then allenyloxime 1 (150 mg, 1.20 mmol) was
added. Mixture was heated at reflux for 5.5 h. The solution was
cooled down to room temperature, then potassium hydroxide
(262 mg, 4.67 mmol) was dissolved and aromatic aldehyde
(1.32 mmol) was added. The mixture was stirred at room temper-
ature for 3 h and then was concentrated under reduced pressure;
water (3 mL) was added and mixture was extracted to dichloro-
methane (8ꢁ5 mL). The combined extracts were dried over MgSO4
and solvents evaporated. Residual oil was purified by column
chromatography (Et2O/EtOAc). Solid products were obtained by
evaporation of residual content of solvent under high vacuum
(10ꢂ1 mbar), if necessary crystallization was supported by re-
frigerating overnight.
3
2
(s, 3H, C–CH3), 1.29 (t, JH,H 7.0, 3H, CH2–CH3), 2.69 (d, JH,H 16.3,
1H, N]C–CH2), 2.89 (d, 2JH,H 16.3, 1H, N]C–CH2), 3.89–4.00 (m, 1H,
O–CH2), 4.38–4.48 (m, 1H, O–CH2), 4.67 (s, 1H, CH–O), 7.53–7.92
(m, 7H), 8.13–8.18 (m, 2H), 8.63–8.75 (m, 2H); dC (CDCl3): 15.5 (CH2–
CH3) 22.3 (C–CH3), 27.4 (C–CH3), 37.2 (C–CH3), 41.3 (N]C–CH2), 69.1
(O–CH2), 107.0 (CH–O), 119.1 (CH), 122.7 (CH), 123.5 (CH), 124.1 (CH),
126.1 (CH), 126.9 (CH), 127.0 (CH), 127.2 (CH), 127.5 (CH), 129.4 (CH),
130.3 (CAr), 130.7 (CAr), 130.9 (CAr), 131.7 (CAr), 132.2 (CAr), 133.7 (CH),
142.7 (C]N); IR (film): 723, 748, 964, 1105, 1130, 1180, 1198, 1269,
1402, 1533, 2846, 2866, 2906, 2926, 2968, 3062; MS m/z (%): 359
(Mþ, 30), 298 (100), 281 (30), 228 (80), 202 (45). Calcd for C24H26NO2
(MHþ) 360.1964, HRMS found 360.1958.
4.4. (E)-2-Hydroxy-3,3-dimethyl-5-(2-phenylethenyl)-
3,4-dihydro-2H-pyrrole 1-oxide (5)
4.3.1. (E)-2-Ethoxy-3,3-dimethyl-5-(2-phenylethenyl)-3,4-dihydro-
2H-pyrrole 1-oxide (4a). Et2O/EtOAc¼7:2, Rf 0.21, yellow solid
(159 mg, 51%), mp 74–76 ꢀC. dH (CDCl3): 1.15 (s, 3H, C–CH3), 1.21 (s,
Potassium hydroxide (269 mg, 4.79 mmol) was dissolved in
water (10 mL), then allenyloxime 1 (150 mg, 1.20 mmol) and
benzaldehyde (140 mg, 1.32 mmol) was added. The mixture was
heated to 60 ꢀC (temperature of oil bath) for 24 h. Afterwards, the
solution was saturated by addition of NaCl (2 g) and extracted to
dichloromethane (5ꢁ10 mL). The combined extracts were dried
over MgSO4 and evaporated. The residual oil was purified by col-
umn chromatography (EtOAc, Rf 0.40) to give white solid (81 mg,
29%), mp 177–179 ꢀC. dH (CDCl3): 1.18 (s, 3H, CH3), 1.29 (s, 3H, CH3),
2.59 (d, 2JH,H 16.2, 1H, CH2), 2.76 (d, 2JH,H 16.5, 1H, CH2), 5.19 (s, 1H,
3
2
3H, C–CH3), 1.26 (t, JH,H 7.0, 3H, CH2–CH3), 2.54 (d, JH,H 16.3, 1H,
N]C–CH2), 2.74 (d, 2JH,H 16.3, 1H, N¼C–CH2), 3.85–3.95 (m, 1H, O–
3
CH2), 4.33–4.44 (m, 1H, O–CH2), 4.61 (s, 1H, CH–O), 6.90 (d, JH,H
16.5, 1H, CAr–CH]CH), 7.29–7.53 (m, 6H, CAr–CH]CHþCHAr); dC
(CDCl3): 15.4 (CH2–CH3) 22.2 (C–CH3), 27.3 (C–CH3), 37.0 (C–CH3),
41.0 (N]C–CH2), 69.0 (O–CH2),106.9 (CH–O),116.3 (CH),127.5 (CH),
129.0 (CH), 129.3 (CH), 136.3 (CAr), 136.8 (CH), 142.7 (C]N); IR
(KBr): 688, 754, 958, 1041, 1105, 1149, 1176, 1194, 1227, 1271, 1292,
1371, 1541, 2868, 2904, 2941, 2958, 2980, 3022, 3037, 3057; MS m/z
(%): 260 (Mþ, 75), 215 (50), 198 (100), 128 (50), 91 (25), 77 (35), 57
(50), 41 (60). Calcd for C16H22NO2 (MHþ) 260.1651, HRMS found
260.1654.
N–CH), 6.94 (d, 3JH,H 16.5, 1H, CAr–CH]CH), 7.34–7.55 (m, 6H, CAr
–
CH]CHþCHAr), 8.49 (s, 1H, OH); dC (CDCl3): 22.1 (CH3), 26.8 (CH3),
37.3 (C–CH3), 40.6 (CH2), 99.8 (CH–O), 116.0 (CH), 127.7 (CH), 129.0
(CH), 129.6 (CH), 135.8 (CAr), 138.6 (CH), 143.4 (C]N); IR (KBr): 754,
976, 1163, 1219, 1277, 1396, 1556, 1616, 2744, 2872, 2927, 2964,
3046; MS m/z (%): 231 (Mþ, 10), 128 (100), 115 (30), 91 (30), 77 (70),
57 (50), 51 (30). Calcd for C14H18NO2 (MHþ) 232.1338, HRMS found
232.1334. Compound was subjected to X-ray diffraction.
4.3.2. (E)-2-Ethoxy-3,3-dimethyl-5-(2-naphthalene-1-ylethenyl)-
3,4-dihydro-2H-pyrrole 1-oxide (4b). Et2O/EtOAc¼5:1, Rf 0.18,
yellow oil (185 mg, 50%). dH (CDCl3): 1.17 (s, 3H, C–CH3), 1.23 (s, 3H,
C–CH3), 1.26 (t, 3JH,H 7.1, 3H, CH2–CH3), 2.64 (d, 2JH,H 16.3, 1H, N]C–
CH2), 2.83 (d, 2JH,H 16.3, 1H, N]C–CH2), 3.84–3.95 (m, 1H, O–CH2),
4.35–4.50 (m, 1H, O–CH2), 4.63 (s, 1H, CH–O), 7.25–7.52 (m, 4H),
7.74–7.87 (m, 4H), 8.11–8.14 (m, 1H); dC (CDCl3): 15.4 (CH2–CH3)
22.2 (C–CH3), 27.4 (C–CH3), 37.1 (C–CH3), 41.2 (N]C–CH2), 69.0 (O–
CH2), 106.9 (CH–O), 118.5 (CH), 123.2 (CH), 124.6 (CH), 125.9 (CH),
126.1 (CH), 126.6 (CH), 129.0 (CH), 129.7 (CH), 131.3 (CAr), 133.1 (CH),
133.2 (CAr), 133.9 (CAr), 142.8 (C]N); IR (film): 658, 702, 775, 796,
966, 1036, 1107, 1180, 1198, 1217, 1261, 1284, 1346, 1371, 1404, 1443,
1468, 1537, 1633, 2870, 2931, 2970, 3057; MS m/z (%): 309 (Mþ, 20),
265 (25), 248 (100), 231 (25), 178 (80), 152 (20). Calcd for
C20H24NO2 (MHþ) 310.1807, HRMS found 310.1806.
4.5. (E)-Dimethyl 6-methoxy-5,5-dimethyl-3a-
(2-phenanthrene-9-ylethenyl)-3a,4,5,6-tetrahydro-
pyrrolo [1,2-b]isoxazole-2,3-dicarboxylate (7)
Nitrone 3d (80 mg, 0.232 mmol) was dissolved in dry toluene
(4 mL) and dimethyl acetylenedicarboxylate (46 mg, 3.24 mmol)
was added. The mixture was heated at reflux for 30 min. The sol-
vent was evaporated and the residual oil was dissolved in methanol
(2 mL). The solution was cooled to ꢂ15 ꢀC and sonificated until
a precipitate was formed. The precipitate was separated by filtra-
tion, washed with methanol and dried under high vacuum to give
yellowish solid (98 mg, 87%), mp 126–127 ꢀC. dH (CDCl3): 1.14 (s, 3H,
C–CH3), 1.16 (s, 3H, C–CH3), 2.36 (d, 2JH,H 13.4, 1H, CH2), 2.44 (d, 2JH,H
13.5, 1H, CH2), 3.67 (s, 3H, O–CH3), 3.80 (s, 3H, O–CH3), 3.92 (s, 3H,
O–CH3), 4.31 (s, 1H, CH–O), 6.55 (d, 3JH,H 15.5, 1H, CH]CH–C), 7.50–
7.64 (m, 5H, CH), 7.77 (s, 1H, CH), 7.84–7.87 (m, 1H, CH), 8.10–8.13
(m, 1H, CH), 8.61–8.70 (m, 2H, CH); dC (CDCl3): 22.3 (C–CH3), 26.8
(C–CH3), 38.7 (C–CH3), 49.3 (CH2), 52.2 (O–CH3), 53.5 (O–CH3), 59.0
(O–CH3), 74.4 (C–N), 107.9 (CH–O), 113.4 (C]C–O), 122.7 (CH), 123.2
(CH), 125.0 (CH), 125.1 (CH), 126.7 (2ꢁCH), 126.8 (CH), 126.9 (CH),
127.4 (CH), 128.8 (CH), 130.4 (CAr), 130.5 (CAr), 130.9 (CAr), 132.0
(CAr), 133.7 (CAr), 134.7 (CHAr), 150.9 (C]C–O), 160.0 (C]O), 162.7
(C]O); IR (KBr): 725, 746, 1088, 1117, 1142, 1201, 1215, 1290, 1331,
1435, 1666, 1711, 1755, 2839, 2870, 2902, 2951, 2970, 2997, 3022,
4.3.3. (E)-5-(2-Anthracene-9-ylethenyl)-2-ethoxy-3,3-dimethyl-3,4-
dihydro-2H-pyrrole 1-oxide (4c). Et2O, Rf 0.29, yellow solid (233 mg,
3
54%), mp 156–158 ꢀC. dH (CDCl3): 1.25 (s, 3H, C–CH3), 1.30 (t, JH,H
7.1, 3H, CH2–CH3), 1.33 (s, 3H, C–CH3), 2.78 (d, 2JH,H 16.4, 1H, N]C–
CH2), 2.96 (d, 2JH,H 16.4, 1H, N]C–CH2), 3.89–4.00 (m, 1H, O–CH2),
4.40–4.50 (m, 1H, O–CH2), 4.72 (s, 1H, CH–O), 7.30 (d, 3JH,H 16.8, 1H,
CAr–CH]CH), 7.45–7.51 (m, 4H, CHAr), 7.92–8.02 (m, 3H, CAr
–
CH]CHþCHAr), 8.26–8.29 (m, 2H, CHAr), 8.41 (s, 1H, CHAr); dC
(CDCl3): 15.5 (CH2–CH3) 22.4 (C–CH3), 27.5 (C–CH3), 37.2 (C–CH3),
41.3 (N]C–CH2), 69.3 (O–CH2), 107.0 (CH–O), 125.0 (CH), 125.5
(CH),125.6 (CH),126.3 (CH),128.0 (CH),129.0 (CH),129.6 (CAr),131.0
(CAr), 131.6 (CAr), 133.4 (CH), 141.9 (C]N); IR (KBr): 735, 912, 989,
1084, 1099, 1171, 1184, 1205, 1269, 1282, 1537, 1620, 2868, 2899,
2927, 2956, 3043; MS m/z (%): 359 (Mþ, 80), 298 (100), 228 (50),

ˇ
M. Buchlovic et al. / Tetrahedron 66 (2010) 1821–1826
1826
3061; Calcd for C29H30NO6 (MHþ) 488.2073, HRMS found 488.2071.
Compound was subjected to X-ray diffraction.
5. For review on biological activity of nitrones see: Hensley, K.; Carney, J. M.;
Steward, C. A.; Tabatabaie, T.; Pye, Q.; Floyd, R. A. Int. Rev. Neurobiol.1997, 40, 299.
6. Rescifina, A.; Chiacchio, M. A.; Corsaro, A.; De Clerq, E.; Iannazzo, D.; Mastino,
A.; Piperno, A.; Romeo, G.; Romeo, R.; Valveri, V. J. Med. Chem. 2006, 49, 709.
7. Floyd, R. A.; Kopke, R. D.; Choi, C. H.; Foster, S. B.; Doblas, S.; Towner, R. A. Free
Radical Biol. Med. 2008, 45, 1361.
Acknowledgements
8. Sar, C. P.; Jeko, J.; Hideg, K. Synthesis 2003, 9, 1367.
9. Vasilevski, S. F.; Klyatskaya, S. V.; Korovnikova, O. L.; Stass, D. V.; Amitina, S. A.;
Gririr’ev, I. A.; Elguero, J. Tetrahedron Lett. 2004, 45, 7741.
10. Nitrone 4a was isolated by gradient elution column chromatography Et2O/
Et2O/EtOAc (1/1); nitrone 5 was isolated by precipitation of crude reaction
mixture in hexane and subsequent separation of formed precipitate.
11. With exception of temperature; 60 ꢀC was necessary to decrease the degree of
decomposition.
The present work has been supported by Masaryk University
Rector’s Program for Students’ Creative Activity Support (Project
Code E0094/2009) and by Grant Agency of the Czech Republic
(No.203/09/1345).
ˇ
The authors thank Marek Necas for X-ray analyses.
12. Based on the NMR spectra of crude reaction mixture.
References and notes
13. SHELXTL, Version 5.10; Bruker AXS: Madison, WI, USA, 1997.
14. Carbon (grey), oxygen (red) and nitrogen (blue) atoms are drawn as principal
ellipses (80% probability level); hydrogen atoms are drawn as fixed-size
spheres (cyan).
15. Crystallographic data for compounds 3c (CCDC deposition number 741761),
5(CCDC deposition number 741762) 7 (CCDC deposition number 741763) have
been deposited at the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK.
ˇ
1. Man, S.; Buchlovic, M.; Potacek, M. Tetrahedron Lett. 2006, 47, 6961.
´ ˇ
ˇ
´ ˇ
2. Buchlovic, M.; Man, S.; Potacek, M. Tetrahedron 2008, 64, 9953.
3. Padwa, A.; Pearson, W. H. Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products; John Wiley & Sons: New
York, NY, 2002.
4. Zhao, H.; Joseph, J.; Zhang, H.; Karoui, H.; Kalyanaraman, B. Free Radical Biol.
Med. 2001, 31, 599.
16. Tietze, L. F. Chem. Rev. 1996, 96, 115.