Novel multicomponent domino approach to 2,5-bifunctionalized five-membered cyclic nitrones

Article abstract of DOI:10.1055/s-0031-1289726

Multicomponent reactions of 2,2-dimethylpenta-3,4-di-enal oxime with aldehydes and primary alcohols were studied and the optimum conditions for preparing a new family of 2,5-substituted five-membered cyclic nitrones were identified. This reaction offers direct access to the target structures in a single synthetic step. The scope and limitations of the reaction were evaluated, and all products were isolated and fully characterized. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289726

PAPER
973
Novel Multicomponent Domino Approach to 2,5-Bifunctionalized
Five-Membered Cyclic Nitrones
Domino
Synthesis of
2
a
,5-Bifuncti
r
onalize
d
i
Five-M
a
embered
C
n
yclic Nitrones Buchlovič, Stanislav Man, Milan Potáček*
Department of Chemistry, Masaryk University, Kotlarská 2, 611 37 Brno, Czech Republic
Fax +420549492688; E-mail: potacek@chemi.muni.cz
Received 11 December 2011; revised 14 January 2012
The reaction protocol that we studied was intended to give
new 2,5-bifunctionalized five-membered cyclic nitrones
in a single synthetic step.
Abstract: Multicomponent reactions of 2,2-dimethylpenta-3,4-di-
enal oxime with aldehydes and primary alcohols were studied and
the optimum conditions for preparing a new family of 2,5-substitut-
ed five-membered cyclic nitrones were identified. This reaction of-
fers direct access to the target structures in a single synthetic step.
The scope and limitations of the reaction were evaluated, and all
products were isolated and fully characterized.
(i), (ii)
OH
+
O
O
(iii)
Key words: allenes, alcohols, aldehydes, domino reactions, multi-
component reactions, nitrones
•
•
42%
(over 4 steps)
N
(iv)
O
Multicomponent and domino reaction protocols1 are pow-
erful, practical, and cost-effective techniques in synthetic
organic chemistry.2,3 Such protocols offer greater brevity
of the synthetic procedure through a reduction in the num-
ber of laboratory operations coupled with a significant in-
crease in the chemical complexity of the resulting
products, providing rapid access to libraries of chemically
diverse molecules.4 Multicomponent syntheses therefore
have a broad range of applications in combinatorial chem-
istry and have led to the discovery of several new pharma-
ceutically important target compounds.5 However,
multicomponent reactions are generally oriented toward
target syntheses rather than toward the preparation of syn-
thetically important scaffolds. In this report, we introduce
a multicomponent strategy for the synthesis of a new fam-
ily of functionalized cyclic nitrones.6 Among the synthetic
building blocks, the nitrone structure is one of the most
important, with a wide range of synthetic applications,7
including the syntheses of biologically important target
compounds.8 In addition, the applications in biology and
biochemistry of nitrones as spin-traps9 and their growing
therapeutic importance10 make compounds of this class of
great general interest, as illustrated by recent efforts to
functionalize the skeletons of cyclic nitrones.11
OH
1
Scheme 1 Synthesis of the starting oxime. Reaction conditions: (i)
HCl (gas), –5 °C, neat; (ii) py, 75–80 °C; (iii) 200 °C, neat; (iv)
NH2OH·HCl, Et3N, CH2Cl2.
In initial experiments, we found that heating a mixture of
allenyl oxime 1, benzaldehyde (3a), and 2-methoxyethan-
ol (2a) in the presence of potassium tert-butoxide in tert-
butanol gave the desired cyclic nitrone framework 4a
bearing alkoxy and styryl substituents at positions 2 and 5,
respectively (Scheme 2).
•
N
H
OH
1
OMe
t-BuOH
heat
O
+
O
N
OMe
3a
O
HO
4a
2a
Scheme 2
A goal of our approach to cyclic nitrones was to introduce
the allenyl oxime 1 as a starting material that is available
from readily accessible commercial chemicals in four
synthetic steps (Scheme 1).12 We have already shown that
oxime 1 is a promising compound with considerable po-
tential in heterocyclization reactions, especially those
leading to the syntheses of nitrones.13 On the basis of our
previous studies, we investigated the possibility of the ap-
plication of multicomponent reactions to this compound.
As shown previously for analogous examples,14 the for-
mation of nitrone 4a is the result of the attack by the alco-
hol 2a at the a-carbon atom of the oxime 1 initiated by a
base (Scheme 3). Subsequent heterocyclization gives the
intermediate 5, which that can be isolated if benzaldehyde
is absent from in the reaction mixture. Otherwise, nitrone
5 undergoes deprotonation of the methyl group in the 5-
position and condensation with an aldehyde 3 to give the
nitrone 4 (Scheme 3). A side reaction pathway is possible
if a significant amount of water is present in the reaction
mixture (see below); in this case, a water molecules re-
SYNTHESIS 2012, 44, 973–982
x
x
.x
x
.2
0
1
2
Advanced online publication: 27.02.2012
DOI: 10.1055/s-0031-1289726; Art ID: T108311SS
© Georg Thieme Verlag Stuttgart · New York

974
M. Buchlovič et al.
PAPER
4), but these gave only minimal improvements in the pu-
rity of the product.
•
4
3
OMe
base
OMe
5
2
+
N
Next, we examined the effect of the base used in the reac-
tion. Various amounts of tert-butoxide were tested in par-
allel runs of the multicomponent reaction of oxime 1,
alcohol 2a, and benzaldehyde (3a). Only traces of nitrone
4a were observed when the base was present in a catalytic
amount (Figure 1, A). The optimal conversion profile and
purity of the product were obtained when the base was
present in an equimolar quantity relative to the oxime 1.
Doubling the concentration of the base had a relatively
small effect on the conversion. Moreover, and to our sur-
prise, neither the addition of a Lewis acid nor the addition
of a Lewis base had any significant effect on the reaction
rate (Figure 1, B).18
O
N
path A
HO
OH
1
O
2a
5 (intermediate)
H
O
base
H2O
3a
path B
base
– H2O
3a
OH
N
O
OMe
6 (side product)
O
N
O
4a
On the basis of our studies, we consider a molar ratio of
1.0:10:1.08:1.0 of components 1, 2a, 3a, and potassium
tert-butoxide, respectively, to be optimal for providing
rapid access to nitrone 4a with satisfactory purity and
yield.19 These reaction conditions were used in a subse-
quent study of the scope of the reaction. Scheme 4 shows
the aldehydes and alcohols that we tested as potential re-
actants. Results of multicomponent reactions using these
aldehydes and alcohols as reactants are summarized in
Table 2. Note that not all the possible combinations of re-
actants were used; entries 1–32 represent experiments that
were, in our opinion, the most suitable for evaluating the
scope of the reaction.
Scheme 3
places the alcohol in the reaction to form the 2-hydroxy-
functionalized nitrone 6 (Scheme 3).
The selection of an appropriate solvent is important in
achieving satisfactory results for the overall procedure. A
polar protic solvent is required for the cyclization step to
take place.13b This condition is fulfilled if alcohol 2a
serves both as a reactant and as a solvent. However, in this
reaction setup, the structural variation that can be
achieved with regard to the alcohol component is limited
by its viscosity, its boiling point, and its ability to dissolve
the other reactants; solid or viscous liquid alcohols are not
suitable as solvents.
Table 1 Effects of the Oxime-to-Alcohol Molar Ratio and Water
Content on the Multicomponent Reaction
Entrya Molar ratio
(1/2a/3a)
Water
Molar ratio Relative
(wt%)b
(4a/6)c
33:67
50:50
54:46
68:32
79:21
78:22
84:16
94:6
conversion (%)d
Because only primary alcohols can effectively undergo
addition to the allenyl oxime,13a tert-butanol was selected
as a solvent that is inactive in the reaction and which ful-
fills all the other requirements. Furthermore, tert-butoxide
in tert-butanol is the most convenient base promoter for
this reaction.15 Having selected the solvent and base, we
then examined the optimization of the other reaction con-
ditions. The multicomponent reaction shown in Scheme 2
was performed under various conditions and the purity of
the product and the conversion were examined. Initial
studies showed a marked difference in the reactivity when
various molar ratios of oxime 1 and alcohol 2a were tested
(Table 1). Because the reaction of oxime 1 produces water
in the condensation reaction step (Scheme 3), the amount
of water in the reaction mixture relative to oxime 1 in-
creases as the reaction proceeds. Therefore, in the case of
an equimolar ratio of oxime 1 and alcohol 2a (Table 1, en-
try 1), the side-reaction pathway B (Scheme 3) predomi-
nates and nitrone 6 is formed as the product of reaction
with more-reactive water rather than with the alcohol 2a.16
The problem of the side reaction can be eliminated by us-
ing 2a in a molar excess (entries 1, 2, 5, and 8). The use of
10:1 molar ratio of alcohol 2a reduced the amount of side
product 6 to a trace and provided better conversion. We
also tested the effects of adding drying agents (entries 3,
1
2
3
4
5
6
7
8
9
1.0:1.0:1.08
1.0:2.0:1.08
1.0:2.0:1.08f
1.0:2.0:1.08h
1.0:5.0:1.08
1.0:10:1.08
1.0:10:1.08
1.0:10:1.08
1.0:10:1.08h
mine
min
min
min
min
0.55i
1.10i
min
min
67
68
ndg
nd
86
nd
nd
quant
nd
97:3
a Reactions were carried out at 80 °C then stopped; the products were
analyzed after 2 h.
b The H2O content of the reaction mixture was determined by the Karl
Fischer method.
c Determined by HPLC of the crude reaction mixture with UV detec-
tion at 307 nm (the isosbestic point for compounds 4a and 6 in
MeOH).
d Relative conversion.17
e Minimal H2O content (£0.04%; all chemicals were dried before use).
f K2CO3 added (1 equiv relative to oxime 1).
g Not determined.
h MS added (1 equiv relative to oxime 1).
i H2O added at the concentration shown.
Synthesis 2012, 44, 973–982
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Domino Synthesis of 2,5-Bifunctionalized Five-Membered Cyclic Nitrones
975
aldehyde framework
alcohol framework
reaction mixture
O
O
O
Me
N
•
OH
HO
2b
HO
3c
HO
3a
HO
HO
N
Me
N
2c
2d
2e
2f
3b
1
OH
O
O
O
O
O
H
OMe
HO
OH
HO
HO
OH
HO
+
R2
2a–n
R1
2g
2h
2a
3d
O
HO
H
N
3a–k
HO
OH
3e
NMe2
N
HO
O
3f
O
2i
2j
2k
t-BuOK
O
OH
t-BuOH, 80 °C
2.5 h
H
N
Fe
O
O
NH2
N
Et
3g
O
CO2Et
HO
SH
HO
HO
O
O
3h
3i
2l
2m
HS
2n
N
SH
NO2
R1
R2
O
HO
HO
O
O
N
2o
2p
2q
O
N
H
N
O
4a–w
O
3j
3k
3l
product
Scheme 4 Alcohols (2) and aldehydes (3) used in the experimental investigation of the scope of the reaction. If more than one reaction site is
available for alcohols 2a–n, the small arrows indicate the site at which the reaction took place; unmarked hydroxy or amino groups in the mo-
lecule remained unchanged after the reaction. For compounds 2o and 2p, no reaction was observed (see Table 2).
Table 2 Multicomponent Reactions of Oxime 1, Alcohols 2a–q, and Aldehydes 3a–l
Entrya
1
Alcohol
2d
none
2f
Aldehyde
3a
Product
NRc
NRc
4b
Yieldb (%) Entrya
Alcohol
2g
2h
2a
2j
Aldehyde
Product
4o
Yieldb (%)
–
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
3f
3f
3f
3f
3f
3f
3f
3f
3f
3f
3g
3h
3i
75
65
63
64
62
57
–
2
3a
–
4p
3
3a
78
80
63
56
76
46d
67
82
77
83
66e
51e
52
74
4q
4
2h
2a
3a
4c
4r
5
3a
4a
2k
2l
4s
6
2i
3a
4d
4t
7
2k
2m
2f
3a
4e
2n
2o
2p
2q
2f
NRf
NRf
NRf
NRf
4u
8
3a
4f
–
9
3b
3c
4g
–
10
11
12
13
14
15
16
2f
4h
–
2f
3d
3e
4i
69
78
75
–
2f
4j
2f
4v
2b
2c
3f
4k
2f
4w
3f
4l
2f
3j
3k
3l
NRf
NRf
NRf
2e
3f
4m
4n
2f
-
2f
3f
2f
-
a Reactions were carried out at 80 °C in t-BuOH with a 1.0:1.08:10:1 molar ratio of allenyl oxime 1, aldehyde 2, alcohol 3, and t-BuOK, re-
spectively, for 2.5 h.
b Isolated yield after purification by column chromatography.
c No target product was detected; a complex mixture was obtained.
d Alcohol 2m partially decomposed under the reaction conditions.
e NaOMe/MeOH and NaOEt/EtOH were used instead of t-BuOK/t-BuOH.
f No reaction; the starting materials were recovered.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 973–982

976
M. Buchlovič et al.
PAPER
Figure 2 ORTEP representation23 of compounds 4a (upper) and 4l
(lower)
Figure 1 (A) Effect of the molar ratio of potassium tert-butoxide to
oxime on the conversion.17 (B) Effects of adding Lewis acid or base
catalysts on the conversion17 of the multicomponent reaction shown
in Scheme 2. The Lewis acid or base was added in a 5 mol% concen-
tration relative to the allenyl oxime 1: (i) no catalyst, (ii) PdCl2 (as its
bisacetonitrile complex), (iii) 4-(N,N-dimethylamino)pyridine. All
curves were fitted by using a polynomial function (second-order) for
greater clarity. All reactions were carried out at 50 °C.
Note that all reactions listed in Table 2 were carried out
under identical conditions. The synthetic procedure gave
23 new cyclic nitrone products from a wide range of alco-
hols 2 and aldehydes 3; all 23 products were fully charac-
terized (see supporting information). The reaction has a
wide scope for application in the synthesis of five-mem-
bered cyclic nitrones bearing various functional groups in
positions 2 and 5.21 Moreover, fair-to-excellent yields of
the products were obtained without further optimization
for individual reactants (Table 2). Two selected products
4a and 4l were studied by single-crystal X-ray diffraction
to confirm their structures (Figure 2).22
It is apparent from Table 2 that a wide range of function-
alized alcohols tolerate the reaction conditions. Moreover,
the multicomponent reaction showed excellent chemose-
lectivity in cases when more than one hydroxy group was
present in alcohol 2 (for example, entries 16–18 and 20);
in each case, only one hydroxy group was transformed. In
addition, we found that tertiary amines (entries 6 and 20),
substituted amides (entries 7 and 21), allylic frameworks
(entry 15), or the furfuryl framework (entry 22) do not dis-
turb the reactivity of the alcohol component and give the
desired products. On the other hand, the reaction is limited
to primary alcohols; none of the desired product was ob-
served if a secondary alcohol (entry 1) or a tertiary alcohol
(entry 2) was used. Similar negative results appeared
when alcohols 2n–q were used. Compound 2m showed
limited stability under the reaction conditions (Entry 8),
resulting in a lower yield.
In summary, we have developed a new multicomponent
synthesis of functionalized five-membered cyclic ni-
trones. Along with formation of the nitrone moiety, vari-
ous functionalities, including hydroxy, amino, and amidic
groups were incorporated in a single synthetic step with-
out any protection or deprotection procedures. All reac-
tions were performed under conditions that comply with
the concept of a domino reaction, making the procedure
simple and rapid; furthermore, it is not necessary to
change the reactions conditions or to add any additional
reagent during the reaction. The scope and limitations of
the reaction were studied extensively. Experiments pro-
duced 23 examples of new functionalized nitrones, all of
which were fully characterized. The examination of the
chemical reactivity and the biological screening of the
products are the subjects of ongoing research efforts that
will be reported in a separate paper.
A significant variability in the size of the polycyclic moi-
ety of the aldehydes 3 was possible. Isolated yields in the
range 67–83% were obtained with a range of different al-
dehydes (entries 3, 9–12, 16, 27–29). The conditions are
suitable for aromatic and some heteroaromatic systems
(entries 27 and 28), and even for a ferrocene-type alde-
hyde (entry 29). The reaction failed in the case of alde-
hydes 3j–l.20
All chemicals were used as purchased. t-BuOH was dried over Na,
distilled, stored over MS (3 Å), and handled under an inert atmo-
sphere. MeOH and EtOH were dried over Na and fractionally dis-
tilled before use. Ethylene glycol was dried with KOH and then over
Synthesis 2012, 44, 973–982
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PAPER
Domino Synthesis of 2,5-Bifunctionalized Five-Membered Cyclic Nitrones
977
sodium; it was fractionally distilled on a Vigreux column before
2-({3,3-Dimethyl-1-oxido-5-[(E)-2-phenylvinyl]-3,4-dihydro-
use. Freshly opened t-BuOK was used in all reaction procedures.
2H-pyrrol-2-yl}oxy)ethanol (4b)
Column chromatography [CHCl3 → CHCl3–MeOH (6:1)] gave an
oil that precipitated on addition of Et2O (10 mL) to form a white sol-
id; yield: 260 mg (78%); mp 108–110 °C.
All HPLC measurements were carried out on Shimadzu 10AVP set-
up with a Phenomenex Gemini C18 column and a UV detector (200–
400nm). Analyses were run in gradient mode with a MeOH/H2O
mobile phase. Column chromatography was performed on a Hori-
zon HPFC system (Biotage, Uppsala) with a FLASH Si 25+M car-
tridge. Melting points are uncorrected. FTIR spectra were recorded
on a Genesis ATI (Unicam) apparatus. NMR spectra were recorded
on a Bruker Avance 300 spectrometer operating at frequencies of
300.13 MHz (1H) and 75.48 MHz (13C). TMS (d = 0.00 ppm) or
CHCl3 (d = 7.27 ppm) for 1H and CDCl3 (77.23 ppm) for 13C NMR
were used as internal standards; coupling constants are reported in
Hz. HRMS data were obtained with a Waters-Micromas Q-TOF in-
strument operating in the ESSI positive mode. Diffraction data were
collected on a Kuma KM-4 four-circle CCD diffractometer and cor-
rected for Lorentz and polarization effects. The structures were
solved by direct methods and refined by using the SHELXTL soft-
ware package.24 Hydrogen atoms were placed in calculated ideal-
ized positions and refined as riding.
IR (KBr): 968, 1076, 1127, 1153, 1175, 1221, 1278, 1395, 1451,
1549, 1613, 2872, 2932, 2961 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.15 (s, 3 H, C-CH3), 1.26 (s, 3 H,
C-CH3), 2.57 (d, 2JH,H = 16.5, 1 H, CH2-C=N), 2.73 (d, 2JH,H = 16.5,
1 H, CH2-C=N), 3.68–3.76 (m, 1 H, CH-O-CH2), 3.89–3.99 (m, 2
H, CH2-OH), 4.17–4.22 (m, 1 H, CH-O-CH2), 4.86 (s, 1 H, CH-O),
6.06 (dd, 3JH,H = 9.3, 3.4, 1 H, OH), 6.97 (d, 3JH,H = 16.6, 1 H, CAr-
CH=CH), 7.32–7.55 (m, 6 H, CAr-CH=CH + CHAr).
13C NMR (75 MHz, CDCl3): d = 22.2 (C-CH3), 27.1 (C-CH3), 37.6
(C-CH3), 40.4 (CH2-C=N), 62.8 (CH2), 77.5 (CH2), 108.0 (CH-O),
115.8 (CH), 127.7 (CH), 129.1 (CH), 129.8 (CH), 135.8 (CAr),
138.8 (CH), 143.7 (C=N).
HRMS (ESSI): m/z [M + H]+ calcd for C16H22NO3: 276.1594;
found: 276.1591.
Cyclic Nitrones; General Procedure
3-({3,3-Dimethyl-1-oxido-5-[(E)-2-phenylvinyl]-3,4-dihydro-
2H-pyrrol-2-yl}oxy)propan-1-ol (4c)
Column chromatography [CHCl3 → CHCl3–MeOH (6:1)] gave a
colorless oil that precipitated on addition of Et2O–hexane (1:1).
Subsequent evaporation gave a white solid; yield: 277 mg (80%);
mp 75–77 °C.
Alcohol 2 (12.0 mmol), allenyl oxime 1 (150 mg, 1.20 mmol), and
aldehyde 3 (1.26 mmol) were added in a portionwise manner to a
stirred soln of t-BuOK (134 mg, 1.20 mmol) in t-BuOH (6 mL) un-
der an inert atmosphere. The mixture was then heated at 80 °C (bath
temperature) under an inert atmosphere for 2.5 h, then cooled r.t.
and concentrated under vacuum. Toluene (15 mL) was added and
evaporated at 40 °C under reduced pressure. H2O (8 mL) was added
and the mixture was extracted with CH2Cl2 (7 × 5 mL). The com-
bined organic phases were washed with brine (15 mL), dried
(MgSO4), and concentrated. In the case of alcohol 2k, the combined
organic phases were washed with brine (10 mL) + 10% KOH (20
mL) and then again with brine (15 mL). The crude nitrone 4 was dis-
solved in toluene (15 mL) and that concentrated. The residue was
purified by column chromatography in the linear-gradient elution
mode with a mobile phase system A → B. Nitrones 4 had Rf ≤ 0.1
in solvent A and Rf = 0.6–0.8 in solvent B. Injection of the sample
was followed by elution with solvent A (about 1.5–2.0 column vol-
umes) and then a linear gradient A → B was started (about 5–6 col-
umn volumes). The mobile phases for each product are listed below.
Evaporated fractions were dried under a high vacuum (~0.5 torr) at
r.t. for 30 min. If necessary, crystallization was carried out the addi-
tion and evaporation of a suitable solvent.
IR (KBr): 968, 1062, 1129, 1153, 1176, 1220, 1278, 1395, 1449,
1468, 1494, 1540, 1613, 2874, 2936, 2958 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.13 (s, 3 H, C-CH3), 1.26 (s, 3 H,
C-CH3), 1.76–1.94 (m, 2 H, CH2-CH2-OH), 2.56 (d, 2JH,H = 16.4, 1
H, CH2-C=N), 2.72 (d, 2JH,H = 16.4, 1 H, CH2-C=N), 3.64–3.74 (m,
1 H, CH2-CH2-OH), 3.78–3.88 (m, 1 H, CH2-CH2-OH), 3.98–4.07
(m, 2 H, CH-O-CH2 + OH), 4.46–4.54 (m, 1 H, CH-O-CH2), 4.72
(s, 1 H, CH-O), 6.93 (d, 3JH,H = 16.6, 1 H, CAr-CH=CH), 7.33–7.54
(m, 6 H, CAr-CH=CH + CHAr)
13C NMR (75 MHz, CDCl3): d = 22.0 (C-CH3), 26.9 (C-CH3), 32.4
(CH2), 37.2 (C-CH3), 40.5 (CH2-C=N), 58.7 (CH2), 70.4 (CH2),
106.3 (CH-O), 115.9 (CH), 127.6 (CH), 128.9 (CH), 129.5 (CH),
135.9 (CAr), 137.8 (CH), 143.1 (C=N).
HRMS (ESSI): m/z [M + H]+ calcd for C17H24NO3: 290.1756;
found: 290.1756.
{1-[2-({3,3-Dimethyl-1-oxido-5-[(E)-2-phenylvinyl]-3,4-dihy-
dro-2H-pyrrol-2-yl}oxy)ethoxy]ethyl}dimethylamine (4d)
Column chromatography [EtOAc–Et3N (95:5) → MeOH–Et3N
(95:5)] gave a yellow-brown oil that was dissolved in CH2Cl2 (15
mL) and washed successively with 10% KOH (2 × 10 mL) and H2O
(1 × 10 mL). The organic phase was dried (MgSO4) and concentrat-
ed to give a yellow-brown oil; yield: 232 mg (56%).
2-(2-Methoxyethoxy)-3,3-dimethyl-5-[(E)-2-phenylvinyl]-3,4-
dihydro-2H-pyrrole 1-Oxide (4a)
Column chromatography [CHCl3 → EtOAc–MeOH (3:1)] gave a
yellowish solid; yield: 220 mg (63%); mp 62–63 °C.
IR (KBr): 968, 1118, 1177, 1223, 1279, 1396, 1451, 1468, 1494,
1538, 1612, 2826, 2875, 2930, 2961, 3058 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.17 (s, 3 H, C-CH3), 1.22 (s, 3 H,
C-CH3), 2.54 (d, 2JH,H = 16.4, 1 H, CH2-C=N), 2.74 (d, 2JH,H = 16.4,
1 H, CH2-C=N), 3.38 (s, 3 H, O-CH3), 3.54–3.66 (m, 2 H, CH2-O-
CH3), 4.05–4.13 (m, 1 H, CH-O-CH2), 4.39–4.45 (m, 1 H, CH-O-
CH2), 4.70 (s, 1 H, CH-O), 6.90 (d, 3JH,H = 16.5, 1 H, CAr-CH=CH),
7.29–7.53 (m, 6 H, CAr-CH=CH + CHAr).
13C NMR (75 MHz, CDCl3): d = 22.2 (C-CH3), 27.3 (C-CH3), 37.0
(C-CH3), 41.0 (CH2-C=N), 59.0 (O-CH3), 72.3 (CH2), 72.5 (CH2),
107.2 (CH-O), 116.2 (CH), 127.5 (CH), 129.0 (CH), 129.3 (CH),
136.2 (CAr), 137.0 (CH), 142.7 (C=N).
IR (neat): 692, 752, 966, 1124, 1222, 1279, 1396, 1466, 1495, 1537,
2769, 2817, 2872, 2941, 3059.
1H NMR (300 MHz, CDCl3): d = 1.13 (s, 3 H, C-CH3), 1.22 (s, 3 H,
3
C-CH3), 2.26 (s, 6 H, N-CH3), 2.50 (t, JH,H = 5.8, 2 H, CH2-N-
CH3), 2.54 (d, 2JH,H = 16.4, 1 H, CH2-C=N), 2.73 (d, 2JH,H = 16.4, 1
H, CH2-C=N), 3.60 (t, 3JH,H = 5.8, 2 H, CH2-CH2-N), 3.66–3.69 (m,
2 H, CH-O-CH2-CH2), 4.08–4.15 (m, 1 H, CH-O-CH2), 4.39–4.45
(m, 1 H, CH-O-CH2), 4.70 (s, 1 H, CH-O), 6.90 (d, 3JH,H = 16.5, 1
H, CAr-CH=CH), 7.29–7.52 (m, 6 H, CAr-CH=CH + CHAr).
13C NMR (75 MHz, CDCl3): d = 22.1 (C-CH3), 27.1 (C-CH3), 36.9
(C-CH3), 40.8 (CH2-C=N), 45.9 (N-CH3), 58.9 (CH2), 69.4 (CH2),
70.5 (CH2), 72.4 (CH2), 107.0 (CH-O), 116.0 (CH), 127.3 (CH),
128.8 (CH), 129.1 (CH), 136.0 (CAr), 136.8 (CH), 142.5 (C=N).
HRMS (ESSI): m/z [M + H]+ calcd for C17H24NO3: 290.1756;
found: 290.1760.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 973–982

978
M. Buchlovič et al.
PAPER
HRMS (ESSI): m/z [M + H]+ calcd for C20H31N2O3: 347.2329;
HRMS (ESSI): m/z [M + H]+ calcd for C21H32N3O3: 374.2439;
found: 347.2333.
found: 374.2443.
N-[2-({3,3-Dimethyl-1-oxido-5-[(E)-2-phenylvinyl]-3,4-dihy-
dro-2H-pyrrol-2-yl}oxy)ethyl]acetamide (4e).
Column chromatography [EtOAc → EtOAc–MeOH (1:2)] gave a
yellowish oil that crystallized from 1:5 EtOAc–Et2O (8 mL) to give
a yellowish solid; yield: 289 mg (76%); mp 100–102 °C.
2-({3,3-Dimethyl-1-oxido-5-[(1E,3E)-4-phenylbuta-1,3-dien-1-
yl]-3,4-dihydro-2H-pyrrol-2-yl}oxy)ethanol (4h)
Column chromatography [CHCl3 → EtOAc–MeOH (4:1)] gave an
oil that crystallized on addition and subsequent evaporation of
EtOAc (10 mL) to form yellow solid; yield: 301 mg (82%); mp
105–107 °C.
IR (KBr): 968, 1129, 1155, 1175, 1222, 1279, 1372, 1395, 1450,
1542, 1661, 2873, 2933, 2961, 3060 cm–1.
IR (KBr): 992, 1125, 1150, 1173, 1249, 1394, 1448, 1538, 1613,
2871, 2935, 2959 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.12 (s, 3 H, C-CH3), 1.23 (s, 3 H,
C-CH3), 2.00 (s, 3 H, C(O)-CH3), 2.55 (d, 2JH,H = 16.5, 1 H, CH2-
1H NMR (300 MHz, CDCl3): d = 1.12 (s, 3 H, C-CH3), 1.24 (s, 3 H,
C-CH3), 2.49 (d, 2JH,H = 16.5, 1 H, CH2-C=N), 2.65 (d, 2JH,H = 16.5,
1 H, CH2-C=N), 3.71–3.76 (m, 1 H, CH-O-CH2), 3.88–3.94 (m, 2
H, CH2-OH), 4.16–4.21 (m, 1 H, CH-O-CH2), 4.82 (s, 1 H, CH-O),
6.05 (m, 1 H, OH), 6.76–6.96 (m, 4 H), 7.28–7.45 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 22.5 (C-CH3), 27.1 (C-CH3), 37.7
(C-CH3), 40.4 (CH2-C=N), 62.9 (CH2), 77.5 (CH2), 108.0 (CH-O),
119.4 (CH), 127.2 (CH), 128.4 (CH), 129.0 (CH), 129.0 (CH),
136.5 (CAr), 138.3 (CH), 139.6 (CH), 143.5 (C=N).
2
C=N), 2.71 (d, JH,H = 16.5, 1 H, CH2-C=N), 3.40–3.50 (m, 1 H,
CH2-NH), 3.55–3.64 (m, 1 H, CH2-NH), 3.99–4.06 (m, 1 H, CH-O-
CH2), 4.15–4.22 (m, 1 H, CH-O-CH2), 4.68 (s, 1 H, CH-O), 6.95 (d,
3JH,H = 16.5, 1 H, CAr-CH=CH), 7.32–7.53 (m, 6 H, CAr-CH=CH +
CHAr), 8.14 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 22.1 (C-CH3), 23.3 [C(O)-CH3]
27.1 (C-CH3), 37.3 (C-CH3), 40.5 (CH2-NH + CH2-C=N), 73.3
(CH2), 107.7 (CH-O), 115.6 (CH), 127.6 (CH), 129.0 (CH), 129.7
(CH), 135.8 (CAr), 138.5 (CH), 143.5 (C=N), 170.7 (C=O).
HRMS (ESSI): m/z [M + H]+ calcd for C18H24NO3: 302.1751;
found: 302.1755.
HRMS (ESSI): m/z [M + H]+ calcd for C18H25N2O3: 317.1860;
found: 317.1857.
2-({3,3-Dimethyl-5-[(E)-2-(2-naphthyl)vinyl]-1-oxido-3,4-dihy-
dro-2H-pyrrol-2-yl}oxy)ethanol (4i)
Column chromatography [CHCl3–EtOAc (1:1) → EtOAc–MeOH
(4:1)] gave a yellow solid; yield: 300 mg (78%); mp 137–141 °C.
N-[2-({3,3-Dimethyl-1-oxido-5-[(E)-2-phenylvinyl]-3,4-dihy-
dro-2H-pyrrol-2-yl}oxy)ethyl]urea (4f)
Column chromatography [EtOAc–Et3N (95:5) → MeOH–Et3N
(95:5)] gave a white amorphous solid; yield: 175 mg (46%).
IR (KBr): 965, 1076, 1098, 1126, 1152, 1172, 1193, 1285, 1398,
1467, 1548, 1609, 2871, 2932, 2960, 3056 cm–1.
IR (KBr): 1176, 1221, 1278, 1395, 1468, 1548, 1613, 1660, 2873,
2934, 2963 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.14 (s, 3 H, C-CH3), 1.25 (s, 3 H,
C-CH3), 2.55 (d, 2JH,H = 16.5, 1 H, CH2-C=N), 2.72 (d, 2JH,H = 16.5,
1 H, CH2-C=N), 3.69–3.76 (m, 1 H, CH-O-CH2), 3.90–3.98 (m, 2
H, CH2-OH), 4.16–4.22 (m, 1 H, CH-O-CH2), 4.85 (s, 1 H, CH-O),
6.14 (dd, 3JH,H = 9.0, 3.0, 1 H, OH), 7.07 (d, 3JH,H = 16.5, 1 H, CAr-
CH=CH), 7.45–7.48 (m, 3 H, CAr-CH=CH + CHAr), 7.71–7.87 (m,
5 H, CHAr).
13C NMR (75 MHz, CDCl3): d = 22.2 (C-CH3), 27.0 (C-CH3), 37.6
(C-CH3), 40.3 (CH2-C=N), 62.8 (CH2), 77.4 (CH2), 108.0 (CH-O),
116.0 (CH), 123.6 (CH), 126.8 (CH), 127.0 (CH), 127.9 (CH),
128.5 (CH), 128.8 (CH), 128.9 (CH), 133.4 (CAr), 134.0 (CAr),
138.8 (CH), 143.7 (C=N).
1H NMR (300 MHz, CDCl3): d = 1.15 (s, 3 H, C-CH3), 1.25 (s, 3 H,
C-CH3), 2.57 (d, 2JH,H = 16.5, 1 H, CH2-C=N), 2.74 (d, 2JH,H = 16.5,
1 H, CH2-C=N), 3.34–3.44 (m, 1 H, CH2-NH), 3.52–3.62 (m, 1 H,
CH2-NH), 3.92–4.00 (m, 1 H, CH-O-CH2), 4.11–4.20 (m, 1 H, CH-
O-CH2), 4.45 (s, 2 H, NH2), 4.71 (s, 1 H, CH-O), 6.96 (d,
3JH,H = 16.5, 1 H, CAr-CH=CH), 7.11 (s, 1 H, NH), 7.33–7.55 (m, 6
H, CAr-CH=CH + CHAr)
13C NMR (75 MHz, CDCl3): d = 22.3 (C-CH3), 27.3 (C-CH3), 37.5
(C-CH3), 40.6 (CH2-C=N), 41.5 (CH2-NH), 74.3 (O-CH2), 108.3
(CH-O), 115.8 (CH), 127.8 (CH), 129.2 (CH), 130.0 (CH), 135.9
(CAr), 138.8 (CH), 144.0 (C=N), 159.3 (C=O)
HRMS (ESSI): m/z [M + H]+ calcd for C17H24N3O3: 318.1818;
HRMS (ESSI): m/z [M + H]+ calcd for C20H24NO3: 326.1751;
found: 318.1818.
found: 326.1753.
2-[(3,3-Dimethyl-5-{(E)-2-[4-(4-methylpiperazin-1-yl)phe-
nyl]vinyl}-1-oxido-3,4-dihydro-2H-pyrrol-2-yl)oxy]ethanol (4g)
Column chromatography [EtOAc–Et3N (95:5) → MeOH–Et3N
(95:5)] gave a yellow solid; yield: 260 mg (67%); mp 185–187 °C.
2-({3,3-Dimethyl-1-oxido-5-[(E)-2-(9-phenanthryl)vinyl]-3,4-
dihydro-2H-pyrrol-2-yl}oxy)ethanol (4j)
Column chromatography [CHCl3 → CHCl3–MeOH (8:1)] gave a
yellowish solid; yield: 373 mg (83%); mp 72–74 °C.
IR (KBr): 917, 980, 1101, 1150, 1193, 1229, 1290, 1378, 1463,
1513, 1558, 1598, 2747, 2802, 2829, 2847, 2938 cm–1.
IR (KBr): 965, 1076, 1098, 1127, 1151, 1193, 1267, 1370, 1403,
1451, 1494, 1549, 1603, 2870, 2932, 2961, 3075 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.13 (s, 3 H, C-CH3), 1.24 (s, 3 H,
C-CH3), 2.35 (s, 3 H, N-CH3), 2.51–2.57 (m, 5 H, N-CH2 + CH2-
C=N), 2.70 (d, 2JH,H = 16.4, 1 H, CH2-C=N), 3.28–3.32 (m, 4 H, N-
CH2), 3.68–3.73 (m, 1 H, CH-O-CH2), 3.87–3.98 (m, 2 H, CH2-
OH), 4.16–4.21 (m, 1 H, CH-O-CH2), 4.84 (s, 1 H, CH-O), 6.86 (d,
1H NMR (300 MHz, CDCl3): d = 1.19 (s, 3 H, C-CH3), 1.30 (s, 3 H,
C-CH3), 2.67 (d, 2JH,H = 16.5, 1 H, CH2-C=N), 2.84 (d, 2JH,H = 16.5,
1 H, CH2-C=N), 3.75–3.78 (m, 1 H, CH-O-CH2), 3.93–4.01 (m, 2
H, CH2-OH), 4.20–4.25 (m, 1 H, CH-O-CH2), 4.90 (s, 1 H, CH-O),
6.06 (d, JH,H = 7.3, 1 H, OH), 7.51–7.89 (m, 7 H), 8.10–8.13 (m, 2
H), 8.62 (d, JH,H = 8.0, 1 H), 8.70 (d, JH,H = 7.6, 1 H).
13C NMR (75 MHz, CDCl3): d = 22.2 (C-CH3), 27.0 (C-CH3), 37.7
(C-CH3), 40.5 (CH2-C=N), 62.8 (CH2), 77.5 (CH2), 108.1 (CH-O),
118.4 (CH), 122.6 (CH), 123.4 (CH), 123.8 (CH), 126.3 (CH),
126.9 (CH), 127.0 (CH), 127.2 (CH), 129.3 (CH), 130.0 (CAr),
130.6 (CAr), 130.9 (CAr), 131.4 (CAr), 131.6 (CAr), 135.5 (CH), 143.5
(C=N).
3
3JH,H = 8.8, 2 H, CHAr), 6.89 (d, JH,H = 16.5, 1 H, CAr-CH=CH),
7.21 (d, 3JH,H = 16.5, 1 H, CAr-CH=CH), 7.44 (d, 3JH,H = 8.8, 2 H,
CHAr).
13C NMR (75 MHz, CDCl3): d = 22.3 (C-CH3), 27.2 (C-CH3), 37.6
(C-CH3), 40.4 (CH2-C=N), 46.3 (N-CH3), 48.0 (CH2), 55.0 (CH2),
63.0 (CH2), 77.4 (CH2), 108.0 (CH-O), 112.4 (CH), 115.2 (CH),
126.4 (CAr), 129.2 (CH), 139.2 (CH), 144.6 (C=N), 152.1 (CAr).
Synthesis 2012, 44, 973–982
© Thieme Stuttgart · New York

PAPER
Domino Synthesis of 2,5-Bifunctionalized Five-Membered Cyclic Nitrones
979
HRMS (ESSI): m/z [M + H]+ calcd for C24H26NO3: 376.1913;
130.2 (CAr), 131.0 (CAr), 131.7 (CAr), 132.2 (CAr), 133.1 (CH), 134.3
found: 376.1917.
(O-CH2-CH=CH2) 143.0 (C=N).
HRMS (ESSI): m/z [M + H]+ calcd for C27H26NO2: 396.1964;
found: 396.1962.
2-Methoxy-3,3-dimethyl-5-[(E)-2-pyren-1-ylvinyl]-3,4-dihy-
dro-2H-pyrrole 1-Oxide (4k)
Column chromatography [Et2O → Et2O–MeOH (3:1)] gave a yel-
low solid; yield: 290 mg (66%); mp 167–169 °C.
2-({3,3-Dimethyl-1-oxido-5-[(E)-2-pyren-1-ylvinyl]-3,4-dihy-
dro-2H-pyrrol-2-yl}oxy)ethanol (4n)
IR (KBr): 839, 958, 1113, 1133, 1202, 1285, 1362, 1532, 2838,
2866, 2925, 2953, 3037 cm–1.
Column chromatography [Et2O → Et2O–MeOH (2:1)] gave an or-
ange solid; yield: 355 mg (74%); mp 195–196 °C.
1H NMR (300 MHz, CDCl3): d = 1.22 (s, 3 H, C-CH3), 1.30 (s, 3 H,
C-CH3), 2.76 (d, 2JH,H = 16.3, 1 H, CH2-C=N), 2.94 (d, 2JH,H = 16.5,
1 H, CH2-C=N), 3.92 (s, 3 H, O-CH3), 4.60 (s, 1 H, CH-O), 7.65 (d,
3JH,H = 16.2, 1 H, CAr-CH=CH), 7.98–8.21 (m, 8 H), 8.38–8.43 (m,
2 H).
13C NMR (75 MHz, CDCl3): d = 22.2 (C-CH3), 27.4 (C-CH3), 37.3
(C-CH3), 41.3 (CH2-C=N), 61.2 (O-CH3), 108.4 (CH-O), 118.1
(CH), 122.4 (CH), 124.0 (CH), 125.0 (CAr), 125.2 (CAr), 125.5
(CH), 125.6 (CH), 126.0 (CH), 126.3 (CH), 127.6 (CH), 128.2
(CH), 128.3 (CH), 129.0 (CAr), 130.1 (CAr), 130.9 (CAr), 131.6
(CAr), 132.1 (CAr), 133.1 (CH), 143.1 (C=N).
IR (KBr): 960, 1030, 1097, 1125, 1152, 1193, 1274, 1397, 1436,
1463, 1538, 1591, 2872, 2931, 2958, 3045 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.22 (s, 3 H, C-CH3), 1.33 (s, 3 H,
C-CH3), 2.75 (d, 2JH,H = 16.4, 1 H, CH2-C=N), 2.92 (d, 2JH,H = 16.4,
1 H, CH2-C=N), 3.69–3.78 (m, 1 H, CH-O-CH2), 3.84–4.02 (m, 2
H, CH2-OH), 4.18–4.27 (m, 1 H, CH-O-CH2), 4.93 (s, 1 H, CH-O),
6.11 (s, 1 H, OH), 7.64 (d, 3JH,H = 16.2, 1 H, CAr-CH=CH), 7.98–
8.20 (m, 8 H), 8.34–8.41 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 22.3 (C-CH3), 27.1 (C-CH3), 37.8
(C-CH3), 40.6 (CH2-C=N), 62.9 (CH2), 77.5 (CH2), 108.1 (CH-O),
117.6 (CH), 122.2 (CH), 124.0 (CH), 124.8 (CAr), 125.1 (CAr),
125.4 (CH), 125.7 (CH), 126.1 (CH), 126.4 (CH), 127.6 (CH),
128.4 (2 × CH), 129.2 (CAr), 129.5 (CAr), 130.8 (CAr), 131.5 (CAr),
132.4 (CAr), 134.9 (CH), 144.0 (C=N).
HRMS (ESSI): m/z [M + H]+ calcd for C25H24NO2: 370.1807;
found: 370.1809.
2-Ethoxy-3,3-dimethyl-5-[(E)-2-pyren-1-ylvinyl]-3,4-dihydro-
2H-pyrrole 1-Oxide (4l)
Column chromatography [Et2O → Et2O–MeOH (4:1)] gave a yel-
low solid; yield: 236 mg (51%); mp 162–163 °C.
HRMS (ESSI): m/z [M + H]+ calcd for C26H26NO3: 400.1907;
found: 400.1906.
2-[2-({3,3-Dimethyl-1-oxido-5-[(E)-2-pyren-1-ylvinyl]-3,4-dihy-
dro-2H-pyrrol-2-yl}oxy)ethoxy]ethanol (4o)
Column chromatography [EtOAc → EtOAc–MeOH (1:2)] gave a
yellow-orange solid; yield: 379 mg (75%); mp 165–167 °C.
IR (KBr): 840, 941, 1107, 1180, 1201, 1214, 1274, 1401, 1530,
2870, 2928, 2973, 3041 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.22 (s, 3 H, C-CH3), 1.27 (s, 3 H,
3
C-CH3), 1.30 (t, JH,H = 7.0,
3
H, O-CH2-CH3), 2.71 (d,
IR (KBr): 841, 1116, 1150, 1190, 1278, 1345, 1385, 1397, 1544,
1590, 2868, 2927, 2958, 3041, 3193 cm–1.
2JH,H = 16.2, 1 H, CH2-C=N), 2.91 (d, 2JH,H = 16.2, 1 H, CH2-C=N),
3.92–3.97 (m, 1 H, O-CH2-CH3), 4.42–4.68 (m, 1 H, O-CH2-CH3),
4.68 (s, 1 H, CH-O), 7.62 (d, 3JH,H = 16.2, 1 H, CAr-CH=CH), 7.94–
8.17 (m, 9 H), 8.31–8.45 (m, 2 H).
1H NMR (300 MHz, CDCl3): d = 1.22 (s, 3 H, C-CH3), 1.27 (s, 3 H,
C-CH3), 2.62 (d, 2JH,H = 16.3, 1 H, CH2-C=N), 2.91 (d, 2JH,H = 16.3,
1 H, CH2-C=N), 3.62–3.66 (m, 2 H, CH2), 3.74–4.78 (m, 4 H, CH2),
4.10–4.17 (m, 1 H, CH-O-CH2), 4.39–4.45 (m, 1 H, CH-O-CH2),
4.80 (s, 1 H, CH-O), 7.62 (d, 3JH,H = 16.2, 1 H, CAr-CH=CH), 7.91–
8.13 (m, 9 H), 8.24–8.33 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 22.3 (C-CH3), 27.4 (C-CH3), 37.3
(C-CH3), 41.2 (CH2-C=N), 61.8 (CH2), 70.8 (CH2), 72.5 (CH2),
72.6 (CH2), 107.2 (CH-O), 118.0 (CH), 122.3 (CH), 123.9 (CH),
124.9 (CAr), 125.1 (CAr), 125.4 (CH), 125.6 (CH), 126.0 (CH),
126.3 (CH), 127.5 (CH), 128.1 (CH), 128.2 (CH), 129.0 (CAr),
129.9 (CAr), 130.8 (CAr), 131.5 (CAr), 132.1 (CAr), 133.5 (CH), 143.6
(C=N).
13C NMR (75 MHz, CDCl3): d = 15.5 (O-CH2-CH3) 22.3 (C-CH3),
27.4 (C-CH3), 37.2 (C-CH3), 41.3 (CH2-C=N), 69.1 (O-CH2-CH3),
107.0 (CH-O), 118.3 (CH), 122.4 (CH), 124.0 (CH), 125.0 (CAr),
125.2 (CAr), 125.5 (CH), 125.6 (CH), 125.9 (CH), 126.3 (CH),
127.6 (CH), 128.2 (CH), 128.3 (CH), 129.0 (CAr), 130.1 (CAr),
130.9 (CAr), 131.6 (CAr), 132.1 (CAr), 133.0 (CH), 143.0 (C=N).
HRMS (ESSI): m/z [M + H]+ calcd for C26H26NO2: 384.1964;
found: 384.1968.
2-(Allyloxy)-3,3-dimethyl-5-[(E)-2-pyren-1-ylvinyl]-3,4-dihy-
dro-2H-pyrrole 1-Oxide (4m)
Column chromatography (CH2Cl2 → EtOAc) gave a yellow solid;
yield: 245 mg (52%); mp 180–183 °C.
HRMS (ESSI): m/z [M + H]+ calcd for C28H30NO4: 444.2169;
found: 444.2171.
IR (KBr): 842, 961, 1130, 1177, 1199, 1216, 1245, 1277, 1399,
1465, 1533, 1591, 2871, 2931, 2962, 3046 cm–1.
3-({3,3-Dimethyl-1-oxido-5-[(E)-2-pyren-1-ylvinyl]-3,4-dihy-
dro-2H-pyrrol-2-yl}oxy)propan-1-ol (4p)
Column chromatography [CHCl3 → CHCl3–MeOH (6:1)] gave a
1H NMR (300 MHz, CDCl3): d = 1.25 (s, 3 H, C-CH3), 1.28 (s, 3 H,
C-CH3), 2.73 (d, 2JH,H = 16.2, 1 H, CH2-C=N), 2.94 (d, 2JH,H = 16.2,
1 H, CH2-C=N), 4.53–4.59 (m, 1 H, O-CH2-CH=CH2), 4.74 (s, 1 H,
CH-O), 4.82–4.88 (m, 1 H, O-CH2-CH=CH2), 5.22–5.26 (dm, 1 H,
O-CH2-CH=CH2), 5.35–5.41 (dm, 1 H, O-CH2-CH=CH2), 5.91–
yellow solid; yield: 324 mg (65%); mp 200–202 °C.
IR (KBr): 842, 965, 1063, 1143, 1193, 1245, 1283, 1359, 1387,
1464, 1538, 1591, 2868, 2925, 2956, 3052 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.17 (s, 3 H, C-CH3), 1.28 (s, 3 H,
C-CH3), 1.85–1.91 (m, 2 H, CH2-CH2-OH), 2.66 (d, 2JH,H = 16.3, 1
H, CH2-C=N), 2.85 (d, 2JH,H = 16.3, 1 H, CH2-C=N), 3.68–3.76 (m,
1 H, CH2-CH2-OH), 3.80–3.88 (m, 1 H, CH2-CH2-OH), 4.03–4.09
(m, 1 H, CH-O-CH2), 4.49–4.57 (m, 1 H, CH-O-CH2), 4.74 (s, 1 H,
3
6.04 (m, 1 H, O-CH2-CH=CH2), 7.62 (d, JH,H = 16.2, 1 H, CAr-
CH=CH), 7.95–8.18 (m, 8 H), 8.33–8.39 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 22.4 (C-CH3), 27.4 (C-CH3), 37.3
(C-CH3), 41.5 (CH2-C=N), 73.7 (O-CH2-CH=CH2), 106.0 (CH-O),
117.6 (O-CH2-CH=CH2), 118.3 (CH), 122.5 (CH), 124.0 (CH),
125.0 (CAr), 125.3 (CAr), 125.5 (CH), 125.7 (CH), 126.0 (CH),
126.4 (CH), 127.7 (CH), 128.3 (CH), 128.3 (CH), 129.1 (CAr),
3
CH-O), 7.60 (d, JH,H = 16.2, 1 H, CAr-CH=CH), 7.92–8.15 (m, 9
H), 8.26–8.34 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 22.2 (C-CH3), 27.0 (C-CH3), 32.6
(CH2), 37.4 (C-CH3), 40.9 (CH2-C=N), 59.0 (CH2), 70.6 (CH2),
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M. Buchlovič et al.
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106.4 (CH-O), 117.8 (CH), 122.3 (CH), 124.0 (CH), 124.9 (CAr),
125.1 (CAr), 125.5 (CH), 125.7 (CH), 126.0 (CH), 126.3 (CH),
127.6 (CH), 128.3 (CH), 128.4 (CH), 129.1 (CAr), 129.8 (CAr),
130.9 (CAr), 131.6 (CAr), 132.3 (CAr), 134.0 (CH), 143.4 (C=N).
HRMS (ESSI): m/z [M + H]+ calcd for C27H28NO3: 414.2064;
found: 414.2063.
CH2), 4.19–4.30 (m, 1 H, CH-O-CH2), 4.77 (s, 1 H, CH-O), 7.64 (d,
3JH,H = 16.2, 1 H, CAr-CH=CH), 7.98–8.19 (m, 9 H), 8.32–8.42 (m,
2 H).
13C NMR (75 MHz, CDCl3): d = 22.4 (C-CH3), 23.5 [C(O)-CH3]
27.3 (C-CH3), 37.6 (C-CH3), 40.7 (CH2), 41.0 (CH2), 73.6 (CH2),
108.0 (CH-O), 117.8 (CH), 122.3 (CH), 124.1 (CH), 125.0 (CAr),
125.3 (CAr), 125.6 (CH), 125.9 (CH), 126.2 (CH), 126.5 (CH),
127.7 (CH), 128.6 (CH), 128.6 (CH), 129.3 (CAr), 129.7 (CAr),
131.0 (CAr), 131.7 (CAr), 132.5 (CAr), 134.7 (CH), 143.9 (C=N),
170.9 (C=O).
2-(2-Methoxyethoxy)-3,3-dimethyl-5-[(E)-2-pyren-1-ylvinyl]-
3,4-dihydro-2H-pyrrole 1-Oxide (4q)
Column chromatography [EtOAc → EtOAc–MeOH (1:1)] gave a
yellow-orange solid; yield: 312 mg (63%); mp 125–127 °C.
HRMS (ESSI): m/z [M + H]+ calcd for C28H29N2O3: 441.2178;
IR (KBr): 840, 1109, 1200, 1273, 1400, 1530, 1590, 2812, 2874,
2926, 2958, 3039 cm–1.
found: 441.2176.
2-(2-Furylmethoxy)-3,3-dimethyl-5-[(E)-2-pyren-1-ylvinyl]-
3,4-dihydro-2H-pyrrole 1-Oxide (4t)
Column chromatography (Et2O → EtOAc) gave a yellow oil that
crystallized on addition and subsequent evaporation of a cold mix-
ture of CH2Cl2 and Et2O (10 mL) to form a bright yellow solid;
yield: 300 mg (57%); mp 55–57 °C.
1H NMR (300 MHz, CDCl3): d = 1.24 (s, 3 H, C-CH3), 1.28 (s, 3 H,
C-CH3), 2.73 (d, 2JH,H = 16.2, 1 H, CH2-C=N), 2.94 (d, 2JH,H = 16.2,
1 H, CH2-C=N), 3.40 (s, 3 H, O-CH3), 3.59–3.70 (m, 2 H, CH2-O-
CH3), 4.10–4.18 (m, 1 H, CH-O-CH2), 4.44–4.51 (m, 1 H, CH-O-
CH2), 4.77 (s, 1 H, CH-O), 7.63 (d, 3JH,H = 16.2, 1 H, CAr-CH=CH),
7.96–8.15 (m, 8 H), 8.28–8.35 (m, 2 H).
IR (KBr): 841, 1093, 1108, 1150, 1198, 1274, 1530, 2871, 2929,
2957, 3237 cm–1.
13C NMR (75 MHz, CDCl3): d = 22.3 (C-CH3), 27.4 (C-CH3), 37.2
(C-CH3), 41.4 (CH2-C=N), 59.2 (O-CH3), 72.4 (CH2), 72.6 (CH2),
107.4 (CH-O), 118.2 (CH), 122.4 (CH), 123.9 (CH), 125.0 (CAr),
125.1 (CAr), 125.4 (CH), 125.6 (CH), 125.9 (CH), 126.3 (CH),
127.6 (CH), 128.2 (CH), 128.3 (CH), 129.0 (CAr), 130.1 (CAr),
130.9 (CAr), 131.6 (CAr), 132.1 (CAr), 133.1 (CH), 143.3 (C=N).
1H NMR (300 MHz, CDCl3): d = 1.17 (s, 3 H, C-CH3), 1.19 (s, 3 H,
C-CH3), 2.70 (d, 2JH,H = 16.2, 1 H, CH2-C=N), 2.90 (d, 2JH,H = 16.2,
1 H, CH2-C=N), 4.82 (s, 1 H, CH-O), 5.15 (d, 2JH,H = 13.2, 1 H, O-
CH2), 5.22 (d, 2JH,H = 13.2, 1 H, O-CH2), 6.36–6.38 (m, 1 H, CH),
6.42–6.47 (m, 1 H, CH), 7.45–7.47 (m, 1 H, CH), 7.62 (d,
3JH,H = 16.3, 1 H, CAr-CH=CH), 7.98–8.19 (m, 8 H), 8.31–8.39 (m,
2 H).
HRMS (ESSI): m/z [M + H]+ calcd for C27H28NO3: 414.2064;
found: 414.2068.
2,2'-{[2-({3,3-Dimethyl-1-oxido-5-[(E)-2-pyren-1-ylvinyl]-3,4-
dihydro-2H-pyrrol-2-yl}oxy)ethyl]imino}diethanol (4r)
Column chromatography [EtOAc → EtOAc–MeOH (1:1)] gave a
bright yellow solid; yield: 375 mg (64%); mp 134–135 °C.
13C NMR (75 MHz, CDCl3): d = 22.3 (C-CH3), 27.2 (C-CH3), 37.1
(C-CH3), 41.4 (CH2-C=N), 66.4 (O-CH3), 104.9 (CH-O), 110.5
(CH), 118.1 (CH), 122.4 (CH), 124.0 (CH), 125.0 (CAr), 125.2
(CAr), 125.5 (CH), 125.7 (CH), 126.0 (CH), 126.4 (CH), 127.7
(CH), 128.3 (CH), 128.3 (CH), 129.1 (CAr), 130.1 (CAr), 131.0
(CAr), 131.7 (CAr), 132.2 (CAr), 133.2 (CH), 143.1 (C=N), 143.3
(CH), 151.3 (CAr).
IR (KBr): 837, 1085, 1155, 1176, 1394, 1414, 1549, 1637, 2803,
2879, 2937, 3040 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.24 (s, 3 H, C-CH3), 1.31 (s, 3 H,
C-CH3), 2.67–2.80 (m, 5 H, CH2), 2.85–2.94 (m, 1 H, CH2), 2.94 (d,
2JH,H = 16.2, 1 H, CH2-C=N), 3.51–3.58 (m, 2 H, CH2), 3.65–3.72
(m, 2 H, CH2), 3.95–4.00 (m, 1 H, CH-O-CH2), 4.22–4.29 (m, 1 H,
HRMS (ESSI): m/z [M + H]+ calcd for C29H26NO3: 436.1913;
found: 436.1917.
2-({5-[(E)-2-(9-Ethyl-9H-carbazol-3-yl)vinyl]-3,3-dimethyl-1-
oxido-3,4-dihydro-2H-pyrrol-2-yl}oxy)ethanol (4u)
Column chromatography [CHCl3–EtOAc (1:1) → EtOAc–MeOH
(4:1)] gave a yellow solid. This was dissolved in toluene (10 mL)
and soln was evaporated. This procedure was repeated twice to give
a bright yellow solid; yield: 326 mg (69%); mp 148–150 °C.
3
CH-O-CH2), 4.83 (s, 1 H, CH-O), 7.67 (d, JH,H = 16.3, 1 H, CAr-
CH=CH), 7.97–8.20 (m, 9 H), 8.34–8.43 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 22.2 (C-CH3), 27.1 (C-CH3), 37.5
(C-CH3), 40.7 (CH2-C=N), 55.2 (O-CH3), 55.2 (CH2), 58.3 (CH2),
60.0 (CH2), 72.8 (CH2), 107.2 (CH-O), 117.8 (CH), 122.1 (CH),
124.0 (CH), 124.8 (CAr), 124.9 (CAr), 125.3 (CH), 125.6 (CH),
125.9 (CH), 126.2 (CH), 127.5 (CH), 128.2 (2 × CH), 129.0 (CAr),
129.6 (CAr), 130.7 (CAr), 131.4 (CAr), 132.1 (CAr), 134.3 (CH), 144.4
(C=N).
IR (KBr): 956, 1098, 1124, 1152, 1195, 1234, 1267, 1348, 1384,
1474, 1492, 1554, 1594, 1627, 2871, 2933, 2971, 3052 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.15 (s, 3 H, C-CH3), 1.25 (s, 3 H,
3
C-CH3), 1.44 (t, JH,H = 7.2,
3 H, N-CH2-CH3), 2.61 (d,
HRMS (ESSI): m/z [M + H]+ calcd for C30H35N2O4: 487.2597;
found: 487.2596.
2JH,H = 16.4, 1 H, CH2-C=N), 2.78 (d, 2JH,H = 16.4, 1 H, CH2-C=N),
3.70–3.77 (m, 1 H, CH-O-CH2), 3.88–4.00 (m, 2 H, CH2-OH),
4.17–4.22 (m, 1 H, CH-O-CH2), 4.34 (q, 3JH,H = 7.2, 2 H, N-CH2-
CH3), 4.85 (s, 1 H, CH-O), 6.46–6.50 (m, 1 H, OH), 7.11–7.49 (m,
6 H), 7.69 (d, 1 H), 8.11 (d, 1 H), 8.24 (s, 1 H).
N-[2-({3,3-Dimethyl-1-oxido-5-[(E)-2-pyren-1-ylvinyl]-3,4-di-
hydro-2H-pyrrol-2-yl}oxy)ethyl]acetamide (4s)
Column chromatography [EtOAc → EtOAc–MeOH (1:1)] gave a
yellow oil that crystallized by addition and subsequent evaporation
of cold EtOAc (10 mL) to form a bright yellow solid; yield: 329 mg
(62%); mp 144–146 °C.
13C NMR (75 MHz, CDCl3): d = 14.0 (N-CH2-CH3), 22.3 (C-CH3),
27.2 (C-CH3), 37.6, 37.9, 40.4 (CH2-C=N), 63.0 (CH2), 77.5 (CH2),
107.9 (CH-O), 109.0 (CH), 109.1 (CH), 112.7 (CH), 119.8 (CH),
120.6 (CH), 120.7 (CH), 123.0 (CAr), 123.6 (CAr), 125.7 (CH),
126.4 (CH), 126.9 (CAr), 140.6 (CAr), 140.8 (CH), 141.1 (CAr), 145.0
(C=N).
IR (KBr): 840, 1094, 1121, 1529, 1619, 1638, 2873, 2925, 2957,
3411 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.22 (s, 3 H, C-CH3), 1.33 (s, 3 H,
HRMS (ESSI): m/z [M + H]+ calcd for C24H29N2O3: 393.2178;
found: 393.2182.
C-CH3), 2.06 (s, 3 H, C(O)-CH3), 2.77 (d, 2JH,H = 16.4, 1 H, CH2-
2
C=N), 2.94 (d, JH,H = 16.4, 1 H, CH2-C=N), 3.42–3.54 (m, 1 H,
CH2-NH), 3.59–3.66 (m, 1 H, CH2-NH), 4.00–4.09 (m, 1 H, CH-O-
Synthesis 2012, 44, 973–982
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Domino Synthesis of 2,5-Bifunctionalized Five-Membered Cyclic Nitrones
981
2-({5-[(E)-2-Dibenzo[b,d]furan-4-ylvinyl]-3,3-dimethyl-1-oxi-
do-3,4-dihydro-2H-pyrrol-2-yl}oxy)ethanol (4v)
Column chromatography [CHCl3 → EtOAc–MeOH (4:1)] gave a
yellow amorphous solid; yield: 337 mg (78%).
however, the term domino reaction is preferred.2a
Multicomponent reactions are a subclass of domino
reactions in which three or more components combine to
form a single product that essentially incorporates all the
reactants within its structure.3a,b Furthermore, not all
multicomponent reactions are domino processes; subsequent
addition of reagents or changes in the reaction conditions are
also acceptable in multicomponent reactions.3b
IR (KBr): 971, 1075, 1097, 1125, 1152, 1186, 1222, 1274, 1330,
1371, 1395, 1422, 1451, 1468, 1548, 1582, 1611, 2871, 2933, 2961
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.16 (s, 3 H, C-CH3), 1.28 (s, 3 H,
C-CH3), 2.63 (d, 2JH,H = 16.5, 1 H, CH2-C=N), 2.80 (d, 2JH,H = 16.5,
1 H, CH2-C=N), 3.71–3.79 (m, 1 H, CH-O-CH2), 3.93–4.01 (m, 2
H, CH2-OH), 4.19–4.25 (m, 1 H, CH-O-CH2), 4.89 (s, 1 H, CH-O),
7.31–7.93 (m, 10 H).
(b) Hudlický, T. Chem. Rev. 1996, 96, 3.
(2) For reviews on domino reactions, see: (a) Tietze, L. F.
Chem. Rev. 1996, 96, 115. (b) Tietze, L. F.; Brasche, G.;
Gericke, K. M. Domino Reactions in Organic Synthesis;
Wiley-VCH: Weinheim, 2006. (c) Tietze, L. F.;
13C NMR (75 MHz, CDCl3): d = 22.2 (C-CH3), 27.0 (C-CH3), 37.7
(C-CH3), 40.2 (CH2-C=N), 62.9 (CH2), 77.5 (CH2), 108.1 (CH-O),
112.0 (CH), 118.2 (CH), 120.9 (CH), 121.0 (CAr), 121.7 (CH),
123.2 (CH), 123.8 (CAr), 125.0 (CAr), 126.1 (CH), 127.7 (CH),
132.5 (CH), 143.9 (C=N), 154.1 (CAr), 156.2 (CAr).
HRMS (ESSI): m/z [M + H]+ calcd for C22H24NO4: 366.1700;
found: 366.1696.
Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967.
(d) Padwa, A.; Bur, S. K. Tetrahedron 2007, 63, 5341.
(e) Bunce, R. A. Tetrahedron 1995, 51, 13103. (f) Parsons,
P. J.; Penkett, C. S.; Shell, A. J. Chem. Rev. 1996, 96, 195.
(g) Tietze, L. F.; Beifuss, U. Angew. Chem. Int. Ed. 1993, 32,
131.
(3) For reviews on multicomponent reactions, see: (a) Zhu, J.;
Bienaymé, H. Multicomponent Reactions; Wiley-VCH:
Weinheim, 2005. (b) Synthesis of Heterocycles via
Multicomponent Reactions; Orru, R. V. A.; Ruijter, E., Eds.;
Springer: Berlin, 2005. (c) Sunderhaus, J. D.; Martin, S. E.
Chem. Eur. J. 2009, 15, 1300. (d) Gahem, B. Acc. Chem.
Res. 2009, 42, 463. (e) Saymala, M. Org. Prep. Proced. Int.
2009, 41, 1. (f) Ramón, D. J.; Yus, M. Angew. Chem. Int.
Ed. 1993, 44, 1602. (g) Bienamé, H.; Hulme, C.; Oddon, G.;
Schmitt, P. Chem. Eur. J. 2000, 6, 3321.
5-[(E)-2-Ferrocenylvinyl]-2-(2-hydroxyethoxy)-3,3-dimethyl-
3,4-dihydro-2H-pyrrole 1-Oxide (4w)
Column chromatography [CHCl3 → CHCl3–MeOH (7:1)] gave a
red solid; yield: 346 mg (75%); mp 131–132 °C.
IR (KBr): 961, 1002, 1029, 1045, 1077, 1104, 1126, 1166, 1201,
1220, 1249, 1284, 1373, 1402, 1464, 1556, 1609, 2871, 2935, 2959,
3096 cm–1.
(4) For the application of multicomponent reactions in the area
of diversity-oriented synthesis, see: Biggs-Houck, J. E.;
Younai, A.; Shaw, J. T. Curr. Opin. Chem. Biol. 2010, 14,
371.
1H NMR (300 MHz, CDCl3): d = 1.14 (s, 3 H, C-CH3), 1.25 (s, 3 H,
C-CH3), 2.52 (d, 2JH,H = 16.4, 1 H, CH2-C=N), 2.68 (d, 2JH,H = 16.4,
1 H, CH2-C=N), 3.67–3.75 (m, 1 H, CH-O-CH2), 3.87–4.00 (m, 2
H, CH2-OH), 4.12–4.22 (m, 1 H, CH-O-CH2), 4.13 (s, 4 H, CpH),
4.41 (t, J = 1.9, 2 H, CpH), 4.50–4.53 (m, 2 H, CpH), 4.81 (s, 1 H,
CH-O), 6.41 (dd, 3JH,H = 8.8, 3.3, 1 H, OH), 6.85 (d, 3JH,H = 16.3, 1
H, CAr-CH=CH), 6.97 (d, 3JH,H = 16.3, 1 H, CAr-CH=CH).
13C NMR (75 MHz, CDCl3): d = 22.3 (C-CH3), 27.1 (C-CH3), 37.4
(C-CH3), 40.3 (CH2-C=N), 62.8 (CH2), 68.2 (CpH), 68.4 (CpH),
69.8 (CpH), 70.9 (CpH), 77.4 (CH2), 80.5 (Cp), 107.8 (CH-O),
113.0 (CH), 140.2 (CH), 144.2 (C=N).
(5) For recent examples, see: (a) Liddle, J.; Allen, M. J.;
Borthwick, A. D.; Brooks, D. P.; Davies, D. E.; Edwards, R.
M.; Exall, A. M.; Hamlett, C.; Irving, W. R.; Mason, A. M.;
McCafferty, G. P.; Nerozzi, F.; Peace, S.; Philp, J.; Pollard,
D.; Pullen, M. A.; Shabbir, S. S.; Sollis, S. L.; Westfall, T.
D.; Woollard, P. M.; Wu, C.; Hickey, D. M. B. Bioorg. Med.
Chem. Lett. 2008, 18, 90. (b) Nishizawa, R.; Nishiyama, T.;
Hisaichi, K.; Matsunaga, N.; Minamoto, C.; Habashita, H.;
Takaoka, Y.; Toda, M.; Shibayama, S.; Tada, H.; Sagawa,
K.; Fukushima, D.; Maeda, K.; Mitsuya, H. Bioorg. Med.
Chem. Lett. 2007, 17, 727.
HRMS (ESSI): m/z [M + H]+ calcd for C20H26FeNO3: 384.1262;
found: 384.1262.
(6) For an excellent review on the synthesis of nitrones, see:
Feuer, H. Nitrile Oxides, Nitrones, and Nitronates in
Organic Synthesis; Wiley-VCH: Weinheim, 2008.
(7) (a) Pellissier, H. Tetrahedron 2007, 63, 3235. (b) Gothelf,
K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, 863.
(c) Brandy, A.; Cardona, F.; Cicchi, S.; Cordero, F. M.; Goti,
A. Chem. Eur. J. 2009, 15, 7808. (d) Bokach, N. A.;
Kukushkin, V. Y. Russ. Chem. Bull. 2006, 55, 1869.
(e) Romeo, G.; Iannazzo, D.; Piperno, A.; Romeo, R.;
Corsaro, A.; Rescifina, A.; Chiacchio, U. Mini-Rev. Org.
Chem. 2005, 2, 59. (f) Pineiro, M.; Pinho e Melo, T. M. V.
D. Eur. J. Org. Chem. 2009, 5287. (g) Frederickson, M.
Tetrahedron 1997, 53, 403. (h) Merino, P.; Tejero, T.
Molecules 1999, 4, 169. (i) Fišera, L. In Heterocycles from
Carbocyclic Precursors; El Ashry, E. S. H., Ed.; Springer:
Berlin, 2007, 287.
(8) (a) Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products;
Padwa, A.; Pearson, W. H., Eds.; Wiley-VCH: Weinheim,
2002. (b) Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247.
(9) (a) Bethell, D. Adv. Phys. Org. Chem. 1998, 23, 91.
(b) Gomez-Mejiba, S. E.; Zhai, Z.; Akram, H.; Deterding, L.
J.; Hensley, K.; Smith, N.; Towner, R. A.; Tomer, K. B.;
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
The research was supported by Masaryk University Rector’s Pro-
gram for Students’ Creative Activity Support (Project Code E0094/
2009) and by the Grant Agency of the Czech Republic (No. 203/09/
1345). The authors thank Marek Nečas for performing the X-ray
crystal structure analysis.
References
(1) (a) A domino reaction is defined as a process involving two
or more bond-forming transformations that take place under
constant reaction conditions without adding any additional
reagent or catalyst and in which subsequent reactions occur
as a consequence of functionality formed in a prior step.2a,b
If the addition of any further reagents or catalysts is required,
consecutive reactions is a more suitable term. See Hudlický’s
discussion on this topic.1b The term tandem reaction is often
used in the literature as a synonym for domino reaction;
© Thieme Stuttgart · New York
Synthesis 2012, 44, 973–982

982
M. Buchlovič et al.
PAPER
(15) The use of an alkali metal hydroxide (KOH) as the base
caused an increase in the side product 6; see ref. 13a.
(16) The formation of nitrone 6 as the major product is in
accordance with our previous observations of the reactivity
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(17) The relative conversion was determined by using diphenyl
ether as an internal standard. A value corresponding to 100%
conversion was obtained by analysis of the reaction
performed at 80 °C for 3 h.
(18) Zinc(II) bromide and copper(II) bromide were also tested as
Lewis acid catalysts and 1,4-diazabicyclo[2.2.2]octane
(DABCO) was tested as a Lewis base catalyst; the same
results were obtained in each case.
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(c) Man, S.; Buchlovič, M.; Potáček, M. Tetrahedron Lett.
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Tetrahedron Lett. 2010, 51, 5801.
(19) For more-detailed information about the purity of the
reaction product, see the supplementary material for this
article.
(20) Enolizable aldehydes were also found to be unsuitable as
reaction components.
(21) We also attempted the synthesis of nitrones functionalized at
position 4 of the nitrone skeleton by employing substituted
derivatives of allenyl oxime 1; however, none of these
reactions was successful.
(22) Carbon (gray), oxygen (red), and nitrogen (blue) atoms are
drawn as principal ellipses (70% probability level).
Hydrogen atoms are drawn as fixed-size spheres (cyan).
(23) Crystallographic data for compounds 4a and 4l have been
deposited with the accession numbers CCDC 822444 and
822443, respectively, and can be obtained free of charge
from the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK; Fax: +44(1223)336033;
E-mail: deposit@ccdc.cam.ac.uk; Web site:
(14) For a more detailed discussion of the reaction pathway, see
www.ccdc.cam.ac.uk/conts/retrieving.html.
refs. 13a and 13b.
(24) SHELXTL, Version 5.10; Bruker AXS Inc.: Madison, 1997.
Synthesis 2012, 44, 973–982
© Thieme Stuttgart · New York