Allenyloxime-a new source of heterocyclizations to stable cyclic nitrones

Article abstract of DOI:10.1016/j.tet.2008.07.113

A variety of conditions including reductive and/or basic reagents in aqueous or alcoholic solution was applied to 2,2-dimethylpenta-3,4-dienal oxime. Formation of various five-membered heterocycles with excellent chemical selectivity was observed. Most of the reactions yielded cyclic nitrones with stable dipolar structure and unique functionalities present. All products of cyclization were isolated and fully characterized.

Full text of DOI:10.1016/j.tet.2008.07.113

Tetrahedron 64 (2008) 9953–9961
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Tetrahedron
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Allenyloximeda new source of heterocyclizations to stable cyclic nitrones
*
ˇ
´ ˇ
Marian Buchlovic, Stanislav Man, Milan Potacek
ˇ
´
´
Department of Chemistry, Masaryk University, Kotlarska 2, 611 37 Brno, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 March 2008
Received in revised form 12 July 2008
Accepted 31 July 2008
Available online 6 August 2008
A variety of conditions including reductive and/or basic reagents in aqueous or alcoholic solution was
applied to 2,2-dimethylpenta-3,4-dienal oxime. Formation of various five-membered heterocycles with
excellent chemical selectivity was observed. Most of the reactions yielded cyclic nitrones with stable
dipolar structure and unique functionalities present. All products of cyclization were isolated and fully
characterized.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Allenyloximes
Nitrones
Cyclization reaction
Heterocyclization
1. Introduction
That methodology is based on the cyclization of allenyloximes
with minimally substituted alkyl chain leading to five- or six-
Although there has been remarkable development in the field of
allene chemistry,1 allenyloximes have not attracted a lot of atten-
tion among chemists during the last decade. There are only several
papers dealing with the allenyloxime cyclizations,2,3 which were
discussed in our previous report.4 A distinct advance in allenylox-
ime chemistry was made by Gallagher et al., who for the first time
presented an idea of approaching nitrone-type compounds by
allenyloxime cyclization using AgBF4 (as electrophilic catalyst) in
dichloromethane (Scheme 1).5
membered cyclic nitrones bearing vinyl substitution.
However, the dipolar compounds could be effectively isolated
only in the case of ketoximes. Due to their lower reactivity in di-
polar cycloadditions, they afforded reasonable yields of nitrones.
The more reactive aldoximes afforded unstable nitrones, which
were trapped in situ by adding a dipolarophile.
This procedure is also complicated by the different reactivity of
E/Z oxime isomers. In particular, Z-isomers showed considerable
yields of cyclization via oxygen (Scheme 1). Nevertheless this
method has got a very good application in preparation of some
synthetically interesting targets.5,6
On the other hand, nitrones (azomethine oxides) were first
prepared in 1890 by Beckman.7 The application and new methods
for the preparation of nitrones, as important building blocks in
organic synthesis, still maintain general interest more than a cen-
tury after their discovery. Most of the studied chemistry is based on
their dipolar properties (Scheme 2).
n
R = Me; n = 1,2
N
O
E isomer
R
R
n
R = H; n = 2
E,Z isomer
R
C
N
R
N
O
N
O
OH
R2
R2
R
R3
R3
R = H, Me; n =1
R1
N
O
R1
N
O
Z isomer
O
N
R
1,2-dipole
1,3-dipole
Scheme 1. Cyclization of allenyloximes.
Scheme 2.
This behaviour provides a relatively easy access to different
heterocyclic structures via 1,3-dipolar cycloadditions. Depending
* Corresponding author. Tel.: þ420 549496615; fax: þ420 549492688.
´ ˇ
E-mail address: potacek@chemi.muni.cz (M. Potacek).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.113

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M. Buchlovic et al. / Tetrahedron 64 (2008) 9953–9961
9954
on the type of dipolarophile used, isoxazoles (with alkene, alkyne
and allene dipolarophiles) or more complex rings (with iso-
cyanates, nitriles and thiocarbonyles) could be obtained. The effi-
ciency of such reactions is documented by a wide application not
only in heterocyclic but also in the natural products chemistry.8
Our interest shown in this paper is on the ability of the prepared
allenyloximes to undergo heterocyclizations. We present several
methods based on simple conditions without any metallic catalyst
involved. The procedure provides a suitable way to construct five-
membered stable cyclic nitrones together with introduction of
various functional groups in one step process.
•
KOH
H2O, 70 °C
OH
5 (70%)
N
O
N
OH
2
Scheme 5. Cyclization of oxime 2 in alkaline aqueous solution.
When oxime 2 was heated in concentrated aqueous ammonia or
ethylamine (with no other base present), cyclization led exclusively
to nitrones 6 and 7, respectively. Both products, as in the previous
cases, involved addition of a nucleophile onto the C]N bond
(Scheme 6).
2. Results and discussion
R2NH2 (aq.)
80 °C
R2
•
We have selected 2,2-dimethylpenta-3,4-dienal oxime 2 as
a principal building block for our experiments. An unsubstituted
allenyl moiety with no additional steric demands and the presence
of geminal methyl groups9 makes this compound ideal for in-
vestigation aimed on the allenyloxime cyclization potential. The
ready avalibility10 of allenylaldehyde 1 and its easy transformation
to desired oxime 2 (Scheme 3) supported our proposal even more.
N
H
N
O
6 (73%, R2 = H)
7 (72%, R2 = Et)
N
OH
2
Scheme 6. Cyclization of oxime 2 in aqueous amine solutions.
Nitrones 5–7 are characterized by high solubility in water (6 is
strongly hygroscopic), which necessarily makes any extraction into
organic solvents difficult. Nitrone 5 is practically insoluble in diethyl
ether. But we found extraction into dichloromethane to be the most
effective. In the case of compound 5, acidifying the pH to neutral
values was necessary, due to its ability to form salts in the presence
both base and acid (for complete procedures see Section 4).
We assume that the mechanism of all the mentioned cycliza-
tions is initiated by the addition of a nucleophile on carbon atom of
C]N bond of the oxime moiety. Then after formation of a nega-
tively charged nitrogen atom of the former oxime, its nucleophile
addition favours the attack upon central allenylic atom described as
5-exo-digonal ring closure.11 The process ends probably at the more
stable tautomer containing endocyclic double bond (Scheme 7).
This intermediate, substituted cyclic enamine, could be stabilized
NH2OH . HCl, Et3N
CH2Cl2, rt
•
•
O
N
OH
1
2 (78%)
Scheme 3. Preparation of starting material.
This work, for the most part, deals with examination of this
particular derivative and through a methodical approach points out
possible applications in synthesis.
2.1. Base catalyzed cyclizations
by protonation on b-nonsaturated carbon forming observed nitrone
One of the first successful attempt at cyclization was based on
application of base catalysis. Oxime 2 undergoes ring closure in an
alcoholic solution of potassium hydroxide yielding alkoxy-
substituted nitrones 3 and 4 (Scheme 4). The base present in
0.1 equiv relative to starting material seems to be the most efficient
choice. At this concentration, the reactions still proceed within 4 h
and the separated crude product possesses a high level of purity
(suitable for further reactions) and yield (>90% for 3, >80% for 4).
product. Such a pathway correlates well with behaviour of alky-
nylhydroxylamine systems published earlier12 and differs from
electrophile catalyzed procedure discussed above.5 The nucleophile
itself could react as an anion, which we believe occurs in the case of
nitrones 3–5 formation, where the alkoxide and hydroxide ion,
respectively, are present in the reaction mixture (shown as lower
path in Scheme 7). That means that the enamine intermediate is
protonated probably with participation of the used solvent. This is
supported by experiments in dry aprotic solvents where the use of
pure alkoxides as nucleophiles did not effect any cyclization.
Alternatively, nitrones 6 and 7 are most probably products of
ammonia/amine molecule addition, followed by consequent
deprotonation of amino moiety in a proton exchange process
(shown as higher path in Scheme 7). Moreover, the role of the base
3
4
•
KOH
R1OH, reflux
R1
5
2
O
N
1
N
OH
3 (70%, R1 = Me)
O
2
4 (60%, R1 = Et)
Scheme 4. Cyclization of oxime 2 in alcohols.
•
5-exo-dig
To obtain nitrones as colourless oils, high vacuum distillation
was used as the only practical method. However, the limited
thermal stability of the concentrated products above 80 ꢀC makes
this procedure less efficient and notably lowers the yields (70% and
60%, respectively).
Based on the high stability of oxime 2 in alkaline aqueous
solution, we were able to switch from organic solvents to water as
a medium and implement the same methodology. Compound 2
showed a rapid cyclization in alkaline water leading to hydroxy-
substituted nitrone 5 (Scheme 5). However, the very low solubility
of the starting compound in water required a higher concentration
of base (2 equiv) to be used to obtain a homogeneous solution and
speed up the process. Otherwise, partial decomposition was
observed.
NuH
N
O
N
OH
NuH
NuH
Proton
exchange
•
Nu
N
OH
N
O
SolvH
Nu
•
5-exo-dig
Nu
base
Solv
N
OH
Nu
N
O
Nu = MeO , EtO , HO ; NuH = NH3; EtNH2
Scheme 7. Proposed mechanism for the formation of nitrones 3–7.

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M. Buchlovic et al. / Tetrahedron 64 (2008) 9953–9961
9955
seems to be crucial for all cyclizations. First, in alcohol or water as
a medium, the presence of the base determines the concentration
of alkoxide and hydroxide ions, respectively, considered as cycli-
zation initiators. It should be mentioned here, that in the absence of
base, no cyclic products were detected. Second, base (including
ammonia) could take part in acid–base reactions with starting
material,13 which is documented by increased solubility of oxime 2
in water, resulting in a notable influence on reaction times and
purity of the isolated products as was mentioned above.
To support the proposed mechanism on a more general basis,
we have done several experiments on substituted oxime 8 that
showed interesting behaviour under conditions of base catalyzed
cyclization. As products of the reaction in methanol, the unusual
nitrone 9 containing an exocyclic double bond and morpholine
were observed (Scheme 8). Because of the difficulties with purifi-
cation process, the structure of compound 9 was determined by 1,3-
dipolar cycloaddition with phenylisocyanate and subsequent X-ray
analysis14 of cycloadduct 10 (Fig. 1). Interestingly the cycloaddition,
according to NMR analysis of the crude reaction mixture, proceeds
with complete diastereoselectivity, yielding exclusively one di-
astereomer 10 (racemate) only.
Figure 2. ORTEP structure representation of compound 11.
characterization and determination of their structure by X-ray
diffraction.14 The structure of nitrone 3 was confirmed by the
analysis of its corresponding picrate.4 Compound 5 containing
a hydroxy group was identified indirectly by the structure analysis
of its cycloadduct 11 with dimethyl acetylenedikarboxylate (Fig. 2)
as a single diastereomer. Cycloaddition had to be used here again
for structural elucidation because by the direct X-ray analysis of 5
we were not able to fully assign the structure. Later we found that
this matches with already published information15 where nitrone 5
was prepared by oxidation of 16 by a peracid.
O
N
6
7
7a
•
KOH
PhNCO
C6H6, reflux
5
Ph
O
O
N
O
N
N
MeOH, reflux
4
1
N
OH
O
3
8
9
10
2
O
The observed interesting and exceptional properties of atoms in
compound 5 that at first caused some problems in the product
identification inspired us to perform additional experiments. Fig-
ure 3 shows that the differentiation in chemical shifts of the dia-
stereotopic hydrogen atoms of CH2 (w2.4 ppm) and methyl groups
(w1.15 ppm) in 1H NMR of 5 was lost when the sample was mea-
sured between 30 ꢀC and 35 ꢀC. Repeated measurements at differ-
ent temperatures showed that methyl signal coalescence
temperature is 30 ꢀC. It could be assumed that it is a consequence of
configuration inversion at the stereogenic centre (hydroxy-
substituted carbon), which necessarily means that a bond cleavage
takes place.
Scheme 8. Cyclization of oxime 8.
Nevertheless, the same mechanism as shown in Scheme 7 as-
suming enamine intermediate as a key step could be fully expected
in this case and so perfectly explaining the cleavage of C–N bond in
oxime 8 (Scheme 9).
Both solvents (alcohol and water) used in the reactions with
starting compound 2 listed above, afforded products with full
If we exclude the possibility of carbon–carbon or carbon–het-
eroatom bond breaking under such mild conditions, there is only
a carbon–hydrogen atom dissociation left as an option (a simple
proton exchange between the two oxygen atoms would not affect
chemical shifts that way as it is observed), which may explain the
described behaviour. If you take into consideration the neigh-
bouring electron attracting nitrogen atom, such a transformation
could be expected.
Figure 1. ORTEP structure representation of compound 10.
O
O
O
9
N
N
N
- MeO
MeO
MeO-H
•
O
O
N
OH
N
O
N
O
8
Morpholine
Figure 3. Influence of the temperature upon 1H NMR signals of compound
5
Scheme 9. Cyclization mechanism of nitrone 9 formation.
(500 MHz, CDCl3).

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M. Buchlovic et al. / Tetrahedron 64 (2008) 9953–9961
H2N
N
H
N
O
12 (78%)
13 (58%)
air
solvent free
OH
N
O
5
N
H
H2N
N
O
Scheme 10. Reaction of nitrone 5 with amines.
1
Figure 4. H NMR spectra (300 MHz, CDCl3, 30 ꢀC) of compound 5 (upper spectrum)
and mixture of compound 5 and 1.5 equiv of picric acid.
Such a process should be strongly influenced by the acidity of
the solution. Based on the experimentally proved ability of nitrone
3 to form picrates,4 we have simulated the same conditions for
compound 5 by addition of picric acid to the measured solution.
The resulted spectra (Fig. 4) demonstrated a notable suppression of
the configuration inversion.
On the other hand, the presence of a base (KOH) in D2O solution
enhanced the process (Fig. 5). However, there is no observable
decrease of the intensity of the hydrogen atom signal at C4 (in-
tegrals were calculated relative to CH2 signal). Therefore, C4 car-
bon–hydrogen bond cleavage cannot be considered.
Bapat et al. presented other possible explanation, in which C4–N
cleavage was proposed as a key step.15a But because the paper lacks
any sufficient experimental evidence, the mechanism won’t be
presented here.
Figure 6. ORTEP representation of compound 12.
The mechanism, however, simple cannot be considered to be
a polar substitution. The most simple and convincing argument is
the fact that the reaction is oxygen dependent and under a pro-
tective argon atmosphere only traces of product are detectable (this
process was studied on the reaction with benzylamine). Secondly,
we were neither able to carry out the procedure in solvent nor in
a solvent when air was bubbled through the reaction mixture. The
oxygen presence requirement could indicate a possible (hidden)
oxidation step in the reaction mechanism. Oxidation or any other
involvement of oxygen in reaction with a nitrone moiety producing
radical species is probably the process trigger. This is supported by
the well known ability of these compounds to act as spin traps and
afford relatively stable radical adducts, e.g., with singlet oxygen16 or
the superoxide anion radical.17 Since the absence of solvent makes
the study of the mechanism difficult, we have not been able to find
any experimentally supported suggestions yet. Despite the un-
solved course of the reaction, the method is very simple, effective
and offers a new type of stable nitrones in good yields.
After solving the composition of compound 5, including ex-
ceptional structural nature, we focused on its chemical reactivity.
The most curious transformation of the structure was observed in
the presence of amines. The most demonstrative behaviour of
compound 5 is a reaction where simple mixing of nitrone 5 at room
temperature with a small excess of benzylamine without any sol-
vent leads to the product of substitution 12 (Scheme 10). The exact
structure of 12 was confirmed by X-ray structure analysis (Fig. 6).14
Analogous conditions, albeit at higher temperatures, were used
for the reaction with aliphatic amine. We chose butyl-amine with
a higher boiling temperature to avoid problems of pressure in-
creases. The reaction afforded the expected product 13 (Scheme 10)
and in combination with method described above (Scheme 6)
represent a second route to amino substituted nitrones.
The second object of our further experimental study, nitrone 6,
is constitutionally a completely new compound with an amino
functionality located right next to the nitrone moiety.
We were interested in its applications in chemical trans-
formations. As demonstrative experiment, treatment with several
para-substituted benzaldehydes was chosen. The reactions led
clearly to the expected condensation products 14a–c (Scheme 11).
O
+
NH2
N
N
O
N
O
R
R
6
14a (81%, R = OH)
14b (67%, R = H)
14c (38%, R = CN)
1
Figure 5. H NMR spectra (300 MHz, D2O, 30 ꢀC) of compound 5 (upper spectrum) and
mixture of compound 5 and 1.5 equiv of KOH.
Scheme 11. Condensation of nitrone 6 with benzaldehydes.

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M. Buchlovic et al. / Tetrahedron 64 (2008) 9953–9961
9957
Nitrone16 formation18 isprobablytheresultofoximereductionto
hydroxylamine, followed by cyclization to the observed product
(Scheme 15). This proposal is based on a published procedure,19
where a set of oxime derivatives transformed to corresponding hy-
droxylamines under similar conditions. Moreover, we have experi-
mentally proved the instability of the isolated nitrone 16 under the
same reductive conditions (Scheme 13, conversion of 16 to 15). Thus,
we can anticipate that the cyclization takes place during the sepa-
rationprocess probablycaused byconcentration of hydroxylamine in
aqueoussolutioninthepresenceofthebaseandbriefheating. Similar
observations were made by House et al. on alkene analogues.20
NaBH4, OH-
MeOH, reflux
N
OH
•
15 (66%)
16 (72%)
N
OH
1. NaBH3CN, MeOH, H+
2. H2O, OH-
2
N
O
Scheme 12. Cyclization of oxime 2 under reductive conditions.
The nitrone group seems to be unaffected by this procedure or
by the purification process. Furthermore no side products were
detected, indicating that any involvement of other molecular parts
in the reaction does not occur. Such knowledge greatly increases
the synthetic potential of compound 6 and indicates a lot of other
possible transformations based on amino group.
•
•
N
OH
HN
OH
N
O
N
OH
2
16
Scheme 15. Proposed mechanism of nitrone 16 formation.
2.2. Cyclizations under reductive conditions
Another interesting transformation was observed when nitrone
3 was acidified by treatment with hydrochloric acid in water. In-
stead of expected chloride, immediate conversion to hydroxy-
substituted nitrone 5 proceeded (Scheme 13, condition E).
Products 15 and 16 were determined by X-ray analysis.14 Com-
pound 15 was analyzed as a corresponding picrate.4 Structure of
nitrone 16 (a liquid) was confirmed in the form of the cycloaddition
product with phenylisocyanate (Fig. 7, structure 17).
The presence of reducing reagents could also initiate the ring
closure of allenyloxime 2. We have observed a great difference in
the product character depending on the property of the reduction
reagent used. Treatment with sodium borohydride under basic
conditions leads to substituted pyrrolidine-1-ol 15, as we have al-
ready reported earlier.4 On the other hand, cyanoborohydride re-
duction affords cyclic nitrone 16 exclusively (Scheme 12).
Surprisingly, no acyclic product of oxime reduction (amine or hy-
droxylamine) was detected.
3. Summary and conclusion
In order to derive a reaction mechanism proposal, we have done
several experiments to search for reaction intermediates, selected
results are shown in Scheme 13.
We have established an effective method to obtain functional-
ized stable five-membered cyclic nitrones synthesis by a tandem
addition–cyclization one step process (Scheme 16). This way alle-
nyloxime 2 was transformed into 12 cyclic products (11 classified as
nitrones, Table 1) differing in functionality and/or reaction pathway
used. All cyclizations were performed in alcoholic or aqueous
solutions. Those reactions offered exclusive products with no side
reactions involved. Additionally, the chemistry of selected products
in relation to their reaction mechanism and possible synthetic
applications were studied. Some of the new unusual reactions were
described and qualified as potentially very helpful in possible
consequent research.
In conclusion, our study demonstrated that chosen allenyloxime
2 is a suitable substrate for heterocyclizations. The presented work
highlights the chemistry of allenyloximes and shows that just one
simple starting compound may be a source of plenty of different
products as presented in Table 1.
E
97%
3
5
O
OH
N
O
N
O
A
B
C
D
83%
B
2
N
OH
N
O
16
15
81%
D
Scheme 13. Interconversion of cyclization products 3, 5, 15 and 16; A: KOH, MeOH,
B: NaBH4, OHꢁ, MeOH, ; C: KOH, H2O, 70 ꢀC; D: NaBH3CN, Hþ, MeOH and then OHꢁ
/H2O; E: H2SO4 (1.5 equiv), H2O. Yields represent isolated crude products.
D;
D
First, the mechanism of pyrrolidine 15 formation was consid-
ered. Based on the experimental proof that conversion of 3 to 15 is
possible under the same conditions as of 2 to 15 (Scheme 13), we
assumed that mechanism of reductive cyclization with sodium
borohydride is stepwise including the base catalyzed cyclization to
nitrone 3 as the first step, followed by the reduction of nitrone
moiety together with C–O bond cleavage (Scheme 14).
•
Base
catalysis
Reduction
O
N
OH
N
O
N
OH
2
3
15
Figure 7. ORTEP representation of compound 17.
Scheme 14. Proposed mechanism of compound 15 formation.

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M. Buchlovic et al. / Tetrahedron 64 (2008) 9953–9961
9958
apparatus at 30 eV in the EI mode. Elemental CHN analyses were
performed at Analytical laboratory of Department of Organic
Chemistry, Faculty of Chemical Technology, University of Pardubice.
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.21 The hydrogen atoms were placed in
calculated idealized positions and refined as riding.
R3
N
N
OH
N
O
15
14a-c
i
vii (R2 = H)
•
R2
ii
vi
H
N
H
N
O
N
O
N
4.2. 2,2-Dimethylpenta-3,4-dienal oxime (2)
2
16
OH
6 (R2 = H)
7 (R2 = Et)
Improved reported4 procedure. A solution of hydroxylamine
hydrochloride (13.9 g, 0.200 mol), triethylamine (20.6 g, 0.204 mol)
and 3 Å molecular sieves (6 g) in dichloromethane (150 mL) were
v
iii
iv
12 (R2 = Bn)
13 (R2 = Bu)
cooled down to 0 ꢀC and then allenylaldehyde10
1 (20.0 g,
O
OH
5
3 (R1 = Me)
4 (R1 = Et)
N
O
N
O
R1
0.182 mol) was added slowly. The mixture was stirred at room
temperature for 5 h. After filtration (to remove molecular sieves),
the solution was washed with water (3ꢂ100 mL) and brine
(1ꢂ100 mL) and dried over MgSO4. Residual solvent was removed
under reduced pressure and subsequent oil was purified by distil-
lation in a Kugelrohr apparatus (121 ꢀC, 8 mbar) to give 2 (colour-
less oil, 17.73 g, 78%). For spectral data see Ref. 4.
Scheme 16. Heterocyclizations of allenyloxime 2 and transformations of products; (i)
NaBH4, OHꢁ, MeOH, ; (ii) NaBH3CN, Hþ, MeOH and then OHꢁ/H2O; (iii) KOH, R1OH,
(iv) KOH, H2O, 70 ꢀC; (v) R2NH2, no solvent, air; (vi) R2NH2, H2O, 80 ꢀC; (vii) aldehyde,
C6H6 or Et2O,
D
D;
D
.
4. Experimental section
4.3. 2-Methoxy-3,3,5-trimethyl-3,4-dihydro-2H-pyrrole
1-oxide (3)
4.1. Instrumentation and materials
Improved reported4 procedure. Potassium hydroxide (645 mg,
11.5 mmol) was dissolved in methanol (100 mL) and then oxime 2
(14.4 g, 0.115 mol) was added. The mixture was heated to reflux for
4 h under an argon atmosphere. Afterwards, the solution was
concentrated under reduced pressure to remove most of the sol-
vent. Then, 30 mL of water was added, followed by extraction with
dichloromethane (5ꢂ30 mL). Combined extracts were dried over
MgSO4 and evaporated. Obtained oil was purified by distillation
using a Kugelrohr apparatus (65 ꢀC, 2.5ꢂ10ꢁ2 mbar) to give nitrone
3 as colourless oil (12.66 g, 70%). For spectral data see Ref. 4. Calcd
for C8H15NO2 (157.21): C, 61.12; H, 9.62; N, 8.91. Found: C, 60.86; H,
9.62; N, 8.97.
All chemicals were used as purchased. Solvents (benzene,
diethyl ether) were dried over sodium/benzophenone and distilled
before use. Column chromatography was performed on Horizon
HPFC System (Biotage), with FLASH Si 25þM cartridge. All distil-
¨
lations were carried out using BUCHI Glass Oven B-580 ‘Kugelrohr’
apparatus. Melting points are uncorrected. FTIR spectra were
recorded with Genesis ATI (Unicam) apparatus. NMR spectra were
collected on a Bruker AC-300 (all experimental section data) and
Bruker AC-500 (low temperature measurements, see Fig. 3). TMS
(d
¼0.00 ppm) and CHCl3
(d
¼7.27 ppm) for 1H and CDCl3 (
¼77.23)
d
for 13C NMR were used as internal standards, interaction constants
are in hertz. MS data were obtained with MS TRIO 1000 (Fisons)
4.4. 2-Ethoxy-3,3,5-trimethyl-3,4-dihydro-2H-pyrrole
Table 1
Summarized yields of cyclic nitrones
1-oxide (4)
Starting
compound
Nitrone
Substitution in
position 2
Number
of steps
Overall
yield (%)
Same procedure as for 3, 6.00 g (47.9 mmol) of oxime 2, KOH
(269 mg, 4.79 mmol), EtOH (60 mL), water (10 mL) and extraction
with dichloromethane (5ꢂ15 mL) was used to get nitrone 7 (4.92 g,
60%) as colourless oil after same distillation method (70 ꢀC,
2.0ꢂ10ꢁ2 mbar). dH (CDCl3): 1.08 (s, 3H, H3C–C–CH3), 1.17 (s, 3H,
2
2
16
5
1
1
72
70
H
OH
3
H3C–C–CH3), 1.24 (t, JH,H 6.9, 3H, O–CH2–CH3), 2.03 (s, 3H, N]C–
CH3), 2.31 (d, 2JH,H 17.5, 1H, N]C–CH2), 2.54 (d, 2JH,H 17.5, 1H, N]C–
CH2), 3.83–3.94 (m, 1H, O–CH2), 4.35–4.45 (m, 1H, O–CH2), 4.55 (s,
1H, CH); dC (CDCl3): 12.9 (N]C–CH3), 15.3 (O–CH2–CH3), 22.1 (H3C–
C–CH3), 27.4 (H3C–C–CH3), 36.5 (H3C–C–CH3), 45.6 (N]C–CH2),
68.9 (O–CH2), 106.2 (CH), 143.8 (C]N); IR (film): 1038, 1111, 1178,
1243,1344, 1387, 1446, 1468, 1610, 2872, 2929, 2972; MS m/z (%):
172 (Mþ, 33), 127 (65), 112 (100), 100 (20), 72 (39), 56 (50), 41 (65).
Anal. Calcd for C9H17NO2 (171.24): C, 63.13; H, 10.01; N, 8.18. Found:
C, 62.92; H, 10.10; N, 7.93.
2
2
2
2
2
2
2
3
1
1
1
1
2
2
2
70
O
4
60
O
NH2
6
73
N
H
7
72
4.5. 2-Hydroxy-3,3,5-trimethyl-3,4-dihydro-2H-pyrrole
1-oxide (5)
13
42
N
H
Potassium hydroxide (269 mg, 4.79 mmol) was dissolved in
water (2.5 mL) and then oxime 2 (300 mg, 2.40 mmol) was added.
The mixture was then heated to 70 ꢀC under argon atmosphere for
3 h. After cooling to room temperature, the solution was neutral-
ized to pH¼7–8 (lacmus) and 0.5 g of NaCl was added to saturate
12
14a–c
57
N
H
28–59
N
R

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M. Buchlovic et al. / Tetrahedron 64 (2008) 9953–9961
9959
the solution. Then, the mixture was extracted with dichloro-
methane (7ꢂ5 mL). Combined extracts were dried over MgSO4 and
evaporated. Crude solid product was crystallized from Et2O/
CH2Cl2¼5:1 to give nitrone 5 as white solid (240 mg, 70%), mp 142–
144 ꢀC. dH (CDCl3): 1.16 (br, 6H, H3C–C–CH3), 2.06 (s, 3H, H3C–C]N),
2.45 (br, 2H, CH2), 5.08 (s, 1H, CH); dC (CDCl3): 13.4 (N]C–CH3),
22.222 (br, H3C–C–CH3), 27.122 (br, H3C–C–CH3), 36.9 (H3C–C–CH3),
45.7 (CH2), 99.7 (CH), 145.6 (C]N); IR (KBr): 821, 1120, 1153, 1174,
1190, 1228, 1330, 1386, 1450, 1468, 1633, 2744, 2844, 2933, 2964;
MS m/z (%): 144 (Mþ, 68), 97 (40), 82 (40), 73 (100), 56 (60), 41 (90).
Calcd for C7H13NO2 (143.18): C, 58.72; H, 9.15; N, 9.78. Found: C,
58.98; H, 9.27; N, 9.65.
mixture. After dissolving the solid, the molecular sieves were fil-
tered off. The organic phase was separated and residual water
phase was extracted with diethylether (6ꢂ25 mL). The combined
extracts were dried over MgSO4 and concentrated under reduced
pressure to give 8 (3.56 g, 80%) as white solid, mp 77–79 ꢀC. dH
(CDCl3): 1.27 (s, 6H, H3C–C–CH3), 2.44 (t, 3JH,H 4.6, 2H, O–CH2–CH2–
N), 2.93 (t, JH,H 2.4, 2H, N–CH2–C¼), 3.69 (t, JH,H 4.6, 4H, O–CH2–
CH2–N), 4.83 (t, 5JH,H 2.4, 2H, H2C]C), 7.43 (s, 1H, CH), 7.67 (br, 1H,
OH); dC (CDCl3): 25.3 (H3C–C–CH3), 38.6 (H3C–C–CH3), 53.7, 58.5,
67.2, 77.6 (C]C]CH2), 105.3 (C]C]CH2), 157.5 (N]C), 207.2
(C]C]CH2); IR (KBr): 875, 945, 1007, 1117, 1303, 1454, 1954 (¼C¼),
2858, 2966, 3074, 3163; MS m/z (%): 225 (Mþ, 10), 207 (90), 122
(30), 100 (100), 56 (25). Calcd for C12H20N2O2 (224.30): C, 64.26; H,
8.99; N, 12.49. Found: C, 64.04; H, 8.87; N, 12.38.
5
3
4.6. 2-Amino-3,3,5-trimethyl-3,4-dihydro-2H-pyrrole
1-oxide (6)
4.9. 2-Methoxy-3,3,5-trimethyl-4-methylene-3,4-dihydro-2H-
Oxime 2 (0.500 g, 3.99 mmol) was mixed with concentrated
(8 mL, 26%) aqueous ammonia solution in a closed apparatus fitted
with a balloon to avoid over pressuring. After 24 h of vigorous
stirring at 80 ꢀC, the homogenous pale yellow solution was con-
centrated under reduced pressure to remove the rest of ammonia,
followed by the addition of NaCl (1.5 g) and extraction with
dichloromethane (8ꢂ10 mL). The combined extracts were dried
over MgSO4 and evaporated. The resulting oil was purified by col-
umn chromatography (EtOAc/MeOH¼1:1, Rf 0.26) to give white
solid (403 mg, 71%), mp (unstable). dH (CDCl3): 1.00 (s, 3H, H3C–C–
CH3), 1.26 (s, 3H, H3C–C–CH3), 2.03 (s, 3H, N]C–CH3), 2.07 (br, 2H,
NH2), 2.31 (dm, JH,H 17.5, 1H, CH2), 2.47 (dm, JH,H 17.5, 1H, CH2),
4.27 (t, 3JH,H 8.4, 1H, CH); dC (CDCl3): 13.2 (N]C–CH3), 21.7 (H3C–C–
CH3), 26.8 (H3C–C–CH3), 36.5 (H3C–C–CH3), 45.2 (CH2), 87.6 (CH),
140.6 (C]N); IR (KBr): 924, 1188, 1217, 1387, 1470, 1631, 2872, 2937,
2958; MS m/z (%): 143 (Mþ, 40), 110 (20), 71 (50), 56 (100), 41 (35).
Calcd for C7H14N2O: 142.20.
pyrrole 1-oxide (9)
Potassium hydroxide (75 mg, 1.34 mmol) was dissolved in
methanol (30 mL) and then allenyloxime 8 (3.00 g, 13.4 mmol) was
added. The mixture was heated to reflux for 11 h. After cooling to
room temperature, the solution was concentrated under vacuum.
Then, water (10 mL) was added and mixture extracted with
dichloromethane (4ꢂ15 mL). The combined extracts were then
washed with water (2ꢂ20 mL) and brine (1ꢂ20 mL), dried over
MgSO4 and evaporated. The obtained oil was purified by column
chromatography (EtAc/MeOH¼18:1, Rf 0.22) to give 65% of yellow-
brown oil. dH (CDCl3): 1.15 (s, 3H, H3C–C–CH3), 1.26 (s, 3H, H3C–C–
CH3), 2.06 (s, 3H, H3C–C]N), 3.90 (s, 3H, O–CH3), 4.57 (s, 1H, CH),
4.99 (s, 1H, CH2), 5.13 (s, 1H, CH2); dC (CDCl3): 8.9 (N]C–CH3), 22.0
(H3C–C–CH3), 27.7 (H3C–C–CH3), 41.1 (H3C–C–CH3), 61.6 (O–CH3),
105.3 (CH2), 106.4 (CH), 143.3, 151.7.
2
2
4.10. (5R,7aS)-5-Methoxy-6,6,7a-trimethyl-7-methylene-1-
phenyltetrahydropyrrolo[1,2-b][1,2,4]oxadiazol-
2(1H)-one (10)
4.7. 2-(Ethylamino)-3,3,5-trimethyl-3,4-dihydro-2H-pyrrole
1-oxide (7)
Oxime 2 (0.350 g, 2.80 mmol) was added into aqueous ethyl-
amine (4 mL, 70%) in a closed apparatus fitted with a balloon to
avoid over pressuring. After 11 h heating at 80 ꢀC, the reaction
mixture was concentrated under reduced pressure to remove the
unreacted amine and then 350 mg of NaCl was added and the
mixture was extracted with dichloromethane (7ꢂ5 mL). Combined
extracts were dried over MgSO4 and evaporated. Resulting oil was
purified by column chromatography (Et2O/MeOH¼6:1, Rf 0.20) to
give yellowish oil (343 mg, 72%). dH (CDCl3): 1.01 (s, 3H, H3C–C–
CH3), 1.12 (t, 3JH,H 7.1, 3H, N–CH2–CH3), 1.18 (s, 3H, H3C–C–CH3), 1.18
(s, 3H, H3C–C–CH3), 1.84 (br, 1H, NH), 2.03 (dd, 4JH,H 3.1, 4JH,H 1.5, 3H,
N]C–CH3), 2.35 (dm, 2JH,H 17.5, 1H, N]C–CH2), 2.42 (dm, 2JH,H 17.5,
1H, N]C–CH2), 2.73–2.86 (m, 1H, N–CH2–CH3), 3.16–3.28 (m, 1H,
N–CH2–CH3), 4.28 (d, 3JH,H 8.3,1H, CH); dC (CDCl3): 12.8 (N]C–CH3),
15.6 (N–CH2–CH3), 22.0 (H3C–C–CH3), 27.6 (H3C–C–CH3), 36.4
(H3C–C–CH3), 41.7 (N–CH2–CH3), 45.5 (N]C–CH2), 92.9 (CH), 141.1
(C]N); IR (film): 1142, 1178, 1207, 1240, 1369, 1389, 1470, 1614,
1666, 2871, 2927, 2964; MS m/z (%): 171 (Mþ, 50), 153 (95), 110 (80),
98 (70), 84 (100), 56 (85), 41 (95). Calcd for C9H18N2O: 170.25.
Phenylisocyanate (289 mg, 2.42 mmol) was added to a solution
of nitrone 9 (410 mg, 2.42 mmol) in dry benzene (8 mL) and heated
to reflux for 4 h. The solvent was removed under vacuum and the
crude product was crystallized from Et2O to give 356 mg (51%) of
white solid, mp 120–122 ꢀC. dH (CDCl3): 1.10 (s, 3H, H3C–C–CH3),
1.32 (s, 3H, H3C–C–CH3), 1.62 (s, 3H, N–C–CH3), 3.67 (s, 3H, O–CH3),
4.43 (s, 1H), 4.63 (s, 1H), 5.14 (s, 1H), 7.15–7.42 (m, 5H, CHAr); dC
(CDCl3): 24.7 (CH3), 25.3 (CH3), 26.2 (CH3), 42.9 (H3C–C–CH3), 59.0
(O–CH3), 86.1 (N–C–CH3), 106.2 (O–CH), 112.7 (C]CH2), 129.1
(CHAr), 129.5 (CHAr), 129.9 (CHAr), 133.8 (CAr), 153.8 (C]CH2), 156.1
(C]O); IR (KBr): 704, 746, 910, 1041, 1101, 1124, 1161, 1209, 1365,
1496, 1763, 2939, 2983; MS m/z (%): 169 (45), 139 (80), 119 (100), 91
(80), 67 (35), 64 (35). Calcd for C16H20N2O3: 288.34 (MS spectrum
does not show Mþ). Compound was subjected to X-ray diffraction.
4.11. (3aR,6S)-Dimethyl-6-hydroxy-3a,5,5-trimethyl-3a,4,5,6-
tetrahydropyrrolo[1,2-b]isoxazole-2,3-dicarboxylate (11)
Nitrone 5 (200 mg, 1.40 mmol) was suspended in dry benzene
(5 mL) and dimethyl acetylenedicarboxylate (218 mg, 1.54 mmol)
was added. The mixture was stirred at room temperature for 5 h.
Then, the solvent was removed under vacuum and the solid
product was crystallized from Et2O to give 11 (white solid, 303 mg,
76%), mp 149–151 ꢀC. dH (CDCl3): 1.07 (s, 3H, H3C–C–CH3), 1.11 (s,
3H, H3C–C–CH3), 1.51 (s, 3H, N–C–CH3), 1.96 (d, 2JH,H 13.9, 1H, CH2),
4.8. 2,2-Dimethyl-3-(morpholinomethyl)penta-3,4-dienal
oxime (8)
2,2-Dimethyl-3-(morholinomethyl)penta-3,4-dienal
(4.15 g,
19.8 mmol), prepared according to the published method,10 was
slowly added to a mixture of hydroxylamine hydrochloride (1.52 g,
21,9 mmol) and 3 Å molecular sieves (3 g) in 40 mL of dichloro-
methane and then stirred under argon atmosphere for 4 h. After-
wards, sodium hydroxide (1.5 g in 20 mL of water) was added to the
2
3
2.28 (d, JH,H 13.9, 1H, CH2), 2.50 (d, JH,H 8.1, 1H, OH), 3.75 (s, 3H,
3
O–CH3), 3.89 (s, 3H, O–CH3), 4.44 (d, JH,H 8.1, 1H, CH); dC (CDCl3):
21.6 (CH3), 26.5 (CH3), 28.1 (CH3), 37.6 (H3C–C–CH3), 49.0 (CH2),
52.0 (O–CH3), 53.4 (O–CH3), 70.0 (N–C–CH3), 99.3 (CH), 115.0 (O–

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M. Buchlovic et al. / Tetrahedron 64 (2008) 9953–9961
9960
C]C), 151.2, 159.9, 162.7; IR (KBr): 1072, 1109, 1167, 1306, 1350,
1433, 1456, 1649, 1720, 1741, 2968, 2983, 3228 (br, OH); MS m/z (%):
286 (Mþ, 30), 268 (20), 238 (20), 200 (100), 168 (35), 71 (55), 42
(50); Calcd for C13H21NO6: 287.31. Compound was subjected to X-
ray diffraction.
(%): 247 (Mþ, 5), 127 (80), 120 (30), 112 (100), 41 (55). Calcd for
14H18N2O2 (246.30): C, 68.27; H, 7.37; N, 11.37. Found: C, 68.12; H,
7.37; N, 11.26.
C
4.14.2. 2-(Benzylideneamino)-3,3,5-trimethyl-3,4-dihydro-2H-
pyrrole 1-oxide (14b)
4.12. 2-(Benzylamino)-3,3,5-trimethyl-3,4-dihydro-2H-
pyrrole 1-oxide (12)
Et2O/MeOH¼3:1, Rf 0.24, white solid (162 mg, 67%), mp 88–
90 ꢀC. dH (CDCl3): 1.09 (s, 3H, H3C–C–CH3), 1.24 (s, 3H, H3C–C–CH3),
2
2.11 (s, 3H, N]C–CH3), 2.44 (d, JH,H 17.5, 1H, N]C–CH2), 2.79 (d,
Nitrone 5 (200 mg, 1.40 mmol) was triturated with benzylamine
(154 mg, 1.44 mmol) and left standing at room temperature in the
presence of air for 9 h. The obtained solid product was then crys-
tallized from Et2O to give 12 (white solid, 253 mg, 78%), mp 91–
93 ꢀC. dH (CDCl3): 1.04 (s, 3H, H3C–C–CH3), 1.15 (s, 3H, H3C–C–CH3),
2JH,H 17.5, 1H, N]C–CH2), 4.63 (s, 1H, N–CH), 7.37–7.47 (m, 3H,
CHAr), 7.80–7.84 (m, 2H, CHAr), 8.42 (s, 1H, N]CH); dC (CDCl3): 13.2
(N]C–CH3), 23.1 (H3C–C–CH3), 28.5 (H3C–C–CH3), 38.0 (H3C–C–
CH3), 46.7 (CH2), 102.1 (N–CH), 128.6 (CHAr), 129.2 (CHAr), 131.6
(CHAr), 135.3 (CAr–C]N), 144.9 (N]C–CH3), 165.0 (N]CH); IR
(KBr): 1178, 1240, 1450, 1610, 1643, 2958; MS m/z (%): 231 (Mþ, 5),
127 (85), 112 (100), 41 (50). Calcd for C14H18N2O: 230.31.
4
2.02 (dd, JH,H 3.0, 4JH,H 1.5, 3H, N]C–CH3), 2.08–2.19 (m, 1H, NH),
2.32 (dm, 2JH,H 17.4, 1H, N]C–CH2), 2.40 (dm, 2JH,H 17.4, 1H, N]C–
CH2), 4.21 (dd, 2JH,H 13.5, 3JH,H 6.3, 1H, N–CH2), 4.33 (dm, 3JH,H 10.9,
1H, CH), 4.48 (dd, 2JH,H 13.5, 3JH,H 5.0, 1H, N–CH2), 7.21–7.43 (m, 5H,
CHAr); dC (CDCl3): 13.1 (N]C–CH3), 22.3 (H3C–C–CH3), 27.2 (H3C–C–
CH3), 37.0 (H3C–C–CH3), 45.3 (N]C–CH2), 51.7 (N–CH2), 92.1 (CH),
127.1 (CHAr), 128.4 (CHAr), 140.6, 140.9; IR (KBr): 706, 758, 1174,
1188,1389,1450,1468,1493,1514,1604, 2867, 2922, 2960, 3253; MS
m/z (%): 233 (Mþ, 5), 215 (50), 91 (100), 65 (30), 56 (30), 41 (70).
Calcd for C14H20N2O (232.32): C, 72.38; H, 8.68; N, 12.06. Found: C,
72.60; H, 8.47; N, 12.11.
4.14.3. 2-(4-Cyanobenzylideneamino)-3,3,5-trimethyl-3,4-dihydro-
2H-pyrrole 1-oxide (14c)
Nitrone 6 (150 mg, 1.05 mmol) was dissolved in dry benzene
(10 mL) and then 3 Å molecular sieves (1.5 g) and cyanobenzalde-
hyde (159 mg, 1.21 mmol) were added. The mixture was heated to
reflux for 9 h and then solvent evaporated. The crude product was
purified by column chromatography (Et2O/MeOH¼4:1, Rf 0.21) to
give 14c (yellowish oil, 102 mg, 38%). dH (CDCl3): 1.10 (s, 3H, H3C–C–
CH3), 1.27 (s, 3H, H3C–C–CH3), 2.12 (s, 3H, N]C–CH3), 2.50 (d, 2JH,H
2
4.13. 2-(Butylamino)-3,3,5-trimethyl-3,4-dihydro-2H-pyrrole
17.7, 1H, N]C–CH2), 2.80 (d, JH,H 17.7, 1H, N]C–CH2), 4.70 (s, 1H,
1-oxide (13)
N–CH), 7.71 (d, 3JH,H 8.1, 1H, CHAr), 7.94 (d, 3JH,H 8.1, 1H, CHAr), 8.49
(s, 1H, N]CH); dC (CDCl3): 13.1 (N]C–CH3), 23.0 (H3C–C–CH3), 28.4
(H3C–C–CH3), 37.9 (H3C–C–CH3), 46.5 (CH2), 101.3 (N–CH), 114.7 (C–
CN), 118.3 (C–CN), 129.3 (CHAr), 132.3 (CHAr), 138.9 (CAr–C]N),
145.5 (N]C–CH3), 163.1 (N]CH); IR (KBr): 1178, 1176, 1244, 1385,
1465, 1610, 1643, 2227, 2872, 2906, 2927, 2962; MS m/z (%):
decomposition.
Nitrone 5 (200 mg, 1.40 mmol) was mixed with butylamine
(1.00 g,13.7 mmol) and heated at 80 ꢀC for 7 h in the presence of air.
Then, the remaining amine was removed under vacuum. The crude
product was purified by column chromatography (Et2O/MeOH¼9:1,
Rf 0.28) to give colourless oil (161 mg, 58%). dH (CDCl3): 0.91 (t, 3JH,H
7.2, 3H, CH2–CH3), 1.00 (s, 3H, H3C–C–CH3), 1.17 (s, 3H, H3C–C–CH3),
4
1.31–1.51 (m, 4H, CH2–CH2–CH3), 1.81 (br, 1H, NH), 2.01 (dd, JH,H
4.15. 2,4,4-Trimethylpyrrolidin-1-ol (15)
4
2
3.1, JH,H 1.5, 3H, N]C–CH3), 2.32 (dm, JH,H 17.4, 1H, N]C–CH2),
2.39 (dm, 2JH,H 17.4,1H, N]C–CH2), 2.70–2.78 (m,1H, N–CH2), 3.14–
3.22 (m, 1H, N–CH2), 4.25 (s, 1H, CH); dC (CDCl3): 12.9 (N]C–CH3),
14.1 (CH2–CH3), 20.3 (CH2–CH3), 22.2 (H3C–C–CH3), 27.7 (H3C–C–
CH3), 33.0 (N–CH2–CH2), 36.6 (H3C–C–CH3), 45.5 (N]C–CH2), 47.2
(N–CH2), 93.3 (CH), 141.0 (N]C–CH3); IR (KBr): 788, 1141, 1192,
1228, 1367, 1389, 1468, 1612, 1668, 2869, 2927, 2956, 3284; MS m/z
(%): 199 (Mþ, 100), 181 (30), 110 (55), 84 (55), 57 (35), 42 (40). Calcd
for C11H22N2O (198.31): C, 66.62; H, 11.18; N, 14.13. Found: C, 66.60;
H, 11.27; N, 13.94.
For preparation and spectral data see Ref. 4.
4.16. 3,3,5-Trimethyl-3,4-dihydro-2H-pyrrole 1-oxide (16)
Allenyloxime 2 (2.00 g, 16.0 mmol) was added to a solution of
NaBH3CN (1 g, 16.0 mmol) in methanol (30 g). Solution was cooled
down to 0 ꢀC and concentrated HCl was dropwise added to set the
pHz3 (lacmus). The mixture was then stirred at room temperature
for 3 h (pH was checked every 30 min and kept acidic). The solvent
was removed under vacuum and then water (8 mL) was added and
finally NaOH pellets were added to make the mixture alkaline.
Then, solution was stirred for 5 min. After extraction with
dichloromethane (5ꢂ10 mL), combined extracts were dried over
MgSO4 and evaporated. The crude product was distilled in
a Kugelrohr apparatus (70 ꢀC, 3ꢂ10ꢁ2 mbar) to give 16 (colourless
oil, 1.46 g, 72%). dH (CDCl3): 1.14 (s, 6H, H3C–C–CH3), 1.96 (s, 3H,
N]C–CH3), 2.45 (s, 2H, N]C–CH2), 3.68 (s, 2H, N–CH2); dC (CDCl3):
12.7 (N]C–CH3), 28.3 (H3C–C–CH3), 32.3 (H3C–C–CH3), 48.2
(N]C–CH2), 74.5 (N–CH2), 144.5 (N]C–CH3); IR (film): 1171, 1240,
1254, 1389, 1458, 1622, 2872, 2958; MS m/z (%): 255 (50), 128 (Mþ,
100). Calcd for C7H13NO (127.18): C, 66.10; H, 10.30; N, 11.01. Found:
C, 66.16; H, 10.30; N, 10.83.
4.14. General procedure for nitrones 14a,b preparation
Nitrone 6 (150 mg,1.05 mmol) was dissolved in dry Et2O (10 mL)
and then aldehyde (1.07 mmol) was added. The mixture was heated
at reflux for 5 h (14a) or 7 h (14b). After solvent evaporation, crude
nitrones were purified by column chromatography (Et2O/MeOH).
4.14.1. 2-(4-Hydroxybenzylideneamino)-3,3,5-trimethyl-3,4-
dihydro-2H-pyrrole 1-oxide (14a)
Et2O/MeOH¼4:1, Rf 0.23, white solid (210 mg, 81%), mp 174–
176 ꢀC. dH (CDCl3): 1.00 (s, 3H, H3C–C–CH3),1.20 (s, 3H, H3C–C–CH3),
2
2.18 (s, 3H, N]C–CH3), 2.47 (d, JH,H 18.0, 1H, N]C–CH2), 2.83 (d,
3
2JH,H 18.0, 1H, N]C–CH2), 4.59 (s, 1H, N–CH), 6.66 (d, JH,H 8.6, 1H,
3
CHAr), 7.17 (d, JH,H 8.6, 1H, CHAr), 7.97 (s, 1H, N]CH), 10.62 (s, 1H,
4.17. 6,6,7a-Trimethyl-1-phenyltetrahydropyrrolo
OH); dC (CDCl3): 13.6 (N]C–CH3), 23.0 (H3C–C–CH3), 28.5 (H3C–C–
CH3), 38.1 (H3C–C–CH3), 47.0 (CH2), 103.3 (N–CH), 116.5 (CHAr),
126.1 (CAr–C]N), 130.8 (CHAr), 149.2 (N]C–CH3), 161.3 (C–OH),
166.1 (N]CH); IR (KBr): 837, 1076, 1163, 1172, 1238, 1286, 1518,
1583, 1606, 1641, 2478, 2569, 2671, 2798, 2873, 2929, 2962; MS m/z
[1,2-b][1,2,4]oxadiazol-2(1H)-one (17)
Phenylisocyanate (187 mg, 1.57 mmol) was added to a solution
of nitrone 16 (200 mg, 1.57 mmol) in dry benzene (4 mL) and stir-
red at room temperature under argon atmosphere for 5 h. The

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M. Buchlovic et al. / Tetrahedron 64 (2008) 9953–9961
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4. Man, S.; Buchlovic, M.; Potacek, M. Tetrahedron Lett. 2006, 47, 6961.
´ ˇ
solvent was removed under vacuum and the crude product was
crystallized from Et2O to give 17 (white solid, 309 mg, 80%), mp
111–113 ꢀC. dH (CDCl3): 1.17 (s, 3H, H3C–C–CH3), 1.21 (s, 3H, H3C–C–
CH3), 1.71 (s, 3H, N]C–CH3), 1.75 (d, 2JH,H 14.2, 1H, N–C–CH2), 2.24
(d, JH,H 14.2, 1H, N–C–CH2), 3.08 (d, JH,H 9.4, 1H, N–CH2), 3.48 (d,
2JH,H 9.4, 1H, N–CH2), 7.30–7.47 (m, 5H, CHAr); dH (CDCl3): 27.3
(CH3), 28.2 (CH3), 28.9 (CH3), 35.8 (H3C–C–CH3), 49.1 (N–C–CH2),
69.1 (N–CH2), 88.9 (N–C–CH2), 125.5 (CHAr), 127.3 (CHAr), 129.7
(CHAr), 135.4 (CAr), 155.9 (C]O); IR (KBr): 705, 1092, 1211, 1244,
1377, 1495, 1753, 2868, 2958, 2970; MS m/z (%): 248 (Mþ, 20), 127
(100). Calcd for C14H18N2O2 (246.30): C, 68.27; H, 7.37; N, 11.37.
Found: C, 68.37; H, 7.32; N, 11.10.
5. Lathbury, D. C.; Shaw, R. W.; Bates, P. A.; Hursthouse, M. B.; Gallagher, T. J. Chem.
Soc., Perkin Trans. 1 1989, 2415.
6. Shaw, R.; Lathbury, D.; Anderson, M.; Gallagher, T. J. Chem. Soc., Perkin Trans. 1
1991, 659.
7. (a) Beckmann, E. Ber. Dtsch. Chem. Ges. 1980, 23, 3331; (b) Beckmann, E. Ber.
Dtsch. Chem. Ges 1894, 27, 1957.
8. Padwa, A.; Pearson, W. H. Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products; John Wiley and Sons: New
York, NY, 2002.
9. For more information on the gem-dialkyl effect (Thorpe–Ingold effect) see:
Jung, M. E.; Gervay, J. J. Am. Chem. Soc. 1991, 113, 224.
10. Zachova´, H.; Man, S.; Necas, M.; Potacek, M. Eur. J. Org. Chem. 2005, 2548.
11. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
12. Fox, M. E.; Holmes, A. B.; Forbes, I. T.; Thompson, M. J. Chem. Soc., Perkin Trans. 1
1994, 3379.
2
2
ˇ
´ ˇ
13. For more information on oxime pKa see: Kurtz, A. P.; D’Silva, T. D. J. J. Pharm. Sci.
1987, 76, 599.
Acknowledgements
14. Crystallographic data for compounds 10 (CCDC deposition number 677703), 11
(CCDC deposition number 677702), 12(CCDC deposition number 677704)
and 17 (CCDC deposition number 677701) have been deposited at
the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK.
The present work has been supported by Masaryk University
Rector’s Program for Students’ Creative Activity Support.
ˇ
´
The authors thank Marek Necas for X-ray analyses and Lubomır
15. (a) Bapat, J. B.; Durie, A. Aust. J. Chem. 1984, 37, 211; (b) Harlow, R. L.; Duncan, C.;
Simonsen, S. H. Cryst. Struct. Commun. 1976, 5, 759.
ˇ
Prokes for Mass spectra measurement.
16. Bilski, P.; Reszka, K.; Bilska, M.; Chignell, C. F. J. Am. Chem. Soc. 1996, 118, 1330.
17. Villamena, F. A.; Xia, S.; Merle, J. K.; Lauricella, R.; Tuccio, B.; HadadCh, M.;
Zweier, J. L. J. Am. Chem. Soc. 2007, 129, 8177.
References and notes
18. For published method of preparation see: Bonnett, R.; Brown, R. F. C.; Clark,
V. M.; Sutherland, I. O.; Todd, A. J. Chem. Soc. 1959, 2094–2102.
19. Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971, 93, 2897.
20. House, H. O.; Lee, L. F. J. Org. Chem. 1976, 41, 863.
21. Shelxtl, Version 5.10; Bruker AXS: Madison, WI, USA, 1997.
22. Signals are of low intensity and could be observed only after longer
measurement.
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Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, 2004.
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