Diverse chemical behaviour of 2-hydroxy-functionalized pyrroline-1-oxide

Article abstract of DOI:10.1016/j.tetlet.2010.08.103

The reactivity of 2-hydroxy-3,3,5-trimethyl-3,4-dihydro-2H-pyrrole 1-oxide was investigated. The title compound showed unexpected reactivity with several different types of reagents.

Full text of DOI:10.1016/j.tetlet.2010.08.103

Tetrahedron Letters 51 (2010) 5801–5803
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Diverse chemical behaviour of 2-hydroxy-functionalized pyrroline-1-oxide
⇑
ˇ
ˇ
Marian Buchlovic, Stanislav Man, Milan Potácek
ˇ
Department of Chemistry, Masaryk University, Kotlárská 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 9 June 2010
Revised 2 August 2010
Accepted 31 August 2010
Available online 6 September 2010
The reactivity of 2-hydroxy-3,3,5-trimethyl-3,4-dihydro-2H-pyrrole 1-oxide was investigated. The title
compound showed unexpected reactivity with several different types of reagents.
Ó 2010 Elsevier Ltd. All rights reserved.
Nitrones are frequently used as versatile building blocks in syn-
thetic organic chemistry.1 Further modification of these compounds
before a key synthetic step could be used for the synthesis of com-
plex target molecule by more effective procedures. We recently re-
ported a new method for the preparation of 2-functionalized five-
membered cyclic nitrones based on the chemistry of allenes.2,3 This
work highlights the unexpected impact of 2-hydroxy substitution
on the reactivity of the five-membered cyclic nitrone 1.
Bapat and Durie reported the synthesis of 2-hydroxy-3,3,5-tri-
methyl-3,4-dihydro-2H-pyrrole 1-oxide (1) via an unusual oxida-
tion of the corresponding pyrroline 1-oxide using a peracid
(Scheme 1).4
position. Open-chain structures 2 were obtained instead as the
exclusive products (Scheme 2). The structures of sulfonates 2 were
confirmed by X-ray analysis5 of compound 2b (Fig. 1).
Our previous study showed that nitrone 1 undergoes configura-
tional isomerism at position 2 when dissolved in organic solvents
or water. We observed a significant loss of diastereotopism of the
methyl groups at position 3 and the hydrogen atoms at position
4, when a CDCl3 solution of 1 was investigated by NMR experi-
ments at different temperatures (for NMR data of compound 1,
see Supplementary data).2
Cleavage of the C–N bond in nitrone 1 under mild reaction con-
ditions (Scheme 2) and the formation of products 2 prompted us to
consider aldehyde 3 as an intermediate of nitrone 1 present in
solution (Scheme 3).
On the other hand, our research group reported an effective
alternative synthesis of nitrone 1, based on cyclization of an allenyl
oxime in aqueous solution in the presence of a strong base
(Scheme 1).2
Compound 1 was obtained as a crystalline solid that was stable
in air at room temperature and showed some interesting proper-
ties and chemical reactivity.
The reaction of 1 with sulfonyl chlorides, to our surprise, did not
lead to the expected derivatives substituted at the 2-hydroxy
R
O
N
O
OH
N
O
RCl
O
N
O
H
2a (R = Ms)
2b (R = Ts)
ArCO3H, 15%
N
O
R
3
4
5
2
Scheme 2.
OH
N
•
O
1
KOH, H2O, 70%
N
OH
4
3
2
5
O
Scheme 1.
OH
OH
N
N
N
HO
1
H
O
O
1
3
1
⇑
Corresponding author. Tel.: +420 549496615; fax: +420 549492688.
ˇ
E-mail address: potacek@chemi.muni.cz (M. Potácek).
Scheme 3.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.103

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M. Buchlovic et al. / Tetrahedron Letters 51 (2010) 5801–5803
R
H2N
R
OH
N
N
N
O
H
O
1
4a-c
R
R
H2N
O
N
N
N H
H O
H
HO
3
Scheme 4.
The proposed formation of intermediate 3 also readily explains
the unusual reactivity of nitrone 1 with primary amines. Treatment
of nitrone 1 with various amines at room temperature under sol-
vent-free conditions led to unexpected 2-amino nitrones 4 that
might wrongly be considered as products of formal substitution
(Scheme 4). Based on the intermediate 3, a reaction pathway can
be proposed. Condensation of the proposed aldehyde 3 with the
amine followed by subsequent cyclization of the formed imine
gives nitrones 4 (Scheme 4).
Figure 1. ORTEP representation6 of compound 2b.
Moreover, we have shown that under basic conditions inversion
of the stereocentre at position 2 of compound 1 is enhanced. On
the other hand, the presence of an acid caused a notable suppres-
sion of the above process.2 Both observations are in full agreement
with the proposed transformation (Scheme 3) as deprotonation of
the 2-hydroxy group seems to be necessary for the formation of
aldehyde 3; such a process should be strongly influenced by the
acidity/basicity of the solution.
However, in our initial experiments neat reactants in the pres-
ence of excess amine had to be mixed, otherwise no reaction would
Table 1
Summary of the reactivity of nitrone 1 under various conditions
Entry
Substrate
Conditions
Time (h)
Product
Yield
Cl
O
S
O
O
1
CH2Cl2, Et3N, 0 °C to ambient
1
2a (79%)
N
O
H
O
S
O
Cl
O
S
O
O
N
O
2
3
Pyridine 0 °C to ambient
2
2b (64%)
4a (79%)
H
O
S
O
N
N
H2N
H2N
Et3N, 4 Å MS, ambient
24
N
N
O
H
4bb (R = H, 83%)
4c (R = OMe, 76%)
R
4
5
Et3N, 4 Å MS, ambient
24
48
N
H
N
O
R
MeOOC
MeOOC
O
Toluene, 60 °C
5a (69%)
OH
OH
N
O
O
O
COOMe
5ba (76%)
N
6
Toluene, ambient
5
O
O
O
O
a
For an experimental procedure and spectral data see Ref. 2.
For spectral data of the final product see Ref. 2.
b

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M. Buchlovic et al. / Tetrahedron Letters 51 (2010) 5801–5803
5803
diastereomers (5a,b)7 and single regioisomer (5a). The structure of
compound 5a was studied by 2D-NMR experiments (see Supple-
mentary data) and by X-ray analysis5 (Fig. 2).
On the other hand, we failed to obtain cycloaddition products
with less reactive electron-poor dipolarophiles (e.g., methyl acry-
late, maleic anhydride, N-substituted maleimides); similar nega-
tive results were obtained with electron-rich dipolarophiles,
(allyl alcohol, phenyl-acetylene).
R1
R2
OH
R1
R2
N
O
OH
N
O
1
1
2
5a
(R = CO2Me; R = H)
5b (R1 = R2 = CO2Me)
In conclusion, compound 1 has shown unusual chemical reac-
tivity against a broad range of reactants. Reactions with electro-
philes (sulfonyl chlorides) gave open-chain aldehydes as the
exclusive products that proved the ability of the 2-hydroxy-substi-
tuted nitrone to undergo spontaneous C–N bond cleavage in solu-
tion. As a consequence, treatment with nucleophiles (primary
amines) under basic conditions led to new 2-amino functionalized
nitrones. Finally, compound 1 also acted as 1,3-dipole that reacted
to give 1,3-dipolar cycloaddition products.
Scheme 5.
Acknowledgements
The present work has been supported by Masaryk University
Rector’s Program for Students’ Creative Activity Support (Project
Code E0094/2009) and by the Grant Agency of the Czech Republic
(No. 203/09/1345).
ˇ
The authors thank Marek Necas for X-ray analyses.
Figure 2. ORTEP representation6 of compound 5a.
Supplementary data
have been observed.2 Since the formation of aldehyde 3 is en-
hanced under basic conditions, we found that the use of triethyl-
amine (as a basic reaction medium) and the presence of 4 Å
molecular sieves were suitable conditions (Table 1).
Supplementary data (containing details of the experimental
procedures) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2010.08.103.
This reaction protocol helped us to solve problems with sol-
vent-free reactions. The presence of air had no effect on the reac-
tions in triethylamine.2 Using this new method nitrone 1 was
treated with various amines and the results are presented in
Table 1, entries 3 and 4. However, the reaction was limited to pri-
mary amines and no products were observed on treatment with
aromatic amines (tested with aniline) and secondary amines
(tested with diethylamine).
Finally, to complete our investigation of the chemical reactivity,
reactions of nitrone 1 with several dipolarophiles were performed.
Nitrone 1 reacted smoothly with reactive dipolarophiles such as di-
methyl acetylene-dicarboxylate and methyl propiolate, to form the
corresponding isoxazoles 5a,b (Scheme 5, Table 1, entries 5 and 6).
The products of 1,3-dipolar cycloadditions were obtained as single
References and notes
1. Padwa, A.; Pearson, W. H. Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products, John Wiley & Sons: New
York, 2002.
ˇ
ˇ
2. Buchlovic, M.; Man, S.; Potácek, M. Tetrahedron 2008, 64, 9953.
ˇ
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3. (a) Buchlovic, M.; Man, S.; Kislitsõn, K.; Mathot, Ch.; Potácek, M. Tetrahedron
ˇ
ˇ
2010, 66, 1821; (b) Man, S.; Buchlovic, M.; Potácek, M. Tetrahedron Lett. 2006, 47,
6961.
4. Bapat, J. B.; Durie, A. Aust. J. Chem. 1984, 37, 211.
5. Crystallographic data for compounds 2b (CCDC deposition number 767570) and
5a (CCDC deposition number 767571) have been deposited at the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK.
6. Carbon (grey), oxygen (red), nitrogen (blue) and sulfur (yellow) atoms are drawn
as principal ellipses (70% probability level); hydrogen atoms are drawn as fixed-
size spheres (cyan).
7. Based on an NMR study of crude reaction mixtures.