Oxazoline azomethine imines preparation and cycloaddition with phenyl isocyanate

Article abstract of DOI:10.1016/S0040-4039(01)02244-4

Various camphor derived oxazoline azomethine imines were prepared. These unstable dipoles led to cycloadducts in the presence of phenyl isocyanate.

Full text of DOI:10.1016/S0040-4039(01)02244-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 607–609
Oxazoline azomethine imines preparation and cycloaddition with
phenyl isocyanate
Olivier Bedel, Dominique Urban and Yves Langlois*
Laboratoire de Synthe`se des Substances Naturelles, associe´ au CNRS, Baˆtiment 410, Universite´ de Paris-Sud, 91405 Orsay,
France
Received 9 November 2001; revised 22 November 2001; accepted 23 November 2001
Abstract—Various camphor derived oxazoline azomethine imines were prepared. These unstable dipoles led to cycloadducts in the
presence of phenyl isocyanate. © 2002 Elsevier Science Ltd. All rights reserved.
not described in the literature, could be of interest from
Oxazoline-N-oxides 1 are useful dipoles which react
with various dipolarophiles.1 These cycloadditions led
to the stereoselective syntheses of a number of natural
products and analogues.2 We present in this paper the
preparation of their nitrogen counter part, oxazoline
azomethine imine 2, and a study of the reactivity of
these dipoles in [2+3] cycloadditions.
several points of view. The possibility of introducing an
electron-withdrawing or electron-donating functional
group on the exocyclic nitrogen could allow a modula-
tion of both reactivity and regioselectivity with several
kinds of dipolarophiles. Furthermore, by analogy with
oxazoline-N-oxide 1, cycloadditions of dipoles 2 with
a,b-unsaturated esters could lead after hydrolysis to
non-racemic b-substituted amino acids.
Hydrazinoisoborneol derivatives 6a–6f, which are direct
precursors of dipoles 2a–2f, were prepared in a three-
step sequence by analogy with the oxazoline–N-oxides
series according to the general Scheme 1. Condensation
of hydrazine derivatives 3a–3f with camphorquinone 4
afforded the corresponding hydrazobornanone deriva-
tives 5a–5f which were isolated and purified by crystalli-
sation in ethanol. Hydrazones 5a–5f were in turn
sequentially reduced with sodium borohydride and then
with sodium cyanoborohydride in acidic medium. In all
Several azomethine imines have been used as dipoles
for the preparation of pyrazolidines3 and an asymmet-
ric version of these cycloadditions has been described
recently.4 Oxazolines derived azomethine imines such as
compound 2, which to the best of our knowledge are
Scheme 1.
* Corresponding author. E-mail: langlois@icmo.u-psud.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02244-4

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O. Bedel et al. / Tetrahedron Letters 43 (2002) 607–609
cases the unstable hydrazoisoborneol intermediates
were not purified, but directly engaged in the following
reduction. As observed previously for the preparation
of precursors dipoles 1, these reductions were highly
stereoselective. Compounds 6a–6f were finally isolated
by crystallisation as hydrochloride salts after treatment
with HCl gas in anhydrous ether.
the overall yield. Molecular sieves are used to trap
methanol. However, in all cases, yields for this two-step
sequence remained modest with hydrazino derivative
6a.
The following reaction conditions were selected for the
preparation and the cycloaddition of other dipoles 2b–
,
2f: HC(OMe)3 (5 equiv.), molecular sieves 4 A, toluene,
As in the case of oxazoline-N-oxide 1, dipoles 2 were
unstable and attempted isolation was precluded by a
rapid hydrolysis. For this reason, dipoles 2 were
directly submitted to cycloaddition with a very reactive
dipolarophile, phenyl isocyanate, and the optimisation
of the dipole formation was followed by this two-step
sequence using hydrazine hydrochloride 6a as a model
dipole precursor.
70°C, 4 h; then Et3N (2 equiv.), PhNCO (5 equiv.),
70°C, 2 h.
As indicated in Scheme 2, yields of cycloadducts were
highly dependent on the nature of the substituent on
nitrogen. Best results were obtained with phenylacetyl
and methoxycarbonyl groups (hydrazino derivatives 6e
and 6f). With the more electron withdrawing benzoyl
group, compound 6c, no cycloadduct was obtained; in
this case, formation of dipole 2d is probably precluded
by the poorer nucleophilicity of the basic nitrogen.
With the methyl substituted compound 6d, dipole was
unstable and led to degradation products. Comparison
between 6a and 6b showed that, contrary to our expec-
tation, the presence of an electron-donating group has
little influence on the overall yield.5
As summarised in Table 1, the formation of dipole 2a
was performed in toluene or dichloromethane in the
,
presence of molecular sieves 4 A and of an excess of
trimethyl orthoformate. In some cases, calcium carbon-
ate was also introduced at this stage, instead of triethyl-
amine introduced after dipole formation (entries 1 and
3). Phenyl isocyanate (5 equiv.) was then introduced
alone (entries 1 and 3) or with triethylamine (entries 2
and 4–7). Cycloadditions were achieved in all cases at
40°C for 1 h. The excess of phenyl isocyanate was
quenched with methanol and the cycloadduct 7a was
purified by chromatography. When hydrazino deriva-
tive 6a was used as a base, the yield was quite low
(entry 6). This experiment showed that the presence of
1 equiv. of hydrochloric acid is necessary for dipole
formation. Thus, introduction of triethylamine after
dipole formation gave better results than the introduc-
tion of calcium carbonate at the beginning of the
reaction sequence (entries 3 and 4). Comparison
between entries 4 and 5 showed that a large excess of
trimethyl orthoformate (entry 5: 20 equiv.) increased
Cycloadditions were highly stereoselective and NOE
experiments in the case of adduct 7f showed a spatial
proximity between C3a-H and C12-H3. Similarly to
cycloadditions with dipole 1, the presence of C12 methyl
prevents the approach of phenyl isocyanate by the
b-face of the dipole.
The extension of use of the most promising dipole 2e
and various dipolarophiles was afterwards studied.
Unfortunately, dipolarophiles such as cyclopentadiene,
styrene, methyl crotonate and dimethyl maleate were
unreactive under the above reaction conditions. In
these experiments, compound 8 which is the result of
Table 1. Preparation of adduct 7a: formation dipole 2a and cycloaddition with phenyl isocyanate
Entry
Solvent
Base
Time (h)c
Temp. (°C)c
HC(OMe)3 (equiv.)
Yield (%) 7a
a
a
1
2
3
4
5
6
7
CH2Cl2
CH2Cl2
PhMe
PhMe
PhMe
PhMe
PhMe
CaCO3
Et3Nb
CaCO3
Et3Nb
Et3Nb
None
4
4
4
4
4
4
8
40
40
70
70
70
70
70
2
2
2
2
20
2
15
19
15
26
34
8
Et3Nb
2
24
a Introduce before dipole formation.
b Introduce after dipole formation.
c Time and temperature for dipole formation.
Scheme 2.

O. Bedel et al. / Tetrahedron Letters 43 (2002) 607–609
609
hydrolysis of dipole 2e was the only product isolated.
The use of nitroalkenes which were highly reactive
dipolarophiles with dipole 16 was in turn examined.
Attempted cycloaddition between dipole 2f, prepared
from 6f, and 1-nitrocyclohexene and nitrostyrene gave
rise to degradation products. This poor reactivity con-
trasts sharply with the results observed with oxazoline-
N-oxide 1.
Lett. 1996, 37, 4323–4326; (h) Huisgens, R.; Temme, R.
Eur. J. Org. Chem. 1998, 387–401; (i) For a recent paper
concerning the regioselectivity of [2+3] cycloadditions, see:
Herrera, R.; Nagarajan, A.; Morales, M. A.; Me´ndez, F.;
Jime´nez-Vazquez, H. A.; Zepeda, L. G.; Tamariz, J. J.
Org. Chem. 2001, 66, 1252–1263 and references cited
therein.
4. Roussi, F.; Chauveau, A.; Bonin, M.; Micouin, L.; Hus-
son, H.-P. Synthesis 2000, 1170–1179.
In conclusion, we describe in the present paper the first
evidence for the formation of the unstable oxazoline
azomethine imine dipoles and their stereoselective
cycloadditions with phenyl isocyanate. The poor reac-
tivity of these compounds precluded their use in
cycloadditions with other dipolarophiles. However,
preparation of differently substituted hydrazino deriva-
tives and the possible use of other reactive dipolar-
ophiles such as ketene derivatives open the way to
further studies in this field.
5. Selected data: 1H NMR (200 MHz, l ppm, TMS=0, J:
Hz, CDCl3): compound 5e: 7.4–7.24 (5H, m, ArH); 4.10
(2H, s, CH2); 3.01 (1H, d, J=4, C4-H); 2.08–1.74 (2H, m,
C5-Ha and C6-Ha); 1.65–1.3 (2H, m, C5-Hb and C6-Hb);
1.05 (3H, s, C8-H3); 0.97 (3H, s, C9-H3); 0.84 (3H, s,
C10-H3). Compound 6e (250 MHz, CDCl3): 7.34–7.20 (5H,
m, ArH); 3.57 (1H, d, J=7.4, C2-H); 3.50 (2H, s, CH2);
2.77 (1H, d, J=7.4, C3-H); 1.76 (1H, d, J=4.3, C4-H);
1.70–1.58 (1H, m, C5-Ha); 1.49–1.35 (1H, m, C6-Ha); 1.0
(3H, s, C9-H3); 0.96–0.83 (2H, m, C5-Hb and C6-Hb); 0.91
(3H, s, C8-H3); 0.75 (3H, s, C10-H3). 13C NMR (62.5 MHz,
CD3OD): 171, (CꢀO); 134.9, 130.2, 129.6, 128.3, (CAr);
78.1 (C2); 71.2 (C3); 50.4 (C1); 48.9 (C4); 46.7 (C7); 40.9
(CH2); 32.7, (C6); 27.2 (C5); 21.7, 21.1 (C8 and C9); 11.2
(C10). Compound 7e (200 MHz, CDCl3): 7.65–7.25 (10H,
m, ArH); 6.29 (1H, s, C3a-H); 4.34 (2H, s, CH2); 4.11 (1H,
d, J=7.3, C4a-H); 3.11 (1H, d, J=7.3, C8a-H); 2.54 (1H, d,
J=4.3, C8-H); 1.80–1.22 (2H, C7-Ha and C6-Ha); 1.08 (3H,
s, C11-H3); 1.01 (3H, s, C12-H3); 0.98–0.82 (2H, m, C7-Hb
and C6-Hb); 0.79 (3H, s, C13-H3). 13C NMR (62.5 MHz,
CDCl3): 167.2 (C2); 150.1 (CꢀO); 135.2, 133.7, 129.7,
129.1, 128.4, 126.9, 126.2, 122 (CAr); 100.4 (C3a); 88.2
(C4a); 77.7 (C8a); 48.1 (C5); 46.1 (CH2); 31.3 (C6); 25.1
(C7); 22.1 (C11); 19.3 (C12); 10.8 (C13).
References
1. Berranger, T.; Langlois, Y. J. Org. Chem. 1995, 60, 1720–
1726.
2. Dirat, O.; Kouklovsky, C.; Mauduit, M.; Langlois, Y.
Pure Appl. Chem. 2000, 72, 1721–1737.
3. (a) Oppolzer, W. Tetrahedron Lett. 1970, 11, 2199–2204;
(b) Oppolzer, W. Tetrahedron Lett. 1972, 13, 1707–1710;
(c) Jacobi, P. A.; Martinelli, M. J.; Polanc, S. J. Am.
Chem. Soc. 1984, 106, 5594–5598; (d) Taylor, E. C.;
Davies, H. M. L. J. Org. Chem. 1984, 49, 4415–4419; (e)
Grigg, R.; Dowling, M.; Jordan, W.; Sridharan, V. Tetra-
hedron 1987, 43, 5873–5886; (f) Kanemasa, S.; Tomoshige,
N.; Wada, E.; Tsuge, O. Bull. Chem. Soc. Jpn. 1989, 62,
3944–3949; (g) Khau, V. V.; Martinelli, M. J. Tetrahedron
6. Kouklovsky, C.; Dirat, O.; Berranger, T.; Langlois, Y.;
Tran Huu Dau, M.-E.; Riche, C. J. Org. Chem. 1998, 63,
5123–5128.