Synthesis of unsaturated [1,2]oxazines by using sigmatropic rearrangements and the ring-closing metathesis reaction

Article abstract of DOI:10.1016/j.tetlet.2003.09.125

Various substituted unsaturated [1,2]oxazines have been synthesized by using a [2,3]- or a [3,3]-sigmatropic rearrangement and a ring-closing metathesis reaction as key steps.

Full text of DOI:10.1016/j.tetlet.2003.09.125

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8577–8580
Synthesis of unsaturated [1,2]oxazines by using sigmatropic
rearrangements and the ring-closing metathesis reaction
Alexandre Le Flohic,a Christophe Meyer,a Janine Cossya,* and Jean-Roger Desmursb
aLaboratoire de Chimie Organique, associe´ au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
bRhodia, Parfum et Spe´cialite´s, 190 avenue Thiers, 69457 Lyon Cedex 06, France
Received 1 August 2003; revised 8 September 2003; accepted 16 September 2003
Abstract—Various substituted unsaturated [1,2]oxazines have been synthesized by using a [2,3]- or a [3,3]-sigmatropic rearrange-
ment and a ring-closing metathesis reaction as key steps.
© 2003 Published by Elsevier Ltd.
Due to the development of the well-defined and stable
ruthenium catalysts 1 and 2 which exhibit high func-
tional group tolerance,1 the ring-closing metathesis
reaction (RCM) has found a wide range of synthetic
applications and has been extensively used to generate
unsaturated carbocycles and heterocycles from readily
available acyclic precursors (Fig. 1).2
starting from the appropriate substituted hydroxyl-
amine derivatives and the introduction of the ethylenic
moieties was carried out according to three different
methods. The first one involves sequential Mitsunobu
reactions with allylic and homoallylic alcohols which
enabled the introduction of one substituent a to both
the oxygen and nitrogen atoms.6 A second method
relied on the addition of N-Boc hydroxylamine to
p-allyl complexes of Ir(I) and Pd(0).7 Finally, the third
method involves sequential N,O-alkylations with unsat-
urated halides (SN2 reactions) to prepare six- to ten-
membered ring heterocycles bearing the NꢀO linkage,
During the course of our studies concerning the prepa-
ration and the evaluation of the synthetic potential of
unsaturated cyclic compounds containing two het-
eroatoms,3,4 the possibility of generating structures con-
taining a nitrogen-oxygen linkage and in particular
3,6-dihydro[1,2]oxazines by RCM was considered.
These compounds have been traditionally obtained by
[4+2] cycloadditions of nitroso derivatives with conju-
gated dienes, although alternative routes have also been
developed.5 Thus, RCM was used for the synthesis of
unsaturated heterocycles bearing the NꢀO linkage. The
requisite dienic precursors were invariably prepared
but no substituents were introduced
a
to the
heteroatoms.8
Due to these results, we would like to report here the
synthesis of substituted unsaturated [1,2]oxazines of
type A substituted by one and/or two substituents a to
Figure 1. Ring-closing metathesis catalysts.
Keywords: ring-closing metathesis; sigmatropic rearrangements;
[1,2]oxazines.
* Corresponding author. Tel.: +33-1-40-79-44-29; fax: +33-1-40-79-
46-60; e-mail: janine.cossy@espci.fr
Scheme 1.
0040-4039/$ - see front matter © 2003 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2003.09.125

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A. Le Flohic et al. / Tetrahedron Letters 44 (2003) 8577–8580
Scheme 3.
Scheme 4.
Scheme 2.
amine should be necessarily an electron-withdrawing
group by analogy with the reported examples of RCM
involving amines (Scheme 3).2d
the oxygen and nitrogen atoms, involving a [2,3]- or a
[3,3]-sigmatropic rearrangement to elaborate the dienic
compounds and a RCM to build the heterocycles.
As a carbonyl-containing electron-withdrawing group
such as benzoyl (R1=Bz) was selected for the nitrogen
atom of the hydroxylamines, it was therefore proposed
to prepare the corresponding hydroxamic acids of type
D by using the [3,3]-sigmatropic rearrangement10 of the
benzimidoates of type E which can be elaborated by
condensation of various allylic alcohols of type F with
the known benziminoyl chloride 1011 (Scheme 4). More-
over, this attractive approach towards the RCM
hydroxylamine precursors would be complementary to
those reported in the literature6–8 which employ allylic
alkylations or SN2-type reactions and cannot accommo-
date the presence of two substituents a to the nitrogen
atom.
Oxazines of type A were seen as arising from a RCM
applied to N,O-substituted unsaturated hydroxylamines
of type B which could be synthesized following two
strategies depending on their substitution pattern. A
[2,3]-sigmatropic rearrangement of allylic hydroxyl-
amines of type C induced by the presence of acryloyl
chloride could provide access to monosubstituted
hydroxylamines of type B. The formation of mixed
acetals of allylic hydroxamic acids of type D, which
could be obtained by a [3,3]-sigmatropic rearrangement
of benzimidoates of type E, was proposed for preparing
mono- or disubstituted oxazines (Scheme 1).
According to the first strategy, the addition of vinyl-
magnesium bromide to the N-benzylnitrone of benz-
aldehyde 3 afforded the corresponding allylic hydroxyl-
amine 4 (84%). The acylation of the hydroxyl group
of 4 with acryloyl chloride did not provide the O-
acylated hydroxylamine compound but the N-acylated
product 5 was obtained (63%). Its formation was
ascribed to a [2,3]-sigmatropic rearrangement (related
to the Meisenheimer rearrangement)9 of the intermedi-
ate N-acryloyl-N-oxide 6 generated by treatment of
4 with acryloyl chloride in the presence of Hu¨nig’s
base (i-Pr2NEt). The [1,2]oxazin-3-one 7 was finally
obtained in 92% yield when a RCM reaction cata-
lyzed by Grubbs’ catalyst 2 was applied to 5 (Scheme
2).
Accordingly, various allylic alcohols were converted to
their sodium alkoxides and condensed with the benz-
iminoyl chloride 10 to afford the corresponding allylic
benzimidoates 11a–d. The [3,3]-sigmatropic rearrange-
ment of these substrates was carried out in refluxing
However, generalization of the [2,3]-sigmatropic rear-
rangement with other acylating reagents and various
substrates did not give the desired products. Nor was
the formation of the O-acylated product observed. In
order to avoid the use of an acylating agent, the allylic
hydroxylamine 4 was subjected to transacetalization
with acrolein dimethyl acetal in the presence of a
catalytic amount of PPTS in benzene. The mixed acetal
8 was obtained in 65% yield but this compound did not
undergo a subsequent RCM reaction. Therefore, it was
concluded that the nitrogen substituent of the hydroxyl-
Scheme 5.

A. Le Flohic et al. / Tetrahedron Letters 44 (2003) 8577–8580
8579
xylenes to afford the rearranged compounds 12a–d.
Deprotection of the hydroxyl group was readily
achieved by treatment with a catalytic amount of PPTS
in ethanol and the benzhydroxamic acids 13a–d were
obtained in modest to excellent overall yields (20–79%)
(Scheme 5).
(58–82%). Indeed, the RCM of acetals 18a–d proceeded
smoothly and afforded the desired 6-alkoxy-3,6-dihy-
dro[1,2]oxazines 19a–d in satisfactory yields (58–97%)
by treatment with catalyst 2 in dichloromethane at
40°C. Worthy of note is the fact that catalyst 1 was also
efficient in the case of compound 18a with no sub-
stituents a to the nitrogen atom. A much better yield
was observed in the case of compound 18d when the
RCM was carried out in benzene at 70°C, due to the
steric bulk of the gem-dimethyl group adjacent to the
nitrogen atom (Scheme 7).
Whereas the allylic ether 14 readily obtained from 13a
was efficiently converted to the 3,6-dihydro[1,2]oxazine
15 (96%) upon treatment with catalyst 2, the a,b-unsat-
urated ester 16 failed to cyclize to 17 whatever the
catalyst or the conditions used (1 or 2, CH2Cl2 or C6H6,
room temperature to 70°C). The presence of Ti(Oi-Pr)4
as an additive did not bring about any improvement
(Scheme 6).12
Although compounds of type A such as 19a–d have
been synthesized by other routes and subjected to a
variety of subsequent transformations,14 an unexplored
possibility of functionalization involves the nucleophilic
displacement of the methoxy group of the acetal moiety
by nucleophiles in the presence of Lewis acids.13 Con-
trary to our expectations, when 19a was treated with
allyltrimethylsilane in the presence of BF3·OEt2 in
dichloromethane at 0°C, the benzhydroxamic acid 20
was obtained in 72% yield. Its formation can be
explained by the formation of the intermediate oxycar-
benium ion 21 involving the cleavage of the endocyclic
CꢀO bond,15 which reacts with allylsilane to give 20.
Neither regioisomers, nor stereoisomers were detected
in the crude reaction mixture (Scheme 8).
This problem was therefore circumvented by the forma-
tion of the mixed acetals13 18a–d which were generated
by transacetalization of the benzhydroxamic acids 13a–
d with an excess of acrolein dimethyl acetal in the
presence of a catalytic amount of PPTS in benzene
In conclusion, efficient syntheses of various substituted
unsaturated [1,2]oxazines have been developed involv-
ing a [2,3]- or [3,3]-sigmatropic rearrangement and a
RCM reaction as key steps. These strategies provided
access to substituted unsaturated [1,2]oxazines which
are complementary to and more versatile than the
previously reported ones. Other subsequent transforma-
tions of this class of compounds are currently being
investigated in order to expand the scope of this
methodology in organic synthesis.
Scheme 6.
Acknowledgements
Financial support from Rhodia and the CNRS (grant
to A.L.F.) is gratefully acknowledged.
References
1. (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R.
H. Angew. Chem., Int. Ed. Engl. 1995, 34, 2039–2041; (b)
Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org.
Lett. 1999, 1, 953–956.
2. Reviews on olefin metathesis: (a) Schuster, M.; Blechert,
S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036–2056; (b)
Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998,
371–388; (c) Grubbs, R. H.; Chang, S. Tetrahedron 1998,
54, 4413–4450; (d) Phillips, A. J.; Abell, A. D. Aldrichim-
ica Acta 1999, 32, 75–89; (e) Fu¨rstner, A. Angew. Chem.,
Int. Ed. 2000, 39, 3012–3043. (f) Trnka, T. M.; Grubbs,
R. H. Acc. Chem. Res. 2001, 34, 18–29.
Scheme 7.
3. Meyer, C.; Cossy, J. Tetrahedron Lett. 1997, 38, 7861–
7864.
Scheme 8.

8580
A. Le Flohic et al. / Tetrahedron Letters 44 (2003) 8577–8580
11. Liu, K.-C.; Shelton, B. R.; Howe, R. K. J. Org. Chem. 1980,
4. Le Flohic, A.; Meyer, C.; Cossy, J.; Desmurs, J.-R.;
Galland, J.-C. Synlett 2003, 667–670.
45, 3916–3918.
12. Fu¨rstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119,
9130–9136.
5. (a) Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996, 96,
137–165; (b) Vogt, P. F.; Miller, M. J. Tetrahedron 1998,
54, 1317–1348; (c) Tsoungas, P. G. Heterocycles 2002, 57,
1149–1178.
6. Koide, K.; Finkelstein, J. M.; Ball, Z.; Verdine, G. L. J.
Am. Chem. Soc. 2001, 123, 398–408.
13. (a) Rutjes, F. P. J. T.; Kooistra, T. M.; Hiemstra, H.;
Schoemaker, H. E. Synlett 1998, 192–194; (b) Crimmins,
M. T.; King, B. W. J. Am. Chem. Soc. 1998, 120, 9084–9085;
(c) Kinderman, S. S.; Doodeman, R.; van Beijma, J. W.;
Russcher, J. C.; Tjen, K. C. M. F.; Kooistra, T. M.;
Mohaselzadeh, H.; van Maarseveen, J. H.; Hiemstra, H.;
Schoemaker, H. E.; Rutjes, F. P. J. T. Adv. Synth. Catal.
2002, 344, 736–748.
14. (a) Defoin, A.; Pires, J.; Streith, J. Helv. Chim. Acta 1991,
74, 1653–1670; (b) Tishkov, A. A.; Reissig, H.-U.; Ioffe,
S. L. Synlett2002, 863–866;(c)Buchholz, M.;Reissig, H.-U.
Synthesis 2002, 1412–1422 and references cited therein; (d)
review on the use of [1,2]oxazines: Tsoungas, P. G.
Heterocycles 2002, 57, 915–953.
7. Miyabe, H.; Yoshida, K.; Matsumura, A.; Yamauchi, M.;
Takemoto, Y. Synlett 2003, 567–569.
8. Yang, Y.-K.; Tae, J. Synlett 2003, 1043–1045.
9. (a) Buston, J. E. H.; Coldham, I.; Mulholland, K. R.
Tetrahedron: Asymmetry 1998, 9, 1995–2009; (b)
Blanchet, J.; Bonin, M.; Micouin, L.; Husson, H.-P.
Tetrahedron Lett. 2000, 41, 8279–8283 and references
cited therein.
10. De la Torre, J. A.; Fernandez, M.; Morgans, D., Jr.; Smith,
D. B.; Talamas, F. X.; Trejo, A. Tetrahedron Lett. 1994,
35, 15–18.
15. Olsson, R.; Berg, U.; Frejd, T. Tetrahedron 1998, 54,
3935–3954 and references cited therein.