A phosphine-mediated construction of 1,4-oxazepines and 1,3-oxazines

Article abstract of DOI:10.1021/ol9024309

Chemical Equation Presented A simple and efficient method for constructing 1,4-oxazepines and 1,3-oxazines was developed with use of a phosphine-mediated tandem reaction of ynones with 2-azido alcohols. The method offers a promising route to synthetically useful as well as biologically active heterocycles under mild conditions and may be exploited for the preparation of interesting chiral ligands.

Full text of DOI:10.1021/ol9024309

ORGANIC
LETTERS
2010
Vol. 12, No. 1
40-42
A Phosphine-Mediated Construction of
1,4-Oxazepines and 1,3-Oxazines
Ce´line Franc¸ois-Endelmond, Thomas Carlin, Pierre Thuery, Olivier Loreau,* and
Fre´de´ric Taran*
CEA, iBiTecS, SerVice de Chimie Bioorganique et de Marquage,
Gif sur YVette, F-91191, France, and CEA, IRAMIS, SerVice de Chimie Mole´culaire,
Gif sur YVette, F-91191, France
frederic.taran@cea.fr; oliVier.loreau@cea.fr
Received October 21, 2009
ABSTRACT
A simple and efficient method for constructing 1,4-oxazepines and 1,3-oxazines was developed with use of a phosphine-mediated tandem
reaction of ynones with 2-azido alcohols. The method offers a promising route to synthetically useful as well as biologically active heterocycles
under mild conditions and may be exploited for the preparation of interesting chiral ligands.
Small, “drug-like” heterocycles are predominant building
blocks in medicinal chemistry.1 Despite the numerous
available methods, there is an ongoing search for simple and
straightforward routes to heterocycles. Herein we disclose a
new method for constructing 6- and 7-membered heterocycle
products that are efficiently mediated by phosphines to
generate 1,3-oxazines and 1,4-oxazepines in high yields.
These new reactions were accidentally found during our work
dealing with phosphine-catalyzed R-addition of pronucleo-
philes on activated alkynes.2 Indeed, following our work on
PBu3-catalyzed R-addition of alcohols on arylpropiolates,3
we investigated the reaction of ynone 1a with 2-azido alcohol
2a in the presence of a substoichiometric amount of
phosphine with the expectation to form the corresponding
R-O-adduct 5 that then should cyclize through an aza-Wittig
reaction to afford 6 (Scheme 1).
Scheme 1. Reaction of 1a with 2a in the Presence of PBu3
(1) See, for example: (a) Hansch, C.; Sammes, P. G.; Taylor, J. B.
ComprehensiVe Medicinal Chemistry; Pergamon Press: Oxford, UK, 1990;
Vol. 2, Chapter 7.1. (b) McReynolds, M. D.; Dougherty, J. M.; Hanson,
P. R. Chem. ReV. 2004, 104, 2239–2258. (c) Baladan, A. T.; Oniciu, D. C.;
Katritzky, A. R. Chem. ReV. 2004, 104, 2777–2812.
However, the monitoring of the reaction showed that imine
formation was the first step of the process inducing the
transitional formation of 7 that then underwent intramolecular
Michael-type cyclization affording 2,3-dihydro-1,4-oxazepine
3a as a sole product. The structure of compound 3a was
assigned by comparison to published analytical data4 and
(2) (a) Lecercle´, D.; Sawicki, M.; Taran, F. Org. Lett. 2006, 8, 4283–
4285. (b) Carboni, M.; Gomis, J.-M.; Loreau, O.; Taran, F. Synthesis 2008,
3, 417–424. (c) Gabillet, S.; Lecercle´, D.; Loreau, O.; Carboni, M.; De´zard,
S.; Gomis, J.-M.; Taran, F. Org. Lett. 2007, 9, 3925–3927. (d) Hanedanian,
M.; Loreau, O.; Taran, F.; Mioskowski, C. Tetrahedron Lett. 2004, 45,
7035–7038. (e) Hanedanian, M.; Loreau, O.; Sawicki, M.; Taran, F.
Tetrahedron 2005, 61, 2287–2294.
(4) Lozada, M. C.; Lobato, C. E.; Enriquez, R. G.; Ortiz, B.; Toscano,
R. A.; Gnecco, D.; Galindo, A.; Reynolds, W. F. Magn. Reson. Chem. 2003,
41, 975–982.
(3) Gabillet, S.; Lecercle´, D.; Loreau, O.; De´zard, S.; Gomis, J.-M.;
Taran, F. Synthesis 2007, 4, 515–522.
10.1021/ol9024309  2010 American Chemical Society
Published on Web 12/04/2009

further confirmed by DEPT 13C NMR experiments conducted
on 13C-labeled 3a prepared from 13C-ynone 1a (see the
Supporting Information).
was observed in the crude reaction mixture although many
other reactions, such as [2+2] cycloaddition of iminophos-
phorane with ynone7 or aziridine formation from intramo-
lecular reaction of 2-iminophosphorane alcohols,8 might have
occurred.
Chiral HPLC analysis of products 3a and 3g confirmed
that no racemization of the chiral centers occurred during
the reaction. We contemplated that a possible application of
this chemistry would be found in the synthesis of chiral
ligands by using diynones as starting material.
Our interest was focused on the preparation of 2,6-
bis(oxazepinyl)pyridines that are interesting 7-membered
analogues of the well-known pybox ligands.9 2,6-(diynone)-
pyridines 1b and 1c were therefore prepared from 2,6-
pyridinedicarbonyl dichloride according to a described pro-
tocole10 and reacted with (S)-2-azido-3-phenyl-1-propanol
in the presence of PBu3. Double cyclization occurred
efficiently affording the desired chiral ligands 3k and 3l with
moderate to excellent yields (Scheme 3).
The preparation of such 7-membered heterocycles 3 has
been only sporadically described despite their reported
biological activities.5 To the best of our knowledge, the
condensation of 2-amino alcohols with ꢀ-diketones is the
only reported one-step method leading to 2,3-dihydro-1,4-
oxazepines.6 This method suffers, however, from severe
drawbacks: yields are often low and only symmetrical
ꢀ-diketones should be used. Another simple route to ox-
azepines would have been the direct condensation of 2-amino
alcohols with ynones. However, all attemps conducted in
our laboratory to run such a reaction failed. Treatment of
1a with 2-benzylaminoethanol in the presence or absence
of catalytic amounts of Bro¨nsted or Lewis acids gave
complex mixtures. N-Michael adduct was the major isolated
product (5-30% yield), and no trace of oxazepine 3a was
observed.
Consequently, we decided to explore further the scope and
limitation of this phosphine-mediated reaction using a panel
of starting reagents (Scheme 2). The reaction proceeded
Scheme 3. Preparation of Bis-oxazepines Pybox Analogues
Scheme 2. Phosphine-Mediated Synthesis of
2,3-Dihydro-1,4-oxazepines 3
During the course of this study an unexpected rearrange-
ment was discovered when 2-phenyl-2-azido-1-ethanol 2b
was used as starting reagent. Upon reaction with ynone 1a
and PBu3 at room temperature, no trace of oxazepine
derivative was observed and 1,3-oxazine 4a was obtained
in high yield (Scheme 4). The structure of 4a was assigned
by comparison to published NMR data11 and further proven
by X-ray crystallography (see the Supporting Information).
To investigate whether or not this rearrangement is
general, we conducted a series of reactions involving azido
(6) (a) Soloshonok, V. A.; Ohkura, H.; Yasumoto, M. J. Fluor. Chem.
2006, 127, 708–711. (b) Soloshonok, V. A.; Ohkura, H.; Yasumoto, M.
MendeleeV Commun. 2006, 16, 165–167. (c) Lozada, M. C.; Enriquez, R. G.;
Soriano-Garcia, M.; Toscano, R. A.; Gnecco, D. J. Chem. Crystallogr. 2007,
37, 119–133.
smoothly at room temperature with a series of substrates
including heterocyclic ynones and disubstituted azido alco-
hols. It is quite remarkable that in all cases only one product
(7) (a) Palacios, F.; Alonso, C.; Pagalday, J.; Ochoa de Retana, A. M.;
Rubiales, G. Org. Biomol. Chem. 2003, 1, 1112–1118. (b) Palacios, F.;
Ochoa de Retana, A. M.; Pagalday, J. Tetrahedron 1999, 55, 14451–14458.
(8) Ittah, Y.; Sasson, Y.; Shahak, I.; Tsaroom, S.; Blum, J. J. Org. Chem.
1978, 43, 4271–4273.
(5) (a) McEvoy, F. J.; Greenblatt, E. N.; Osterberg, A. C.; Allen, G. R.,
Jr. J. Med. Chem. 1970, 13, 295–297. (b) Yale, H. L.; Sowinski, F. J. Med.
Chem. 1964, 7, 609–614. (c) Yale, H. L.; Beer, B.; Pluscec, J.; Spitzmiller,
E. R. J. Med. Chem. 1970, 13, 713–722. (d) Yale, H. L.; Sowinski, F.
J. Med. Chem. 1967, 10, 1022–1025. (e) Allen, R. C.; Reitano, P. A.;
Urbach, H. J. Med. Chem. 1978, 21, 838–841. (f) Pan, W.; Liu, H.; Xu,
Y.-J.; Chen, X.; Kim, K. H.; Milligan, D. L.; Columbus, J.; Hadari, Y. R.;
Kussie, P.; Wong, W. C.; Labelle, M. Bioorg. Med. Chem. Lett. 2005, 15,
5474–5477.
(9) For a review on pybox ligands see: (a) Nishiyama, H. AdV. Catal.
Processes 1997, 2, 153–188. (b) Desimoni, G.; Faita, G.; Quadrelli, P. Chem.
ReV. 2003, 103, 3119–3154.
(10) Cox, R. J.; Ritson, D. J.; Dane, T. A.; Berge, J.; Charmant, J.;
Kantacha, A. Chem. Commun. 2005, 1037.
(11) Manning, J. R.; Davies, H. M. L. Tetrahedron 2008, 64, 6901–
6908.
Org. Lett., Vol. 12, No. 1, 2010
41

Scheme 4
.
PBu3-Mediated Reaction of 1a with 2b
Scheme 6. PBu3-Mediated Reaction of 1b with 2c
alcohols bearing aryl moieties in the R position of the
azido group. As shown in Scheme 5, oxazines 4 were
to oxazines 4. Once formed, 2-aryl-1,4-oxazepine 3 may
undergo proton abstraction at the benzylic position and then
ꢀ-elimination yields enamine 8. Intramolecular nucleophilic
attack of the enolate to the iminium form of 8 then affords
4 (Scheme 7).
Scheme 5. Phosphine-Mediated Synthesis of 1,3-Oxazines 4
Scheme 7. Proposed Mechanism for the Formation of 4
In conclusion, we have developed a simple and practical
method for the preparation of 1,4-oxazepines and 1,3-
oxazines derivatives via an nBu3P-mediated tandem aza-
Wittig reaction and intramolecular cyclization. This synthetic
methodology offers a straighforward route to 7-membered
heterocycles whose synthesis is poorly reported and that
might attract biological interest. The reaction has been
successfully extended to the preparation of chiral ligands that
are 7-membered analogues of pybox structures. Preliminary
results conducted in our laboratory showed that these ligands
are very interesting in a series of Cu-catalyzed asymmetric
transformations. These results will be published in due time.
systematically obtained with use of these kinds of sub-
strates.
While some examples of similar rearrangements have been
reported in the literature,12 a plausible mechanism for the
formation of 4 was rather unclear. Therefore, we focused
on isolation of any possible intermediates that would give
us a valuable clue to a possible mechanism leading to
compounds 4. To this end, we conducted the PBu3-mediated
reaction between ynone 1b and bicyclic 2-azido alcohol 2c
(Scheme 6) and fortunately were able to isolate enamine 8a,
which structure was determined by X-ray analysis (see the
Supporting Information).
Acknowledgment. We thank D. Buisson (CEA) for
experimental assistance with MS and LC/MS measurements.
Supporting Information Available: Experimental pro-
cedures for the synthesis and full characterization for
compounds, 1HNMR and 13CNMR spectra of products 3 and
4, and RX structure of product 8a. This material is available
free of charge via the Internet at http://pubs.acs.org.
With enamine 8a in hand as an intermediate, we can
suggest the following sequence of transformations leading
(12) Krapcho, A. P.; Shaw, K. J. J. Org. Chem. 1983, 48, 3341–3343.
OL9024309
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Org. Lett., Vol. 12, No. 1, 2010