Expeditive access to 2-substituted 4 h -pyrido[1,3]oxazin-4-ones via an intramolecular O-arylation

Article abstract of DOI:10.1021/ol401516e

Unreported 2-substituted 4H-pyrido[e][1,3]oxazin-4-ones are synthesized via an unprecedented intramolecular O-arylation of N-aroyl- and N-heteroaroyl-(iso)nicotinamides under microwave irradiations, in good to excellent yields. The broad applicability was demonstrated by 24 examples with a variety of substituents at the 2-position of the final compounds and 3 possible positions for the nitrogen atom of the pyridine ring. In addition, transformation of one of these compounds into 2-hydroxypyridyl-substituted 1,2,4-triazole and 1,2,4-oxazinone was realized. This approach opens a rapid access to a new bicyclic heteroaromatic chemical series with high potential in medicinal chemistry.

Full text of DOI:10.1021/ol401516e

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Expeditive Access to 2‑Substituted
4H‑Pyrido[1,3]oxazin-4-ones via an
Intramolecular O‑Arylation
Franck Slowinski,*,† Omar Ben Ayad,† Ozge Ziyaret,† Candice Botuha,*,‡
Laetitia Le Falher,‡ Kamel Aouane,‡ and Serge Thorimbert*,‡
Sanofi R&D, Exploratory Unit, 1 Avenue Pierre Brossolette, 91385 Chilly Mazarin
ꢀ
Cedex, France, and UPMC Sorbonne Universites, Institut Parisien de Chimie
Moleculaire, UMR CNRS 7201, 4 Place Jussieu, C. 43, 75005 Paris, France
ꢀ
franck.slowinski@sanofi.com; candice.botuha@upmc.fr; serge.thorimbert@upmc.fr
Received February 18, 2013
ABSTRACT
Unreported 2-substituted 4H-pyrido[e][1,3]oxazin-4-ones are synthesized via an unprecedented intramolecular O-arylation of N-aroyl- and
N-heteroaroyl-(iso)nicotinamides under microwave irradiations, in good to excellent yields. The broad applicability was demonstrated by
24 examples with a variety of substituents at the 2-position of the final compounds and 3 possible positions for the nitrogen atom of the pyridine
ring. In addition, transformation of one of these compounds into 2-hydroxypyridyl-substituted 1,2,4-triazole and 1,2,4-oxazinone was realized. This
approach opens a rapid access to a new bicyclic heteroaromatic chemical series with high potential in medicinal chemistry.
In the past two decades, 2-substituted 4H-benzo[e][1,3]-
oxazin-4-ones have emerged not only as promising medicinal
compounds (SCCE and GSK-3β inhibitors, antiischemics,
fluorescent probes)1 but also as central intermediates for the
preparation of 2-hydroxyphenyl-substituted 1,2,4-triazoles,2
unsymmetrical 1,3,5-triazines,3 and 1,2,4-oxadiazoles.4 The
latter find numerous applications in various fields from UV
absorbers to a wide panel of therapeutic indications.5 One of
the well-known examples is certainly the synthesis of the
marketed drug Deferasirox for the treatment of iron overload
in blood (Figure 1).6
In this context and in the course of our medicinal pro-
grams, we were interested in the development of 2-substituted
4H-pyrido[e][1,3]oxazin-4-ones, which could be considered
as aza-analogues of 2-substituted 4H-benzo[e][1,3]oxazin-4-
ones. Such compounds have been recently identified as a new
potential source of an original and unreported medicinal
† Sanofi R&D.
‡
ꢀ
UPMC Sorbonne Universites.
(1) (a) Rasmussen, P.; Linschoten, M. PCT Int. Appl. 2004 WO
2004108139 A2. (b) Vadivelan, S.; Sinha, B. N.; Tajne, S.; Jagarlapudi, S.
A. R. P. Eur. J. Med. Chem. 2009, 44, 2361–2371. (c) Rieu, J. P.; Duflos,
A.; Tristani, J. C.; Patoiseau, J. F.; Tisne-Versailles, J.; Bessac, A. M.;
Bonnafous, R.; Marty, A.; Verscheure, Y.; Bigg, D. C. H. Eur. J. Med.
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A. P. J. Med. Chem. 2012, 55, 3088–3100. (b) Kline, T.; Fromhold, M.;
McKennon, T. E.; Cai, S.; Treiberg, J.; Ihle, N.; Sherman, D.; Schwan,
W.; Hickey, M. J.; Warrener, P.; Witte, P. R.; Brody, L. L.; Goltry, L.;
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2010, 110, 1809–1827. (b) For a recent review on 1,2,4-oxadiazoles: Pace,
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10.1021/ol401516e
XXXX American Chemical Society

Figure 2. Synthetic approaches to 4H-pyrido[e][1,3]oxazin-4-ones.
Figure 1. General access to 1,2,4-oxadiazoles, 1,3,5-triazines,
and 1,2,4-triazoles from 4H-benzo[e][1,3]oxazin-4-ones.
We first explored the reaction conditions to perform the
intramolecular O-arylation step able to provide the desired
cyclized compound, i.e. 2-phenyl-4H-pyrido[4,3-e][1,3]-
oxazin-4-one 3a, used as a model. Starting from 5a
(obtained by benzoylation of 4a), several protocols re-
ported to perform intramolecular O-arylation at a C-3
halogenated position of a pyridine were tested (see Table 1
in the Supporting Information (SI)).11,12 Surprisingly, de-
spite the use of transition metal catalysts or thermal neutral
conditions, only the starting material or degradation pro-
ducts were obtained. Moreover, several basic conditions
were explored, and only the sequential deprotonation of 5a
using NaH in DMF or NMP, followed by microwave
(MW) irradiation, led to the isolation of 3a in 40% and
50% yield respectively (Scheme 1). During this chemical
process, the synthesis of 3a from 4a required the use of
3 equiv of sodium hydride. To develop a more expeditive
protocol, we decided to isolate the imide sodium salt of 5a
and then to submit it to microwave irradiation in various
solvents. Thereby, 6a was isolated in 97% yield from the
benzoylation step (from 4a) by applying a concentration/
trituration sequence (Scheme 1).
chemical series.7 They could also lead, following the pro-
cesses above-mentioned, to hydroxy-pyridynyl substituted
triazoles and oxadiazoleswhichexhibitactivitiesonseveral
biological targets (HIV-1 integrase, PI3K inhibitors, and
S1P1 agonists).8
Herein, we disclose our study to establish the optimal
reaction conditions for the preparation of the 2-phenyl-
4H-pyrido[4,3-e][1,3]oxazin-4-one 3a, used as a model,
the extension of this process to a wide panel of N-oxo-
substituted bromonicotinamides, and finally one example
of derivatization into triazole and oxadiazole.
Since the initial synthesis of 2-phenyl-4H-benzo[e][1,3]-
oxazin-4-one reported by Titherley,9 the preparation of
2-(hetero)aryl substituted benzo[e][1,3]oxazin-4-ones basi-
cally relies on the condensation between a salicylamide and
an (hetero)aroyl chloride followed by an intramolecular
cyclodehydration.1À4,10 Applying this method to 3-hydro-
xyisonicotinamide 1, we isolated compound 2, resulting
from the simultaneous esterification of the hydroxy group
and the dehydration of the carboxamide into a cyano
group (Figure 2a). We then envisioned developing a new
approach based on an intramolecular O-arylation step
of N-oxo-substituted bromonicotinamides (Figure 2b). To
the best of our knowledge, no example of an intramolecular
O-arylation on a 3-halogenated position of a pyridine ring
with the oxygen atom of an amide or a diamide functional
group has been reported so far.
Scheme 1. Intramolecular O-Arylation of 5a or 6a into 3a
(7) Pitt, W. R.; Parry, D. M.; Perry, B. G.; Groom, C. R. J. Med.
Chem. 2009, 52, 2952–2963.
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Med. Chem. Lett. 2009, 19, 5842–5847. (b) Johns, B. A.; Weatherhead,
J. G.; Allen, S. H.; Thompson, J. B.; Garvey, E. P.; Foster, S. A.; Jeffrey,
J. L.; Miller, W. H. Bioorg. Med. Chem. Lett. 2009, 19, 1802–1806. (c)
Tintori, C.; Manetti, F.; Veljkovic, N.; Perovic, V.; Vercammen, J.;
Hayes, S.; Massa, S.; Witvrouw, M.; Debyser, Z.; Veljkovic, V.; Botta,
M. J. Chem. Inf. Model. 2007, 47, 1536–1544. (d) Slassi, A.; Van
Wagenen, B.; Stormann, T. M.; Moe, S. T.; Sheehan, S. M.; McLoed,
D. A.; Smith, D. L.; Isaac, M. B. PCT Int. Appl. 2002 WO 02068417 A2.
(e) Roberts, E.; Rosen, H.; Brown, S.; Morales, M.; Peng, X.; Poddutoori, R.
PCT Int. Appl. 2009 WO 2009/151529 A1.
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(10) (a) Mustafa, A.; Hassan, A. E. A. A. J. Am. Chem. Soc. 1957, 79,
3846–3849. (b) Kemp, D. S.; Vellaccio, F.; Gilman, N. J. Org. Chem.
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The structure of 6a was unambiguously confirmed by
NMR, IR, mass, and X-ray crystal analysis (Figure 3 and
S2 in the SI). It revealed a conformation where the sodium
(11) (a) Kuwabe, H.-I.; Torraca, K. E.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 12202–12206. (b) Singh, B. K.; Cavalluzzo, C.; De
Maeyer, M.; Debyser, Z.; Parmar, V. S.; Van der Eycken, E. Synthesis
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B
Org. Lett., Vol. XX, No. XX, XXXX

atom is positioned at an equal distance between the two
oxygen atoms, thus forming a central six-membered ring
(Figure 3). Several polar and chelating solvents were then
tested under microwave-assisted cyclization conditions
to solvate the sodium cation and thereby to allow the
rotation of one amide bondin the correct conformation for
the O-arylation to proceed. Among all the tested solvents
(Table S2 in the SI), the use of DMSO significantly
improved the yield of the cyclization up to 68% while
NMP or DMF provided 3a with similar yields to the pre-
vious sequential method (Scheme 1).
Scheme 2. Synthesis of 2-Substituted 4H-Pyrido[e][1,3]oxazin-
4-ones via MW-Assisted Intramolecular O-Arylationa
X-ray crystal analysis of 3a (Figure 3 and S1 in the SI)
definitively confirmed the desired intramolecular O-arylation.
Figure 3. ORTEP diagrams of compounds 6a and 3a with
thermal ellipsoids at 50% probability.
Extension of this synthetic process was carried out with
several substituted benzoyl chlorides and heteroaroyl chlo-
rides with four different bromonicotinamides (Scheme 2).
The imide sodium salts 6aÀx were obtained in good
to excellent yields from 4aÀd (yields in parentheses,
Scheme 2).13
In terms of limitations, the use of alkoyl chlorides was
unable to generate the corresponding imide sodium salt
(R = Me), or led to degradation during the cyclization
process (R = t-Bu). Similarly, starting from 3-bromo-
picolinamide (compound 4, Scheme 2, with W = Br, no X
and N4), the generation of the corresponding imide so-
dium salt (R = Ph) failed or the cyclization of the cor-
responding imide sodium salts (R = p-MeO-Ph) led to
the complete degradation of the cyclization precursor
(Table S3 in the SI). Although a 3-halogenated pyridine
ring is not the most reactive substrate toward nucleophilic
aromatic substitutions, compounds 3aÀi were obtained in
moderate to good yields. The yield dropped dramatically
for the ortho-substituted example 3c (compared to 3d and
3e). This could be explained by an unfavorable stereoelec-
tronic 1,3-interaction between the methoxy group and the
nitrogen or oxygen atom of the oxazinone ring. This
interaction would lead to the rotation of the phenyl sub-
stituent. Accordingly, the resulting nonplanar structure
would present less steric interactions while losing the
stabilizing electronic resonance between the bicyclic core
and the phenyl substituent (see X-ray structure of 3c,
Figure S3 in the SI). Besides, a meta disubstituted phenyl
a Isolated yield of 3aÀx from the intramolecular O-arylation of the
corresponding precursor 6aÀx. In parentheses: isolated yields for the
preparation of 6aÀx. b Reaction was run for 30 min at 180 °C in DMSO.
c Reaction was run for 1 h at 180 °C in DMSO. d For the preparation of
e
6f, 4-bromobenzoyl chloride was added at 0 °C. To satisfy purity,
6h was prepared from the corresponding purified diamide (NH) 5h with
1 equiv of NaH in THF at 0 °C for 1 h. f Reaction was run for 20 min at
g
180 °C in DMSO. Reaction was run either for 30 min at 180 °C in
DMSO or for 15 min at 150 °C in MeCN (3q isolated respectively in 63
h
and 56% yield). Yields of the crude 6qÀx which were immediately
engaged in the cyclization process due to their unstability. I Reaction was
run for 15 min at 150 °C in MeCN. j Reaction was run for 5 min at 180 °C
in DMSO.
substituent is well-tolerated (3i isolated in 68% yield) as
well as a heteroaromatic substituent (3h). The presence of
an additional electron-withdrawing bromine atom at the
C-5 position of the pyridine ring significantly improved the
yield of the final cyclized compounds (3jÀn vs 3a, d, e, g, h).
For these examples, good to excellent yields were obtained,
from 72% (3k) to 94% (3l). Moreover, the presence of a
bromine in the pyridine ring of the final products intro-
duces a potential site for further functionalizations. Next,
starting from 4c and 4d, the thus generated imide sodium
salts 6qÀx exhibit a halogen atom respectively at the C-2
and C-4 positions of the pyridine, which is known to be
(13) Compounds 4a, c, d are commercially available. 4b was easily
prepared in one step from commercially available 3,5-dibromo-4-
cyanopyridine (see Supporting Information).
Org. Lett., Vol. XX, No. XX, XXXX
C

more reactive toward nucleophilic aromatic substitution.14
Surprisingly, they appeared to degrade rapidly, which was
more pronounced for 6w, x either in the presence of a
bromine or a chlorine atom. Consequently, 6qÀx have
been freshly prepared and immediately engaged in the
cyclization process. The corresponding cyclized products
3qÀv were isolated mainly in good to excellent yields using
relatively milder reaction conditions (150 °C, 15 min)
in acetonitrile. Cyclizations of 6w, x were successful in
DMSO at 180 °C for 5 min leading to 3w, x in respectively
47% and 55% yield.
complementary alternative for the preparation of hydroxy-
pyridine substituted 1,2,4-triazoles and 1,2,4-oxadiazoles.
In conclusion, we have developed a two-step synthesis
of unreported 2-substituted 4H-pyrido[1,3]oxazin-4-ones.
Notably, we isolated the sodium salt of N-aroyl- and
N-heteroaroyl-bromo(iso)nicotinamides in good to excel-
lent yields. Engaged in an undescribed microwave-assisted
intramolecular O-arylation reaction, these sodium salts
provided the desired bicyclic pyrido-oxazinones in yields
up to 94%. This process was successfully applied to a wide
panel of aryl and heteroaryl substituents and with three
possible positions for the nitrogen atom in the pyridine
ring. One-step derivatization into 1,2,4-triazole and 1,2,4-
oxadiazole was performed with good yields on a model
compound, illustrating the chemical potential of these
structures used as intermediates. Importantly, this syn-
thetic pathway opens an efficient, metal-free, and rapid
route to 2-substituted 4H-pyrido[e][1,3]oxazin-4-ones, as a
new heteroaromatic bicyclic chemical series with high
medicinal potential.
Scheme 3. Preparation of 1,2,4-Triazole 7 and 1,2,4-Oxadiazole
8 from 3a
Acknowledgment. The authors thank the analytical
sciences department of Sanofi R&D, France, CNRS &
UPMC (L.L.F.) for funding, G. Gontard (IPCM, UPMC)
for the X-ray diffraction analysis, and Dr. L. Dechoux
(IPCM) for helpful discussions. Analytical equipment was
generously offered through FR 2769.
Finally, we explored the chemical potential of these
4H-pyrido[e][1,3]oxazin-4-ones. Exposure of 3a to phenyl
hydrazine15 or hydroxylamine4b led respectively to the
corresponding hydroxypyridine substituted 1,2,4-triazole
7 and 1,2,4-oxadiazole 8 in 78% yield each (Scheme 3).
These derivatization examples enhance the medicinal
potential of the 4H-pyrido[e][1,3]oxazin-4-ones, by
using them as intermediates, and provide a rapid and
Supporting Information Available. Experimental pro-
cedures, Tables S1 and S2, characterization data for all
compounds described, crystallographic data for com-
pounds 3a, 3c, and 6a and CIFs. This material is available
free of charge via the Internet at http://pubs.acs.org.
(14) Comins, D. L.; O’Connor, S.; Al-awar, R. S. Comprehensive
Heterocyclic Chemistry III 2008, 7, 41–99.
(15) Kielar, F.; Wang, Q.; Boyle, P. D.; Franz, K. J. Inorg. Chim. Acta
2012, 393, 294–303.
The authors declare no competing financial interest.
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