The preparation of 2H-1,4-benzoxazin-3-(4H)-ones via palladium-catalyzed intramolecular C-O bond formation

Article abstract of DOI:10.1039/c1cc14209g

Pd/PtBu₃-catalyzed intramolecular C-O bond formation has been used to access aryl- and alkyl-substituted benzoxazinones.

Full text of DOI:10.1039/c1cc14209g

View Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2011, 47, 10608–10610
www.rsc.org/chemcomm
COMMUNICATION
The preparation of 2H-1,4-benzoxazin-3-(4H)-ones via
palladium-catalyzed intramolecular C–O bond formationw
Kai E. O. Ylijoki and E. Peter Kundig*
¨
Received 13th July 2011, Accepted 11th August 2011
DOI: 10.1039/c1cc14209g
Pd/PtBu3-catalyzed intramolecular C–O bond formation has
PtBu3 resulted in the best conversion rates, although 30 mol%
Pd(dba)2 was required for complete conversion in 16 hours
when K3PO4ꢀH2O was used as a base. Reproducibility difficulties
were encountered when using the free PtBu3 ligand. These
were effectively eliminated through the use of the [HPtBu3]BF4
salt.6 Various Pd(II) sources were examined (PdCl2, Pd(OAc)2,
(phen)Pd(OAc)2, (dppf)PdCl2) to compare with Pd(dba)2, yet
none proved as effective. This difference in reactivity is likely
due to catalyst stabilization by dba, preventing decomposition
to palladium black. The nature of the base has a significant
effect on the reaction rate. Only minimal conversion was
observed after 16 hours at 80 1C and 10 mol% Pd(dba)2 with
K3PO4ꢀH2O, K2CO3, or DBU. The strong bases NaOtBu and
KOtBu resulted in complete conversion within one hour,
however significant decomposition was observed. The best
results were obtained with Cs2CO3, allowing the catalyst
loading to be reduced to 1 mol% while maintaining very clean
conversion.
been used to access aryl- and alkyl-substituted benzoxazinones.
The preparation of benzoxazinones has been extensively
studied, driven by the prevalence of these moieties in the cores
of natural products and pharmaceuticals of interest.1 Many
synthetic strategies involve the coupling of a 1,2-disubstituted
aminophenol with an a-halo ester or related method.1a Such
methodologies can proceed via either initial C–O or C–N bond
formation, with metal-catalysis being invoked in several
reports. Our interest in this area stems from our studies on
the preparation of 3-hydroxyoxindoles 2 by intramolecular
nucleophilic addition of Pd–aryl species to ketones (eqn (1)).2
We reasoned that this system could be modified to incorporate
the hydroxyl oxygen into the ring through Hartwig–Buchwald
etherification.3 Such a reaction would be attractive given that
the preparation of benzoxazinone compounds containing
sterically large substituents or quaternary centres is difficult
in systems requiring nucleophilic substitution. Large substituents
also hamper the formation of enantioenriched benzoxazinone
products. Herein, we report our preliminary investigations in
the development of this strategy.4
These optimized reaction conditions were then applied to
the preparation of the compounds shown in Table 1. The
requisite substrates were prepared in analogy to 3a, with non-
commercially available b-keto acids prepared by addition of
the appropriate alkyl- or arylmagnesium bromide reagent to
diethyloxylate7 followed by saponification. The cyclization
yields are generally good, with the notable exceptions being
for those products bearing alkyl substituents. We did not
observe any significant reactivity difference between the
o- and p-substituted aryl substituents, nor electron-donating
or withdrawing groups. N-Bn substrate 3j reacted very slowly,
necessitating an increased 20 mol% catalyst loading, and
still only proceeded with mediocre 38% yield. Increasing
the temperature resulted in rapid catalyst degradation. This
reduction in reactivity is puzzling and will require further
investigation. It is tempting to ascribe the difference in reac-
tivity to a difference in amide rotamer populations, however
the spectroscopically observed 1.7 : 1 ratio does not vary
significantly from that generally observed for other substrates
(approx. 2 : 1). Furthermore, an MMFF computational
conformational analysis on 3j suggests the preferred rotamer
is that placing the reactive moieties in a close spatial arrange-
ment. Chromatographic separation of the benzoxazinone
product 4j from the residual dba proved difficult. This was
addressed by reducing the residual dba with excess NaBH4
prior to purification.
ð1Þ
The model compound 3a was prepared by condensation of
N-methyl-2-bromoaniline with 2-oxo-2-phenylacetic acid via
an acylhalide intermediate, followed by NaBH4 reduction. As
we previously observed in the preparation of 3-hydroxyoxin-
doles,2 ligands such as PPh3, dppe, dppf, and phenanthroline
resulted in only trace conversion to products. While PCy3
showed improvement,5 the electron-rich and sterically large
Department of Organic Chemistry, University of Geneva, 30 Quai
Ernest Ansermet, 1211 Geneva 4, Switzerland.
E-mail: peter.kundig@unige.ch; Fax: +41 22 379 3215;
Tel: +41 22 379 6093
w Electronic supplementary information (ESI) available: Experimental
details, spectral characterisation, and analytical data of reported
compounds. See DOI: 10.1039/c1cc14209g
c
10608 Chem. Commun., 2011, 47, 10608–10610
This journal is The Royal Society of Chemistry 2011

View Online
Table 1 Substrate scope
Scheme 1
desired enantioenriched benzoxazinone product took place
with complete retention of enantiomeric purity.
Extension to pyridyl substrate 6 afforded smooth conversion
to a 1 : 2 mixture of products (eqn (2)). The minor product is
tentatively identified as the expected pyridyloxazinone 7 on the
1
basis of H NMR spectroscopy,8 while the major product is
assigned to the Smiles rearrangement isomer 8.9 In the absence
of Pd catalyst or prolonged reaction time at rt, 8 was obtained
in quantitative yield. It is interesting that this Smiles-type
product does not react further. Non-protected secondary
amides were completely unreactive in our previously reported
3-hydroxyoxindole syntheses.2 It is likely that the readily
formed Smiles product behaves as a catalyst poison, shutting
down the catalytic cycle.
a
20 mol% Pd(dba)2, 40 mol% [HPtBu3]BF4, 1.5 equiv. Cs2CO3,
b
PhMe, 80 1C, 16 hours; NaBH4 (xs), MeOH, 0 1C. 30 mol%
ð2Þ
Pd(dba)2, 60 mol% PtBu3, 1 equiv. K3PO4ꢀH2O, PhMe, 80 1C,
16 hours.
Through the above observations, we propose that the
mechanism of this reaction involves initial oxidative addition
of the C–Br bond to Pd(0) to yield palladacycle 9 (Scheme 2).
Subsequent nucleophilic attack of the hydroxyl oxygen
and reductive elimination closes the catalytic cycle. The key
role of the Cs2CO3 base may be due to a facile, concerted
intramolecular deprotonation/HCO3ꢁ elimination sequence to
yield intermediate 11.10
To explore the possibility of performing cyclizations with
tertiary alcohols, amido alcohols 3k–m were prepared by
addition of MeMgBr to the appropriate amido ketone. We
were pleased to find clean conversion to the expected products
despite the complex nature of the starting amido alcohol
NMR spectra. All benzoxazinone products and amido alcohol
starting materials displayed excellent stability at room tempera-
ture with the exception of amido alcohol 3e, which underwent
slow decomposition to unidentified materials.
In summary, we have presented a method for the prepara-
tion of benzoxazinones through palladium-catalyzed intra-
molecular C–O bond formation. The nature of the base and
ligand is important, with the electron-rich PtBu3 and Cs2CO3
giving the best results. This method can be effectively employed
to prepare both mono- and disubstituted benzoxazinone
products, including enantioenriched species with retention of
configuration. While both N-Me and N-Bn substrates are
reactive, Bn protected compounds require significantly higher
catalyst loading. We have also found that in pyridyl systems
the predominant reaction product is that arising from Smiles
rearrangement.
To probe the possibility of preparing enantioenriched
benzoxazinone compounds,3d we synthesized model amido
alcohol compound 3a in 70% ee via condensation of MOM-
protected S-mandelic acid 5 with N-methyl-2-bromoaniline,
followed by deprotection (Scheme 1). Significant racemization
was observed during the condensation step. Milder coupling
conditions such as DCC with 1-hydroxybenzotriazole and
diisopropylethylamine resulted in low conversions. However,
we were pleased to find that Pd-catalyzed cyclization to the
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 10608–10610 10609

View Online
A. Oliveros-Bastidas and J. M. G. Molinillo, Nat. Prod. Rep.,
2009, 26, 478.
2 (a) Y.-X. Jia, D. Katayev and E. P. Kundig, Chem. Commun.,
¨
2010, 46, 130; (b) J.-X. Hu, H. Wu, C.-Y. Li, W.-J. Sheng,
Y.-X. Jia and J.-R. Gao, Chem.–Eur. J., 2011, 17, 5234. For an
asymmetric version, see: L. Yin, M. Kanai and M. Shibasaki,
Angew. Chem., Int. Ed., 2011, 50, 7620.
3 For lead references, see: (a) G. Mann, C. Incarvito,
A. L. Rheingold and J. F. Hartwig, J. Am. Chem. Soc., 1999,
121, 3224; (b) Q. Shelby, N. Kataoka, G. Mann and J. Hartwig,
J. Am. Chem. Soc., 2000, 122, 10718; (c) K. E. Torraca, X. Huang,
C. A. Parrish and S. L. Buchwald, J. Am. Chem. Soc., 2001,
123, 10770; (d) S.-I. Kuwabe, K. E. Torraca and S. L. Buchwald,
J. Am. Chem. Soc., 2001, 123, 12202; (e) C. H. Burgos,
T. E. Barder, X. Huang and S. L. Buchwald, Angew. Chem., Int.
Ed., 2006, 45, 4321.
4 For related studies on Pd-catalyzed aminations to yield benzo-
fused heterocycles see: (a) J. F. Bower, P. Szeto and T. Gallagher,
Org. Lett., 2007, 9, 3283; (b) P. Thansandote, E. Chong,
K.-O. Feldmann and M. Lautens, J. Org. Chem., 2010, 75, 3495.
5 A previous report suggested that the reaction of compound 3a with
Pd(OAc)2/PCy3 resulted only in a complex mixture. J. M. Hillgren
and S. P. Marsden, J. Org. Chem., 2008, 73, 6459.
6 M. R. Netherton and G. C. Fu, Org. Lett., 2001, 3, 4295.
7 C. Fizet, Helv. Chim. Acta, 1982, 65, 2024.
8 While 7 has been previously reported, no NMR spectral data is
available: N. Clauson-Kaas, J. Lei and H. Heide, Acta Chem.
Scand., 1971, 25, 23.
Scheme 2
9 (a) A. A. Levy, H. C. Rains and S. Smiles, J. Chem. Soc., 1931,
3264; For a review, see: (b) W. E. Truce, E. M. Kreider and
W. W. Brand, Org. React., 2011, 99. For lead references on
rearrangements in pyridine systems, see: (c) Y. Maki, K. Yamane
and M. Sato, Yakugaku Zasshi, 1966, 86, 50 and references cited
therein; (d) J. Li and L. Wang, Aust. J. Chem., 2009, 62, 176 and
references cited therein.
Financial support by the Swiss National Science Founda-
tion and the University of Geneva is acknowledged with
thanks.
Notes and references
1 For reviews, see: (a) J. Ilas, P. S. Anderluh, M. S. Dolenc and
D. Kikelj, Tetrahedron, 2005, 61, 7325; (b) F. A. Macıas, D. Marın,
´ ´
´
10 L. Donati, S. Michel, F. Tillequin and F.-H. Poree, Org. Lett.,
2010, 12, 156.
c
This journal is The Royal Society of Chemistry 2011
10610 Chem. Commun., 2011, 47, 10608–10610