Sequential C-N and C-O bond formation in a single pot: Synthesis of 2 H -benzo[ b ][1,4]oxazines from 2,5-dihydroxybenzaldehyde and amino acid precursors

Article abstract of DOI:10.1021/ol2031747

Functionalized β-aryl alanine ester derivatives were found to undergo rapid C-N and C-O bond formation with quinol carbonyl compounds to afford 2H-benzo[b][1,4]oxazines in good to excellent yields. This unprecedented finding reported herein offers a straightforward, highly efficient, and rapid method for the synthesis of 2H-benzo[b][1,4]oxazines.

Full text of DOI:10.1021/ol2031747

ORGANIC
LETTERS
2012
Vol. 14, No. 2
552–555
Sequential CꢀN and CꢀO Bond
Formation in a Single Pot: Synthesis of
2H-Benzo[b][1,4]oxazines from
2,5-Dihydroxybenzaldehyde and
Amino acid Precursors
Javed Iqbal,*,† Neelima D. Tangellamudi,*,† Balakrishna Dulla,†,§ and
Sridhar Balasubramanian‡
Department of Medicinal Chemistry, Institute of Life Sciences, University of Hyderabad
Campus, Hyderabad 500046, India, Institut fur Organische Chemie, Universitat
Regensburg, Universitatsstr. 31, 93053 Regensburg, Germany, and Indian Institute of
Chemical Technology, Hyderabad 500607, India
jiqbal@ilsresearch.org; neelimadt@ilsresearch.org
Received November 28, 2011
ABSTRACT
Functionalized β-aryl alanine ester derivatives were found to undergo rapid CꢀN and CꢀO bond formation with quinol carbonyl compounds to
afford 2H-benzo[b][1,4]oxazines in good to excellent yields. This unprecedented finding reported herein offers a straightforward, highly efficient,
and rapid method for the synthesis of 2H-benzo[b][1,4]oxazines.
2H-Benzo[b][1,4]oxazines have been part of molecular
skeletons for the design of biologically active compounds,
ranging from herbicides and fungicides to therapeutically
useful drugs (Figure 1).1 A few well-known methods
reported for the synthesis of 2H-benzo[b][1,4]oxazines
are cyclocondensation of aminophenols with suitable
dihalo derivatives,2 intramolecular copper-catalyzed
O-arylation of β-aminoalcohols,3 and epoxide opening of
aminoalcohols followed by cyclocondensation.4
Alternative methods include alkylation of o-nitrophenol
with haloester followed by reductive cyclization5 and epoxide
opening with o-halosulfonamides followed by cyclization.6
More recently, the formation of aryl CꢀX bonds (X =
N, O, S, etc.) by Ullmann coupling was successfully ex-
tended to the preparation of many such heterocycles.7
Oxidative dearomatization of phenolshas been long per-
ceived as an attractive tactic in the syntheses of complex
natural products of various kinds. Several reports
† University of Hyderabad Campus.
§ Universitat Regensburg.
‡ Indian Institute of Chemical Technology.
ꢀ
(1) (a) Ilas, J.; Anderluh, P. S.; Dolenc, M. S.; Kikelj, D. Tetrahedron
2005, 61, 7325. (b) Cho, S.-D.; Park, Y.-D.; Kim, J.-J.; Lee, S.-G.; Ma,
C.; Song, S.-Y.; Joo, W.-H.; Falck, J. R.; Shiro, M.; Shin, D.-S.; Yoon.,
ꢁ
ꢁ
Y.-J. J. Org. Chem. 2003, 68, 7918. (c) Chylinska, J. B.; Urbanski, T.;
Mordarski, M. J. Med. Chem. 1963, 6, 484. (d) Largeron, M.; Dupuy,
H.; Fleury, M. B. Tetrahedron 1995, 51, 4953. (e) Adib, M.; Sheibani, E.;
Mostofi, M.; Ghanbary, K.; Bijanzadeh, H. R. Tetrahedron 2006, 62,
3435. (f) Kurz, T. Tetrahedron 2005, 61, 3091. (g) Zhang, P.; Terefenko,
E. A.; Fensome, A.; Wrobel, J.; Winneker, R.; Zhang, Z. Bioorg. Med.
(2) Kuroita, T.; Sakamori, M.; Kawakita, T. Chem. Pharm. Bull.
1996, 44, 756.
(3) Zhangqin Liu, Z.; Chen, Y. Tetrahedron Lett. 2009, 50, 3790.
(4) Brown, D. W.; Ninan, A.; Sainsbury, M. Synthesis 1997, 895.
(5) Matsumoto, Y.; Tsuzuki, R.; Matsuhisa, A.; Takayama, K.;
Yoden, T.; Uchida, W.; Asano, M.; Fujita, S.; Yanagisawa, I.; Fujikura,
T. Chem. Pharm. Bull. 1996, 44, 103.
ꢁ
Chem. Lett. 2003, 13, 1313. (g) Bourlot, A.-S.; Sanchez, I.; Dureng, G.;
Guillaumet, G.; Massingham, R.; Monteil, A.; Winslow, E.; Pujol,
ꢁ
M. D.; Merour, J.-Y. J. Med. Chem. 1998, 41, 3142. (h) Combs,
D. W.; Rampulla, M. S.; Bell, S. C.; Klaubert, D. H.; Tobia, A. J.;
Falotico, R.; Haertlein, R. B.; Lakas-Weiss, C.; Moore, C. J. B. J. Med.
Chem. 1990, 33, 380.
(6) Albanese, D.; Landini, D.; Lupi, V.; Penso, M. Ind. Eng. Chem.
Res. 2003, 42, 680.
r
10.1021/ol2031747
Published on Web 01/04/2012
2012 American Chemical Society

In an experiment designed to synthesize the napththoxazine
cycloadduct 2 by intramolecular DielsꢀAlder cyclization
from an imine precursor 2a of 2,5-dihydroxybenzaldehyde
and a chirally pure phenylalanine ester derivative, we
observed that racemic 2H-benzo[b][1,4]oxazine 1 was
obtained as the only product, in good yields (Scheme 1).
This new finding lead us to believe that an electrocycli-
zation precursor possessing extended conjugation or a
β-aryl substituent may be essential for the adjacent 1,4-
benzoquinone system to cause benzylic oxidation, in a
way that is similar to benzylic oxidations caused by
DDQ (Figure 1).11
Scheme 1. Formation of 2H-Benzo[b][1,4]oxazines
Table 1. Synthesis of 2H-Benzo[b][1,4]oxazines from Quinol
and Natural Amino Acid Derivatives
previously highlighted oxidative dearomatization as a
powerful strategy for the total synthesis of architecturally
complex molecules wherein planar, aromatic scaffolds are
converted to three-dimensional molecular architectures.8
Oxidative dearomatization has been previously adapted
to nitrogen-tethered ortho-quinol acetates for azacycliza-
tion reactions for the synthesis of lycorine-type Amarylli-
daceae alkaloids.9
In light of these classical and elaborated examples, the
present report puts forward an application of oxidative
dearomatization of 2,5-dihydroxy carbonyl compounds
using silver oxide10 for the synthesis of 2H-benzo[b]-
[1,4]oxazines that provides an easy access to nitrogenꢀ
carbon (NꢀCx) and oxygenꢀcarbon (OꢀCy) strategic
bonds in a single operation.
a No reaction in acetonitrile and methanol. Reaction in THF with
4 equiv of silver oxide resulted in 10% yield; product obtained in 70%
yield with THF and 2 equiv of silver oxide.
Figure 1. Representative structure of electrocyclization precursor.
(7) (a) Cacchi, S.; Fabrizi, G.; Parisi, L. M. Org. Lett. 2003, 5, 3843.
(b) Yang, T.; Lin, C.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2005, 7, 4781.
(c) Evinder, G.; Batey, R. A. J. Org. Chem. 2006, 71, 1802. (d) Fang, Y.;
Li, C. J. Org. Chem. 2006, 71, 6427. (e) Martin, R.; Larsen, C. H.;
Cuenca, A.; Buchwald, S. L. Org. Lett. 2007, 9, 3379. (f) Viirre, R. D.;
Evindar, G.; Batey, R. A. J. Org. Chem. 2008, 73, 3452. (g) Chen, Y.;
Wang, Y.; Sun, Z.; Ma, D. Org. Lett. 2008, 10, 625. (h) Bao, W.; Liu, Y.;
Lv, X.; Qian, W. Org. Lett. 2008, 10, 3899.
(8) (a) Liao, C. C.; Peddinti, R. K. Acc. Chem. Res. 2002, 35, 856.
(b) Lin, K. C.; et al. J. Org. Chem. 2002, 67, 8157. (c) Gao, S.-Y.; Lin,
Y.-L.; Rao, P. D.; Liao, C.-C. Synlett 2000, 421. (d) Roche, S. P.; Porco,
J. A., Jr. Angew. Chem., Int. Ed. 2011, 50, 4068. (e) Tsai, Y.-F.; Peddinti,
R. K.; Liao, C.-C. Chem. Commun. 2000, 475. (f) Nicolaou, K. C.;
Vassilikogiannakis, G.; Simonsen, K. B.; Baran, P. S.; Zhong, Y.-L.;
Vidali, V. P.; Pitsinos, E. N.; Couladouros, E. A. J. Am. Chem. Soc.
2000, 122, 3071.
Thus similar reaction conditions were applied to esters
of other natural amino acids which contain a β-aryl
substituent like phenylalanine and tryptophan esters.
We were pleased to obtain 2H-benzo[b][1,4]oxazines 3
and 4 in good to excellent yields in all the cases (Table 1).
One of the 2H-benzo[b][1,4]oxazines, 4, was isolated
as a bright yellow solid that crystallized well, whose
ꢁ
(10) (a) Valderrama, J. A.; Gonzalez, M. F.; Mahana, D. P.; Tapia,
R. A.; Fillio, H.; Pautet, F.; Rodriguez, J. A.; Theoduloz, C.; Schmeda-
Hirschmann, G. Bioorg. Med. Chem. 2006, 14, 5003. (b) Valderrama,
ꢁ
J. A.; Colonelli, P.; Gonzalez, M. F.; Rodriguez, J. A.; Theoduloz, C.
Bioorg. Med. Chem. 2008, 16, 10172.
ꢁ
(9) (a) Quideau, S.; Pouysegu, L.; Deffieux, D. Synlett 2008, 4, 467.
ꢁ
(b) Pouysegu, L.; Avellan, A. V.; Quideau, S. J. Org. Chem. 2002, 67,
3425–3436. Braun, N. A.; Ousmer, M.; Bray, J. D.; Bouchu, D.; Peters,
K.; Peters, E.-V.; Ciufolini, M. A. J. Org. Chem. 2000, 65, 4397.
(11) (a) Lee, H.; Harvey, R. G. J. Org. Chem. 1988, 53, 4587. (b) Fu,
P. F.; Harvey, R. G. Chem. Rev. 1978, 78, 317. (c) Walker’, D.; Hiebert,
J. D. Chem. Rev. 1967, 67, 153.
Org. Lett., Vol. 14, No. 2, 2012
553

structure was unequivocally characterized by single
crystal X-ray diffraction studies (see Supporting
Information).
Table 3. Synthesis of 2H-Benzo[b][1,4]oxazines from Unnatural
Amino Acid Derivatives
Table 2. Synthesis 2H-Benzo[b][1,4]oxazines from Quinol and
Tyrosine Derivatives
a No reaction.
a 2 equiv of silver oxide in CH2Cl2 resulted in only a 10% yield. No
reaction when R = p-CF3C6H4, p-NO2C6H4, and 40-C6H4N.
However tyrosine ester did not cyclize to a similar
product (entry 1, Table 2). We have attributed this ob-
servation to oxidation of the hydroxyl moiety in tyrosine in
the presence of silver oxide. Thus we chose to prepare
different derivatives of tyrosine with electron-releasing and -
withdrawing groups and to apply the same reaction condi-
tions. Quantitative yields of 2H-benzo[b][1,4]oxazines were
obtained from aminoester derivatives possessing electron-
donating groups (entry 2, Table 2), and no such product was
observed with the electron-withdrawing counterparts (entry
3, Table 2).
synthesized using the method reported in literature.12
These unnatural racemic aminoesters were also subjected
to similar reaction conditions, and the results are summa-
rized in Table 3.
The observations demonstrated a striking influence of
electronic factors in the arylmoiety on this transformation.
2H-Benzo[b][1,4]oxazines were obtained in good yields
from aminoesters containing electron-donating moie-
ties (entries 1ꢀ5, Table 3). Aminoesters with p-CF3 and
Therefore we presumed that the reaction mechanism is
influenced by the electronic factors of the β-aryl ring which
merits further validation. The initial cyclization studies
using 4 equiv of silver oxide and dichloromethane as solvent
provided the 2H-benzo[b][1,4]oxazines in good yields.
We then attempted further optimization of the reaction
conditions using 2 equiv of silver oxide and CH2Cl2, which
failed to afford products, except in the case of phenylala-
nine (footnote a, Table 1).
(12) (a) Aldrichimica ACTA 2001, 34 (1), 1ꢀ14. (b) Lee, J.; Kim, S. Y.;
Park, S.; Lim, J.-O.; Kim, J.-M.; Kang, M.; Lee, J.; Kang, S. U.; Choi,
H.-K.; Jin, M.-K.; Welter, J. D.; Szabo, T.; Tran, R.; Pearce, L. V.; Toth,
A.; Blumberg, P. M. Bioorg. Med. Chem. 2004, 12, 1055.
(13) Formation of intermediate C may be occurring via an initial rate-
limiting hydride transfer involving A to give cation B which results in the
formation of a double bond by proton transfer followed by further
oxidation to give C as shown below.
Further, methanol, acetonitrile, and THF too have
either decreased the yield drastically or failed to afford
products. Therefore, we continued using 4 equiv of silver
oxide for the synthesis of 2H-benzo[b][1,4]oxazines. After
these optimization studies, we then set out to validate our
results using esters of a variety of unnatural amino acids to
evaluate the scope of our strategy.
Thus, a range of unnatural racemic aminoesters with
different electron-donating and -withdrawing groups were
554
Org. Lett., Vol. 14, No. 2, 2012

p-NO2 substituents on phenyl did not afford the desired
2H-benzo[b][1,4]oxazines, thus validating our assumption.
We have further observed that 3-(4-pyridyl)alanine ester
too did not result in the formation of 2H-benzo[b][1,4]-
oxazines (footnote a, Table 3).
The most plausible mechanistic pathway delineated for
the reaction to account for the formation of the product is
shown in Figure 2. The initial event may be considered as
the nucleophilic attack of amine in a Michael fashion on
the transient enone to generate an intermediate A. Inter-
mediate A may undergo benzylic oxidation leading to C.13
Subsequent electrocyclization of the latter and eventual
rearomatization leads to D which further undergoes oxida-
tion to final product E (Figure 2).
Anelectron-richarylgroup can significantly enhance the
yield of 2H-benzo[b][1,4]oxazines by an apparent stabili-
zation of benzylic cation B that may be destabilized by
electron-withdrawing substituents on R.
In conclusion we have demonstrated a facile synthesis of
2H-benzo[b][1,4]oxazines by sequential generation of
CꢀN, CꢀO bonds in a single pot via oxidative dearoma-
tization of 2,5-dihydroxybenzaldehyde in the presence of
functionalized aminoacidderivatives. Furthermechanistic
studies of this reaction are underway.
Acknowledgment. We are thankful to the Department
of Science and Technology for financial support (DST-
Fast-track Grant No. 0078/2010). We also acknowledge
COSMIC services for NMR support.
Supporting Information Available. Experimental pro-
cedures, characterization and copies of 1H and 13C NMR
spectra for all new products, ORTEP diagram, and CIF
for 4. This material is available free of charge via the
Internet at http://pubs.acs.org.
Figure 2. Plausible mechanism for oxidative dehydrogenation,
CꢀN and CꢀO bond generation.
Org. Lett., Vol. 14, No. 2, 2012
555