4H-1,2-benzoxazines with electron-withdrawing substituents on the benzene ring: Synthesis and application as potent intermediates for oxygen-functionalized aromatic compounds

Article abstract of DOI:10.1021/ja0343151

A new general method for synthesizing functionalized 4H-1,2-benzoxazine derivatives is described. Although 4H-1,2-benzoxazine is one of the fundamental structure of the oxazine group, no general synthetic method for the heterocycle has been established. We found that 3-methoxycarbonyl-4H-1,2-benzoxazine was obtained in good yield when methyl 2-nitro-3-phenylpropionate was treated with an excess amount of trifluoromethanesulfonic acid. This methodology was also applicable for the synthesis of 4H-1,2-benzoxazine rings functionalized with various electron-withdrawing substituents on the benzene ring. Furthermore, we also show that the resulting 4H-1,2-benzoxazines can be used as precursors of functionalized o-quinone methides and multisubstituted phenols. This type of heterocycle can be a potent intermediate to oxygen-fuctionalized aromatic compounds. Copyright

Full text of DOI:10.1021/ja0343151

Published on Web 04/12/2003
4H-1,2-Benzoxazines with Electron-Withdrawing Substituents on the Benzene
Ring: Synthesis and Application as Potent Intermediates for
Oxygen-Functionalized Aromatic Compounds
Satoshi Nakamura,† Masanobu Uchiyama,†,‡ and Tomohiko Ohwada*,†
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
Received January 23, 2003; E-mail: ohwada@mol.f.u-tokyo.ac.jp
Scheme 1. Acid-Catalyzed Cyclization of 1-Nitro-2-Phenylethane
Derivatives
Although 4H-1,2-benzoxazine is one of the fundamental struc-
tures of the oxazine group, its chemical nature has not been well
studied simply because of the lack of the general synthetic methods
for 4H-1,2-benzoxazines. Some derivatives of 4H-1,2-benzoxazine
were synthesized for the first time by means of a Friedel-Crafts
type reaction of nitroalkenes with benzene in the presence of a
superacid such as trifluoromethanesulfonic acid (TFSA).1a-d How-
ever, the method has limitations for synthesizing 4H-1,2-benzox-
azine derivatives bearing substituents on the benzene ring, because
biaryl compounds are obtained as major products in the intermo-
lecular reaction with substituted benzenes and nitroalkenes.1d Other
reports have also described synthesis of derivatives of 4H-1,2-
benzoxazines, but the yields were low, and the methods lack
generality, since only limited starting materials can be employed
and the structures of the products are too complicated for easy
further modification.1e-k Thus, a general synthetic method of 4H-
1,2-benzoxazines has not been established, and the potential of this
heterocycle in organic synthesis and functional molecular sciences,
such as materials and pharmaceutical sciences, remains unknown.1l
Herein, we present the acid-catalyzed cyclization reaction of
1-nitro-2-arylethane derivatives as a general method to obtain the
corresponding 4H-1,2-benzoxazines. We also show that this type
of heterocycle can be a potent intermediate to oxygen-functionalized
aromatic compounds, which represent basic architecture for func-
tionalized materials such as medicines.
Table 1. Cyclization of Methyl 3-Aryl-2-Nitropropionates to
Substituted 4H-1,2-Benzoxizines
We first examined the acid-catalyzed cyclization reaction of
2-nitro-3-phenylpropane 1 as a model substrate. No cyclization
reaction of 1 took place in the presence of acids such as TFA or
TFSA. We found, however, that the sodium salt 2 gave 3-methyl-
4H-1,2-benzoxazine 3 in 27% yield in the presence of TFA (Scheme
1). These results suggest that an aci-nitro species or O-protonated
aci-nitro species participates in the cyclization reaction.1c Thus, we
studied the reaction of methyl 2-nitro-3-phenylpropionate 4a, in
which the ester group facilitates enolization to the aci-nitro species.2
When methyl 2-nitro-3-phenylpropionate 4a was added to 10 equiv
of TFSA with CHCl3 as a cosolvent and the mixture was heated at
50 °C for 30 min, 3-methoxycarbonyl-4H-1,2-benzoxazine 5a was
obtained in 85% yield. Without the use of the cosolvent, the yield
of 5a was decreased (<58%). The reaction did not proceed at all
in TFA even when it was carried out for 2 days under reflux. This
result indicates that the reaction requires extremely high acidity,
which probably catalyzes both enolization of 4a to the aci-nitro
form and the cyclization process. This is consistent with the fact
that R-ethoxycarbonylnitromethane is enolized to the aci-nitro form
in TFSA, while such enolization does not occur in a weaker acid
such as TFA.2 The reaction also proceeded in the presence of an
a Typical reaction conditions: a solution of the substrate (1.0 mmol) in
10 mL of CHCl3 was added to 10 equiv amount of TFSA (0.89 mL) at 0
°C. The mixture was heated at 50 °C for 30 min. b 50 equiv of TFSA was
used.
excess amount of a Lewis acid such as TiCl4, but the yield was
moderate (45%).
† Graduate School of Pharmaceutical Sciences, The University of Tokyo.
‡ PRESTO, Japan Science and Technology Corporation (JST).
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10.1021/ja0343151 CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Then, similar reactions of methyl 3-aryl-2-nitropropionates (4b-
4l) with various substituents on the benzene ring were investigated
(Table 1). To our surprise, the reactions proceeded smoothly to
give the corresponding 4H-1,2-benzoxazines in moderate to good
yields even when the substituent on the benzene ring was an
electron-withdrawing group such as a halogen 4b-4e, ester 4f,
amide 4g, trifluoromethyl 4h, cyano 4i, or nitro group 4j. In contrast,
the reaction of substrates with an electron-donating group on the
benzene ring resulted in low yields of the 4H-1,2-benzoxazines. In
the case of 4k (methyl), the yield of 5k was only 16%. In particular,
the reaction of 4l (methoxy) gave the spiro compound 6 as a major
product together with a trace amount of the corresponding 4H-1,2-
benzoxazine 5l.1f
Next, the potential to generate oxygen-functionalized aromatic
compounds via the 4H-1,2-benzoxazines obtained here was exam-
ined (Scheme 2). It was reported that 3-alkyl analogues of 4H-1,2-
benzoxazine such as 3 can undergo thermal formation of o-ben-
zoquinone methide 7a,4 which is a useful reactive intermediate in
organic synthesis.1c,5-7 Gentle heating of a solution of 5a in toluene
in the presence of styrene gave a chroman derivative 8a in 56%
yield. This product was formed by the Diels-Alder reaction of
the in-situ formed 7a with styrene. Similar reactions proceeded in
good yields (77-93%) when we used 5b (p-Cl), 5f (p-CO2Me),
5g (p-CON(i-Pr)2), or 5i (p-CN). These results support the genera-
tion of o-benzoquinone methides bearing a halogen 7b, ester 7f,
amide 7g, or cyano group 7i on the benzene ring, which have not
been reported before. These aromatic substituents can easily be
further transformed in various ways so that the synthetic value of
o-benzoquinone methide would be greatly extended by this ap-
proach.
a new scaffold for medicinal chemistry. We have also preliminarily
established the potential intermediacy of the 4H-1,2-benzoxazines
for synthesizing o-benzoquinone methides and phenols. These
transformations can be regarded as an intramolecular transfer of
an oxygen atom of the nitro group of 2 to the benzene ring through
the 4H-1,2-benzoxazines 3. Further studies on the reaction mech-
anisms and other possible applications of 4H-1,2-benzoxazines in
organic synthesis and pharmaceutical sciences are under way.
Acknowledgment. This work was supported in part by a Grant-
in-Aid from the Ministry of Education, Science, Sports, Culture
and Technology, Japan, Uehara Memorial Foundation, and Tokuya-
ma Science Foundation.
Supporting Information Available: Experimental procedures and
characterizations (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
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Furthermore, basic hydrolysis of 5a in aqueous sodium hydroxide
in THF gave (2-hydroxyphenyl)acetonitrile 10a in 80% yield. This
product is assumed to be formed through decarboxylative N-O
bond cleavage of the resulting carboxylate ion 9. We confirmed
that other derivatives, 5b and 5i, gave the corresponding phenols,
10b and 10i, respectively, under the same reaction conditions. This
is a new synthetic route to multisubstituted phenols.
In conclusion, we have established a general synthetic method
of 4H-1,2-benzoxazine derivatives with various substituents, es-
pecially electron-withdrawing groups, on the benzene ring from
arylnitroalkanes. The compounds obtained by this method provide
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