Formation of 4H-1,2-Benzoxazines
A R T I C L E S
Scheme 1
particularly those with high substrate generality and high chemo-
and regioselectivity, is still of great interest.
aci-nitro species in the cyclization reaction. Thus, we studied
the reaction of methyl 2-nitro-3-phenylpropionate 4a, in which
the ester group should facilitate enolization to the aci-nitro
species. When methyl 2-nitro-3-phenylpropionate 4a was added
to 10 equiv of TFSA in 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 the solution
was heated at reflux for 2 days. The reaction also proceeded in
1,2-dichloroethane (1,2-(CH2Cl)2) as a cosolvent, while aprotic
polar solvents such as acetonitrile or ethers were inappropriate,
because they worked as bases to neutralize the high acidity of
TFSA. We also examined various Lewis acids, which might
promote the present intramolecular cyclization of 4a. When
TiCl4 (2.5 equiv) or ZrCl4 (10 equiv) was employed, the
cyclization proceeded, and the cyclized product (5a) was
obtained in moderate to low yield (41% and 18%, respectively).
Other Lewis acids such as Ti(OiPr)4, Sc(OTf)3, FeCl3, ZnCl2,
AlCl3, or GaCl3 did not catalyze the reaction or did not provide
a pure product.
Direct introduction of an oxygen atom into a C-H bond is
a very attractive idea, but its feasibility is still very limited, for
both aromatic and aliphatic C-H bonds. In particular, there has
been little study of the utilization of an oxygen atom of the
nitro group as an oxygen source for aromatic-oxygenation,
although aromatic nitrogen-functionalization via reduction of a
nitro group is well established.11
Acid-catalyzed Friedel-Crafts-type cyclization reaction of
nitro olefins in the presence of benzene has been reported to
generate 4H-1,2-benzoxazine.12 This reaction could be regarded
as the first example of intermolecular oxygen transfer reaction
from a nitro group to a benzene ring. However, this reaction
turned out to lack generality, because substituted aromatic com-
pounds failed to provide the desired heterocyclic compounds.12
Thus, oxygen functionalization from a nitro group is still little
explored, although it is of great interest because of its singular
character. We will report herein several chemical features of
the acid-catalyzed intramolecular transfer of an oxygen atom
of the nitro group of nitroalkanes to provide cyclized products,
4H-1,2-benzoxazines, and the results of a mechanistic study of
this aromatic oxygen-functionalization reaction.13
Next, similar reactions of methyl 3-aryl-2-nitropropionates
bearing various substituents on the benzene ring were investi-
gated (Table 1). Unexpectedly, when the substituent on the
benzene ring was an electron-withdrawing group such as a
halogen 4b-4f, ester 4g, amide 4h, trifluoromethyl 4i, cyano
4j, or nitro group 4k, the reactions proceeded smoothly to give
the corresponding 4H-1,2-benzoxazines 5 in moderate to good
yields. This substituent preference of the substrates is in sharp
contrast to the case of 3-aryl-2-nitropropanes (Scheme 1); only
unsubstituted 1 (in the form of the salt 2) gave the cyclized
product 3, while the cyclization of the sodium salt of 3-aryl-
2-nitropropanes failed to proceed when the aromatic moiety was
substituted with a chloride, cyano, nitro, or methyl group at the
p-position, or two methyl groups at the m,p-positions. Further-
more, 4l, bearing an aromatic nitro group at the o- and
p-positions with respect to the cyclizing carbon atom, also gave
the cyclization products, a mixture of p-cyclized (5l, yield 23%)
and o-cyclized products (5l′, yield 51%) (Table 1, entry 12). It
seems unlikely that this regioselectivity of the cyclization was
controlled by steric factors; it seems more likely to depend on
electronic factors, that is, the electron deficiency of the aromatic
carbon atom, because the o-cyclization with respect to the nitro
group was favored over the p-cyclization.
2. Results and Discussion
Acid-Catalyzed Cyclization of Nitro Alkanes to 4H-1,2-
Benzoxazines. Scheme 1 shows the acid-catalyzed cyclization
reaction of 2-nitro-3-phenylpropane 1. Its sodium salt 2 gave
3-methyl-4H-1,2-benzoxazine 3 in 27% yield in the presence
of TFA as a Brønsted catalyst, while no cyclization reaction of
free 1 took place even in the presence of acids such as TFA or
trifluoromethanesulfonic acid (CF3SO3H, TFSA). These results
suggested involvement of an aci-nitro species or O-protonated
(9) For representative reactions of oxygen electrophiles, see: (a) Davidson,
A. J.; Norman, R. O. C. J. Chem. Soc. 1964, 5404-5416. (b) Vesely, J.
A.; Schemerling, L. J. Org. Chem. 1970, 35, 4028-4033. (c) Kurz, M. E.;
Johnson, G. J. J. Org. Chem. 1971, 36, 3184-3187. (d) Olah, G. A.;
Ohnishi, R. J. Org. Chem. 1978, 43, 865-867. (e) Prakash, G. K. S.; Krass,
N.; Wang, Q.; Olah, G. A. Synlett 1991, 39-40. The review of aromatic
hydroxylation by an electrophilic process: (f) Jacquesy, J. C.; Gesson, J.
P.; Jouannetaud, M. P. ReV. Chem. Intermed. 1988, 9, 1-26. For direct
hydroxylation of aromatic compounds, see: (g) Larock, R. C. Compre-
hensiVe Organic Transformations; Oxford: New York, 1989; pp 485-
486.
(10) (a) Panov, G. I. CATTECH 2000, 4, 18-32. (b) Notte, P. P. Top. Catal.
2000, 13, 387-394. (c) Ribera, A.; Arends, I. W. C. E.; de Vries, S.; Perez-
Ramirez, J.; Sheldon, R. A. J. Catal. 2000, 195, 287-297. (d) Taboada, J.
B.; Jensen, E. J. M.; Arends, I. W. C. E.; Mul, G.; Overweg, A. R. Catal.
Today 2005, 110, 221-227. (e) Centi, G.; Perathoner, S.; Pino, F.; Arrigo,
R.; Giordano, G.; Katovic, A.; Pedula, V. Catal. Today 2005, 110, 211-
220.
In contrast, the reaction of substrates bearing an electron-
donating group on the benzene ring gave the cyclized products,
4H-1,2-benzoxazines, in low yields. In the case of methyl (4m)
and 3,4-dimethyl (4n) substituents, the yields were only 16%
and 4%, respectively, and the cyclization reaction of the
(11) (a) Khenkin, A. M.; Neumann, R. J. Am. Chem. Soc. 2004, 126, 6356-
6362. (b) Topiwala, U. P.; Whiting, D. A. J. Chem. Soc., Chem. Commun.
1994, 21, 2443-2444.
(12) Nakamura, S.; Uchiyama, M.; Ohwada, T. J. Am. Chem. Soc. 2003, 125,
5282-5283.
(13) A part of the work was communicated in ref 12.
9
J. AM. CHEM. SOC. VOL. 129, NO. 6, 2007 1725