Efficient synthesis of tricyclic benzobisoxazines by silica gel catalysis

Article abstract of DOI:10.1021/jo062670e

A new method for the synthesis of tricyclic benzobisoxazines, based upon silica gel-catalyzed formation of two 3,1-oxazine rings, is reported. The reversibility of the condensation reaction, forming an oxazine ring, allows for implementation of silica gel

Full text of DOI:10.1021/jo062670e

Efficient Synthesis of Tricyclic Benzobisoxazines
by Silica Gel Catalysis
Gae¨lle Spagnol, Andrzej Rajca,* and Suchada Rajca
Department of Chemistry, UniVersity of Nebraska,
Lincoln, Nebraska 68588-0304
arajca1@unl.edu
ReceiVed December 28, 2006
FIGURE 1. 1,3-, 1,4-, and 3,1-benzoxazine cores. Examples of 6-aryl-
1,2-dihydro-4H-3,1-benzoxazines, 6-aryl-1,2-dihydro-4H-3,1-benzox-
azine-2-thiones, benzobisoxazine core, and Rassat’s diradical.
activity relationship (SAR) studies of 6-aryl-1,2-dihydro-4H-
3,1-benzoxazines and 6-aryl-1,2-dihydro-4H-3,1-benzoxazine-
2-thiones led to the development of the potent and selective
nonsteroidal progesterone receptor agonist Tanaproget (Figure
1).5,6 In addition, acridines with 1,2-dihydro-4H-3,1-benzoxazine
cores showed potent cytotoxic activities against selected human
cancer lines.7
A new method for the synthesis of tricyclic benzobisoxazines,
based upon silica gel-catalyzed formation of two 3,1-oxazine
rings, is reported. The reversibility of the condensation
reaction, forming an oxazine ring, allows for implementation
of silica gel catalyzed ketone exchange in benzobisoxazine,
thus enabling access to nonsymmetric derivatives of benzo-
bisoxazines.
The most effective, and widely used, approaches to 1,2-
dihydro-4H-3,1-benzoxazines are based upon the classical
method of condensation, that is the acid-catalyzed condensation
of o-aminobenzyl alcohols and aldehydes, or simple ketones.9,10
The condensation conditions using acetic acid11,12 or p-tolu-
enesulfonic acid5 in benzene or toluene provide moderate-to-
good yields of the benzoxazines products. This method was
applied by Rassat and co-workers to prepare the octamethyl
derivative of benzobisoxazine, which was oxidized to form
stable nitroxide diradical (Figure 1).11 To our knowledge, this
Benzoxazines, a well-known class of heterocyclic compounds,
are of importance in the development of high-performance
polymeric materials and in medicinal chemistry. Polybenzox-
azines, which are conveniently obtained by ring-opening
polymerization of 3,4-dihydro-2H-1,3-benzoxazine monomers,
provide a new class of thermosetting resins for polymer
composites with superior mechanical, flame-retardant, and
superhydrophobic properties, especially for aerospace applica-
tions.1 Derivatives of 3,4-dihydro-2H-1,3-benzoxazines and 2,3-
dihydro-1,4-benzoxazines are well explored in medicinal chem-
istry,2,3 with several drugs in clinical use. In contrast, 1,2-
dihydro-4H-3,1-benzoxazines have received less attention,
though derivatives with promising biological activity were
recently discovered (Figure 1).5-8 Recent syntheses and structure-
(5) Zhang, P.; Terefenko, E. A.; Fensome, A.; Zhang, Z.; Zhu, Y.; Cohen,
J.; Winneker, R.; Wrobel, J.; Yardley, J. Bioorg. Med. Chem. Lett. 2002,
12, 787.
(6) (a) Fensome, A.; Bender, R.; Chopra, R.; Cohen, J.; Collins, M. A.;
Hudak, V.; Malakian, K.; Lockhead, S.; Olland, A.; Svenson, K.; Terefenko,
E. A.; Unwalla, R. J.; Wilhelm, J. M.; Wolfrom, S.; Zhu, Y.; Zhang, Z.;
Zhang, P.; Winneker, R. C.; Wrobel, J. J. Med. Chem. 2005, 48, 5092. (b)
Zhang, Z.; Olland, A. M.; Zhu, Y.; Cohen, J.; Berrodin, T.; Chippari, S.;
Appavu, C.; Li, S.; Wilhem, J.; Chopra, R.; Fensome, A.; Zhang, P.; Wrobel,
J.; Unwalla, R. J.; Lyttle, C. R.; Winneker, R. C. J. Biol. Chem. 2005, 280,
28468.
(7) Charmantray, F.; Demeunynck, M.; Carrez, D.; Croisy, A.; Lansiaux,
A.; Bailly, C.; Colson, P. J. Med. Chem. 2003, 46, 967.
(8) N-Haloacetyl 1,2-dihydro-4H-3,1-benzoxazines with herbicidal activ-
ity: Kobzina, J. W. Chem. Abstr. 1977, 87, 79678e. Kobzina, J. W. U.S.
Patent 3,917,592, 1975.
(9) Holly, F. W.; Cope, A. C. J. Am. Chem. Soc. 1944, 66, 1875.
(10) Annelation of (2-iodophenyl)acetonitrile onto sterically hindered
propargylic alcohols was reported to produce 1,2-dihydro-4H-3,1-benzox-
azine derivatives in moderate yields: Tian, Q.; Pletnev, A. A.; Larock,
R. C. J. Org. Chem. 2003, 68, 339.
(11) Rassat, A.; Sieveking, U. Angew. Chem., Int. Ed. 1972, 11, 303.
(12) (a) Nguyen, T. T.; Amey, R. L.; Martin, J. C. J. Org. Chem. 1982,
47, 1024. (b) Neuvonen, K.; Pohtola, R.; Pihlaja, K. Magn. Reson. Chem.
1989, 27, 725. (c) Oka, H.; Tamura, T.; Miura, Y.; Teki, Y. J. Mater. Chem.
2001, 11, 1364.
(1) (a) Wang, C. F.; Su, Y. C.; Kuo, S. W.; Huang, C. F.; Sheen, Y. C.;
Chang, F. C. Angew. Chem., Int. Ed. 2006, 45, 2248. (b) Lin, C. H.; Cai,
S. X.; Leu, T. S.; Hwang, T. Y.; Lee, H. H. J. Polym. Sci. A 2006, 44,
3454. (c) Ishida, H.; Ohba, S. Polymer 2005, 46, 5588. (d) Burke, W. J. J.
Am. Chem. Soc. 1949, 71, 609.
(2) Biologically active 1,3-benzoxazine derivatives. (a) Scarborough,
R. M.; Venkatraman, M. S.; Zhang, X.; Pandey, A. U.S. Pat. Appl. Publ.
2006. (b) Urbanski, T.; Radzikowski, Cz.; Ledochowski, Z.; Czarnocki,
W. Nature 1956, 178, 1351. (c) Urbanski, T.; Slopek, S. Nature 1951, 168,
562.
(3) (a) Recent review on biologically active 1,4-benzoxazine deriva-
tives: Achari, B.; Mandal, S. B.; Dutta, P. K.; Chowdhury, C. Synlett 2004,
2449. (b) Asymmetric synthesis and biological activity of levofloxacin, a
potent 1,4-benzoxazine-based antibacterial: Mitscher, L. A.; Sharma,
P. N.; Chu, D. T. W.; Shen, L. L.; Pernet, A. G. J. Med. Chem. 1987, 30,
2283.
(4) Gromachevskaya, E. V.; Kvitkowskii, F. V.; Kosulina, T. P.;
Kulnevich, V. G. Chem. Heterocycl. Compd. Chem. 2003, 39, 137.
10.1021/jo062670e CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/01/2007
J. Org. Chem. 2007, 72, 1867-1869
1867

TABLE 1. Condensations of Diol-Diamine 1 with Aldehydes and
TABLE 2. Condensations of Diol-Diamine 3 with Aldehydes and
Ketonesa
Ketonesa
entry
Y
Z
product yield (%)
9
10
11
12
13
CH3
CH3
H
CH3
4a
4b
4c
4d
4e
84
66-76
76
66-85
34-48
CH2O(CH2CH2O)3CH3 CH3
CH2COOCH3
CH2COOCH3
CH3
CH2COOCH3
a The general procedure was used. All reported yields are isolated.
SCHEME 1a
a The general procedure was used. All yields are isolated. b 0.05 M 1
and 50:1 w/w ratio of silica to 1 were used.
is the only report on benzobisoxazine with two saturated 3,1-
oxazine rings annelated to a benzene ring.13
With our interest in high-spin organic molecules and polymers
as building blocks for polymer magnets,14 we have undertaken
an investigation of the Rassat’s nitroxide diradical and its
derivatives. We optimized conditions for formation of octam-
ethylbenzobisoxazine11 in moderate yields, using the classical
method of condensation.15 In this process, we prepared the
starting diol-diamines, e.g., 1 (R ) CH3) and 3 (R ) (CH2)11-
CH3). Compound 3 was purified by preparative TLC (PTLC),
with a mixture of pentane and acetone used as eluent. To our
surprise, only one dominant band was observed, which was
determined to correspond to the desired tricyclic benzobisox-
azine product 4b (Table 2). We suspected that silica gel, which
is a mild acid, acted as catalyst in the condensation reaction.
Silica gel, which is easily available, low cost, and nontoxic,
has been used as a catalyst in organic synthesis.16 The use of
such a heterogeneous catalyst offers several advantages, such
as the ease of crude product separation, potential catalyst reuse,
and minimization of waste production. Therefore, we took
further steps to explore an efficient, simple, and versatile method
for synthesis of benzobisoxazines, using silica gel as catalyst.
We first investigated the silica gel catalyzed condensation
b
a All reported yields are isolated. Treatment with pentane allowed for
c
partial separation of diastereomers. Isolated with a 5-10% admixture of
6. Isolated as 5:1 mixture of 6 and 4d.
d
of diol-diamine 111,15 with aldehydes and ketones (Table 1).
The condensation reactions were carried out in pentane, at
room temperature, in the presence of silica gel. When diol-
diamine 1 was treated with aldehydes, the corresponding
benzobisoxazine products were obtained cleanly and efficiently
(entries 1-3, Table 1). 4-Nitrobenzaldehyde provided the
benzobisoxazine product 2c with 99% yield after purification
(entry 3). Cyclohexanone and methyl alkyl ketones (entries 4-6)
led to the expected products with good to moderate yields.
Condensation of 1 with the PEGylated ketone, which is of
interest for preparation of water-soluble high-spin diradicals,17
gave 2g with a good 65% isolated yield. Condensation of 1
with methyl acetoacetate progressed slowly and produced
numerous side products; 2h was isolated in a moderate 37%
(13) Two 3,1-oxazine rings could be annelated to acridine using relatively
reactive formaldehyde ref 7.
(14) (a) Rajca, A.; Wongsriratanakul, J.; Rajca, S. Science 2001, 294,
1503. (b) Rajca, A. AdV. Phys. Org. Chem. 2005, 40, 153.
(15) Rajca, A.; Takahashi, M.; Pink, M.; Spagnol, G.; Rajca, S. To be
submitted.
(16) Banerjee, A. K.; Mimo, M. S. L.; Vegas, W. J. V. Russ. Chem.
ReV. 2001, 70, 971.
(17) Spagnol, G.; Shiraishi, K.; Rajca, S.; Rajca, A. Chem. Commun.
2005, 5047.
1868 J. Org. Chem., Vol. 72, No. 5, 2007

yield. For comparison, the acetic acid-catalyzed condensations
provided 2d, 2e, and 2g in 43-54%,15 20-34%,15 and 22%
yields, respectively, due to the formation of significant amounts
of byproducts.
To further test the efficiency of this method, condensation
of diamine-diol 3 with various carbonyl compounds were
carried out (Table 2).
6 in ∼20% yield, with an admixture of 4d, as chromatographic
separation of the benzobisoxazine products was difficult, due
to close Rf values.
Benzobisoxazines 2h and 4d were formed as ∼1:1 mixtures
of diastereomers with indistinguishable Rf values on deactivated
silica gel (Scheme 1). This is analogous to the benzobisoxazines
that were obtained from condensations of diol-diamines (1 and
3) with aldehydes or unsymmetrically substituted ketones
(entries 1-3, 6-9, 11, and 12).
The condensation reactions were carried out as described for
diol-diamine 1. When diol-diamine 3 was treated with
acetaldehyde, the reaction was completed after 1 h, to provide
the bisannelation product 4a in good yield. Condensations with
methyl-substituted ketones (entries 10-12) also proceeded as
expected. Although a large excess of ketone and long reaction
times were required in the case of acetone, the resultant crude
product 4b already had adequate purity for synthetic purposes.
For condensations with pegylated ketone as well as methyl
acetoacetate, the target products were obtained in good to very
good yields. It should be noted that benzobisoxazine 4c, which
contains both hydrophilic triethylene glycol groups and hydro-
phobic dodecane chains, is an amphiphilic heterocyclic mol-
ecule. From our perspective, 4c is a precursor to a novel
amphiphilic high-spin nitroxide diradical, with potential for
biological and biomedical applications. Finally, we investigated
the condensation with dimethyl 1,3-acetonedicarboxylate (entry
13). In this case, the condensation reaction progressed slowly
(1-2 days) to give the bisannelation product in ∼30-50% yield
after purification.
Benzobisoxazines 2h, 4d, and 4e could have high synthetic
value, as their ester groups can be readily reduced to the
corresponding primary alcohols and then further functionalized.
It is expected that condensations of diol-diamines with
ketones, leading to the benzobisoxazine products, are reversible.
Therefore, we explored silica gel catalyzed exchange reaction
to provide another approach to benzobisoxazines, including
nonsymmetric benzobisoxazines with differently substituted
oxazine rings, i.e., derived from two different ketones
(Scheme 1).
Reaction of benzobisoxazines 2e and 4b with an excess
amount of methyl acetoacetate gave benzobisoxazines 2h and
4d in ∼40% and ∼60% yields, respectively. This reaction
corresponds to a complete exchange of acetone moiety for
methyl acetoacetate moiety in both 3,1-oxazine rings.
When reactions of benzobisoxazines 2e and 4b with an excess
amount of methyl acetoacetate were stopped at an intermediate
stage, nonsymmetric benzobisoxazines 5 and 6 were obtained
(Scheme 1). This result indicates a partial exchange of acetone
moiety for methyl acetoacetate moiety. For the reaction of 2e
with methyl acetoacetate, benzobisoxazines 5, 2h, and unreacted
2e were isolated in ∼20%, ∼10%, and ∼10% yields, respec-
tively. However, reaction of 4b with methyl acetoacetate gave
Experimental Section
General Procedure for Condensation of Diol-Diamines 1 and
3 with Ketones and Aldehydes: Symmetric Benzobisoxazines
2a-h and 4a-e. Ketone or aldehyde (5-50 equiv) was added to
a ∼0.1 M suspension of diol-diamine (5-500 mg) in pentane,
followed by silica gel (5:1 w/w with respect to the diol-diamine).
The reaction mixtures were vigorously stirred at room temperature.
The disappearance of the starting material and the appearance of
monoannelated, and then bisannelated products, were followed by
TLC and, in selected cases, by 1H NMR spectroscopy. After
addition of ethyl acetate and filtration of silica, evaporation under
reduced pressure gave the crude products, which were purified by
PTLC or flash chromatography (silica, deactivated with 2%
triethylamine in pentane). For benzobisoxazine 2e, an alternative
purification procedure involved treatment with pentane/ether (1:
1). For benzobisoxazines 2g and 4c, the pegylated ketone, which
was remaining in the crude reaction mixture, was washed off with
water prior to chromatography.
General Procedure for Exchange Reaction of Benzobisox-
azines 2e and 4b with Methyl Acetoacetate: Symmetric Ben-
zobisoxazines 2h and 4d and Nonsymmetric Benzobisoxazines
5 and 6. Methyl acetoacetate (10-25 equiv) was added to a ∼0.05
M suspension of benzobisoxazine (5-60 mg) in pentane, followed
by silica gel (5:1-35:1 w/w with respect to the benzobisoxazine).
The reaction mixtures were vigorously stirred at room temperature.
The disappearance of the starting material and the appearance of
nonsymmetric, and then symmetric, benzobisoxazine products were
1
followed by TLC and reactions leading to 5 or 6 by H NMR
spectroscopy. After addition of ethyl acetate and filtration of silica,
evaporation under reduced pressure gave the crude products, which
were purified by PTLC or flash chromatography (silica, deactivated
with 2% triethylamine in pentane).
Acknowledgment. The National Science Foundation (Chem-
istry Division) and the Air Force Office of Scientific Research
(Polymer Chemistry Program) supported this investigation
through Grant Nos. CHE-0414936 and FA9550-04-1-0056,
respectively. This research was performed in facilities renovated
with support from the NIH (Grant No. RR16544-01).
Supporting Information Available: Complete description of
experimental details and product characterization. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO062670E
J. Org. Chem, Vol. 72, No. 5, 2007 1869