J . Nat. Prod. 1998, 61, 821-822
821
Syn th esis of 4-Acetylben zoxa zolin -2(3H)-on e Rep or ted fr om Zea m a ys
Michael Kluge and Dieter Sicker*
Institute of Organic Chemistry, University of Leipzig, Talstrasse 35, D-04103 Leipzig, Germany
Received November 21, 1997
A three-step alternative synthesis of 4-acetylbenzoxazolin-2(3H)-one (4) is reported. Starting
from inexpensive 3-hydroxyacetophenone (1) 3-hydroxy-2-nitroacetophenone (2) is prepared
by nitration followed by catalytic hydrogenation to yield 2-amino-3-hydroxyacetophenone (3)
in which a CdO unit is inserted by means of bis(trichloromethyl)carbonate (triphosgene) in
the presence of triethylamine to afford 4 in 35% overall yield.
Sch em e 1. Synthesis of 4-acetylbenzoxazolin-2(3H)-one
(4-ABOA) (4)
Recently, the isolation and characterization of 4-acetyl-
benzoxazolin-2(3H)-one (4-ABOA, 4) was reported from
kernels of a special Zea mays hybrid line.1 This hybrid
is tolerant to Fusarium graminearum and has insecti-
cidal activity against Sitophilus zeamais.2 A biosyn-
thetic relationship of 4-ABOA to benzoxazolin-2(3H)-
one (BOA) and 6-methoxybenzoxazolin-2(3H)-one
(MBOA) known from gramineous plants3 has been
postulated.2 We have shown that, at least synthetically,
4-ABOA (4) can indeed be prepared from a benzoxazi-
noid precursor, that is, by ether cleavage and subse-
quent hydrolysis of 5-acetyl-4-hydroxy-2-methoxy-2H-
1,4-benzoxazin-3(4H)-one.4 Therefore, we assume that
the 4-ABOA isolated may have originated from the
degradation of 5-acetyl-2,4-dihydroxy-2H-1,4-benzox-
azin-3(4H)-one as the natural precursor. A four-step
synthesis starting from the sensitive 3-hydroxyanthra-
nilic acid has been reported5 to produce 4-ABOA (4) in
quantities sufficient for biological tests. We now report
on an alternative synthesis of 4-ABOA (4) (Scheme 1)
on the gram scale, based on an inexpensive starting
material and avoiding the handling of phosgene and of
light- and air-sensitive intermediates.
(MeOH) (lit.6 mp 131-132 °C), together with 3-hydroxy-
4-nitroacetophenone (6.4 g, 6%) of mp 68-69 °C (MeOH)
(lit.6 mp 71.5-72.5 °C). 2-Amino-3-hydroxyacetophe-
none (3) obtained by hydrogenation4 of 2 on the 20-mmol
scale was used without recrystallization. Melting points
were determined on a Boetius micro hot-stage apparatus
and are corrected.
4-Acetylben zoxa zolin -2(3H)-on e (4). To a rapidly
stirred solution of 2-amino-3-hydroxyacetophenone (3)
(10 mmol, 1.51 g) in dry THF (150 mL) was added
triethylamine (20 mmol, 2.02 g) and, in one portion, a
solution of bis(trichloromethyl)carbonate (3.37 mmol,
1.00 g) in dry THF (10 mL) at 0 °C. After stirring at 0
°C for 1 h the solution was filtered, and the solvent was
removed in vacuo. The remaining residue was recrys-
tallized from H2O (300 mL) to yield 4-acetylbenzoxazo-
lin-2(3H)-one (4) (1.68 g, 95%) as pale yellow needles,
pure according to TLC [Merck aluminum sheets Si gel
60 F254, eluent toluene/EtOAc 1:1 (v/v), Rf ) 0.46]: mp
202-204 °C (H2O); mp 210-211° (MeOH) (lit.1 mp 217-
218 °C (Me2CO-H2O)]. Compound 4 proved to be
identical with our synthetic sample previously reported
by comparison of full spectroscopic data4 and with the
natural product described.1
3-Hydroxy-2-nitroacetophenone (2) was prepared by
nitration of 3-hydroxyacetophenone (1) with a mixture
of 67% nitric acid and 96% sulfuric acid as described.6
Compound 2 was hydrogenated over Pt-C in THF to
yield 2-amino-3-hydroxyacetophenone (3) in 96% yield;4
amine 3 is stable and storable. It was carbonylated by
means of bis(trichloromethyl)carbonate (triphosgene) in
the presence of a tertiary amine in THF in 95% yield.
Triphosgene has been rediscovered as a solid, safe, and
convenient phosgene substitute.7 4-ABOA (4) was
finally obtained in 35% overall yield based on 1 by this
procedure, which is similar to our synthesis of MBOA.8
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. The crude
product obtained by nitration6 of 80 g (0.588 mol)
commercial 3-hydroxyacetophenone (1) (Lancaster) was
purified by crystallization from MeOH followed by
column chromatography [Merck Si gel 0.063-0.200 mm,
eluent toluene-EtOAc 5:1 (v/v)] to yield 3-hydroxy-2-
nitroacetophenone (2) (41.0 g, 38%) of mp 134-136 °C
Ack n ow led gm en t . The financial support for this
work by the Deutsche Forschungsgemeinschaft and the
Fonds der Chemischen Industrie is gratefully acknowl-
edged.
Refer en ces a n d Notes
* To whom correspondence should be adressed: Tel.: 0049-341-
9736574. Fax: 0049-341-9736599. E-Mail: sicker@organik.orgchem.uni-
leipzig.de.
(1) Fielder, D. A.; Collins, F. W.; Blackwell, B. A.; Bensimon, C.;
ApSimon, J . W. Tetrahedron Lett. 1994, 35, 521-524.
S0163-3864(97)00525-9 CCC: $15.00
© 1998 American Chemical Society and American Society of Pharmacognosy
Published on Web 05/01/1998
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