A convenient synthesis of 2H-1,4-benzoxazines, 3H-indol-3-ones, and 2,3-dihydrobenzoxazoles

Article abstract of DOI:10.1246/bcsj.75.2481

3,5-Di-tert-butyl-1,2-benzoquinone 1-oxime (1b) reacted with ester ylides 2a,b to give the corresponding 2H-1,4-benzoxazin-2-ones 9a,b along with the 3H-indol-3-one 11, whereas with keto ylides 12a,b, 2,3-dihydrobenzoxazoles 13a,b were isolated. Conversel

Full text of DOI:10.1246/bcsj.75.2481

c. Jpn.
© 2002 The Chemical Society of Japan
Bull. Chem. Soc. Jpn., 75, 2481–2485 (2002) 2481
e Chemical
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A Convenient Synthesis of 2H-1,4-Benzoxazines, 3H-Indol-3-ones, and
2,3-Dihydrobenzoxazoles
o-Quinonimines in N-Heterocyclic Synthesis
W. M. Abdou et al.
Wafaa Mahmoud Abdou,* Mounir Abdou Ibrahim Salem,† and Ashraf Ahmed Sediek
02
81
85
SJA8
09-2673
067
Department of Pesticide Chemistry, National Research Centre, Dokki, D-2622, Cairo, Egypt
†Department of Chemistry, Faculty of Science, Ain-Shams University, Cairo, Egypt
(Received March 18, 2002)
3,5-Di-tert-butyl-1,2-benzoquinone 1-oxime (1b) reacted with ester ylides 2a,b to give the corresponding 2H-1,4-
benzoxazin-2-ones 9a,b along with the 3H-indol-3-one 11, whereas with keto ylides 12a,b, 2,3-dihydrobenzoxazoles
13a,b were isolated. Conversely, the reaction of 1b with moderated phosphonium salt 15 proceeded under phase-transfer
catalysis conditions to afford the 2H-1,4-benzoxazine derivative 19, instead of the expected Wittig reaction product.
02
02
3
We reported earlier1 that 3,5-di-tert-butyl-1,2-benzoquinone
reacted with trialkyl phosphites to give pentaoxyphosphoranes,
as presumably observed with o-quinones, whereas with dialkyl
phosphonates an anomalous behavior was shown, whereupon a
ring attack occurred to give phosphonate adducts. We also
found that the dione system in the quinone in question behaved
differently toward Wittig2a,b and Wittig-Horner reagents.2c
Later on, in a continuing exploration of the attack of alkyl-
idenephosphoranes on carbon–nitrogen systems,3 we de-
scribed3g the synthesis of substituted 2,3-dihydro-1H-inda-
zoles 4a,b, 2H-1,4-benzoxazin-2-one 5 and 1,2-dihydrocinno-
line 6 by applying phosphorus ylides 2 or 3 on 3,5-di-tert-
butyl-1,2-benzoquinone 1-phenylhydrazone (1a) (e.g. Scheme
1). It has been pointed out that the substitution pattern in 1 is
such as to obstruct (for steric hindrance reasons) a nucleophilic
approach by a ylide phosphorane to the aryl-carbonyl in 1a.
The effect of the neighboring t-Bu moiety on the C–2(O)
group would be expected to be quite unfavorable.
zo[1,2-b]-fused N-heterocycles, which constitute an important
class of compounds, many of which exhibit significant phar-
maceutical and biological potency.4,5
Results and Discussion
The required o-quinone monoxime 1b was easily obtained
in a reasonable yield (48%) from a reaction of the parent o-
quinone with hydroxylamine hydrochloride in boiling ethyl al-
cohol for 24 h. The treatment of 1b with (ethoxycarbonylme-
thylene)triphenylphosphorane (2a, 2 molar amounts) in boiling
chloroform (or in toluene; best yield in chloroform) gave ethyl
6,8-di-tert-butyl-2-oxo-2H-1,4-benzoxazine-3-acetate (9a)
(41%) along with unexpected 4,6-di-tert-butyl-7-hydroxy-3H-
indol-3-one (11) (28%) (Scheme 2). A similar treatment of 1b
with (methoxycarbonylmethylene)triphenylphosphorane (2b)
led to 2H-1,4-benzoxazin-2-one 9b and 3H-indol-3-one 11 in
44 and 22% yields, respectively. The 1H and 13C NMR spectra
of 9b are similar to those of 9a, except for the ester group,
which displays characteristic resonances with appropriate
chemical shifts. Repetition of the reaction between equimolar
amounts of 1 and 2a,b again afforded 9a,b and 11 in addition
to the unchanged 1b. The structures 9 and 11 were assigned
based on elemental analyses and spectral data. Thus, 2H-1,4-
As a sequel, the work detailed herein describes the reactions
of 3,5-di-tert-butyl-1,2-benzoquinone 1-oxime (1b) with stabi-
lized ester-2a,b or keto-12a,b ylide phosphoranes and a mod-
erate allyltriphenylphosphonium bromide 15. The methodolo-
gy has led to a facile synthesis of the title compounds, ben-
Scheme 1.

2482 Bull. Chem. Soc. Jpn., 75, No. 11 (2002)
o-Quinonimines in N-Heterocyclic Synthesis
Scheme 2.
Scheme 3.
benzoxazin-2-ones 9a,b showed strong absorptions at 1763
(9a) and 1772 cm−1 (9b), characteristic of the carbonyl groups
in similar six-membered heterocyclic compounds (cf. δ
lactones6). Other bands appeared at ~1720 [C(O), ester] and
~1590 cm−1 (CwN). The 1H NMR spectra of compounds 9a,b
exhibit a singlet for their C-9-methylene protons around δ 2.6,
in agreement with the suggested structure, and rule out the
alternative arylidene form. Furthermore, the distinguishing
features of the 13C NMR spectra of 9a,b were the presence of
signals at δ ~28 (CH2COR), ~160 [C(O), ester] and at ~172
[C-1-(O)].
The respective mechanism for the formation of 9 might in-
volve an initial Wittig olefination of 1b in its tautomeric ni-
troso form 1bA,7 leading to intermediate 7, followed by the ad-
dition of a second ylide species, 2a or 2b. The further elimina-
tion of triphenylphosphine and δ-lactonization of the thus-
formed intermediate 8 yielded the final products 9a,b accom-
panied by extrusion of an alcoholic moiety (Scheme 2-i).
Meanwhile, according to a mechanism suggested by the refer-
ee, and outlined in Scheme 2-ii, the formation of compound 11
involved the intermediate 10, which arose from an intramolec-
ular Friedel–Crafts type condensation of intermediate 7.8 Fur-
ther elimination of the appropriate alcoholic moiety from 10
afforded 11. However, the latter step occurred through a carb-
abion mechanism, driven by the resulting gain of aromaticity.
In favor of the assigned structure 11, its 1H NMR spectrum re-
vealed the absence of a doublet at δ 6.23, assignable to the pro-
ton on C-6 in 1,9 or C-5 in 9 in their 1H NMR spectra. Instead,
signals at δ 6.05 (C-2-H), 6.87 (C-5-H) and 10.24 (OH) were
present in the 1H NMR spectrum of 11. The absorption at νmax
1733 cm−1 in the IR spectrum of 11 is also in better agreement
with the carbonyl absorption (1725–1735 cm−1) of several 3-
oxoindoline derivatives.10
The monoxime 1b reacted with benzoyl-12a and acetyl-12b
methylenetriphenylphosphoranes in boiling toluene, giving the
dihydrobenzoxazoles 13a,b advantageously. The structure of
13 was assigned from its molecular weight, its single carbonyl
peak at νmax 1666 (13a) or 1675 (13b); its 1H NMR absorption
at δ ~3.7 [CH-C(O)] and δ ~11 (NH), and its conversion by
N-bromosuccinimide (NBS) (Scheme 3) to 14 [78%, νmax
~1595 cm−1, CwN].
Next, we studied the reaction of 1b with allyltriphenylphos-
phonium bromide 15; the obtained product is depicted in
Scheme 4. The treatment of 1b with 15 in the presence of lith-
ium hydroxide in CHCl3 yielded 6,8-di-tert-butyl-2-methyl-
2H-1,4-benzoxazine (19) (48%) (and unidentified products of

W. M. Abdou et al.
Bull. Chem. Soc. Jpn., 75, No. 11 (2002) 2483
Scheme 4.
h. After removing the solvent, the residue was chromatographed
on silica gel. Elution with hexane/CHCl3 (9:1, v/v) afforded yel-
low crystals of ethyl 6,8-di-tert-butyl-2-oxo-2H-1,4-benzoxazine-
3-acetate (9a) (480 mg, 41%), mp 131.5–133 °C (CH2Cl2); Anal.
Found: C, 69.66; H, 7.82; N, 3.93%. Calcd for C20H27NO4
(345.44): C, 69.54; H, 7.88; N, 4.05%; IR (KBr) 1763 (CwO, lac-
tone), 1722 (CwO, ester), 1595 cm−1 (CwN); 1H NMR (CDCl3) δ
0.95 (3H, t, JHH = 6.5 Hz, OC–CH3), 1.24, 1.28 (2 × 9H, 2s,
C(CH3)3), 2.64 (2H, s, CH2–), 4.05 (2H, q, JHH = 6.5 Hz, OCH2),
6.23, 6.82 (2 × 1H, 2d, JHH = 4.2 Hz, Ar-H); 13C NMR δ 18.4
(OCCH3), 27.8 (CH2–), 31.2, 32.4 [2 × C(CH3)], 34.6, 35.8 (2 ×
C(CH3)3), 58.3 (OCH2), 123.7, 125.5 (C-5 & C-7), 129.4 (C-4a),
133.1 (C-3), 142.0 (C-6), 144.2 (C-8), 151.5 (C-8a), 159.3 (C(O),
ester), 171.5 (C-2-(O)); MS m/z (%) 345 (M+, 55), 330 (11), 300
(15), 272 (19), 271 (100), 246 (23), 186 (5).
Elution with hexane/CHCl3 (8:2, v/v) afforded yellow leaflets
of 4,6-di-tert-butyl-7-hydroxy-3H-indol-3-one (11) (245 mg,
28%), mp 155–157 °C (benzene); Anal. Found: C, 74.17; H, 8.24;
N, 5.32%. Calcd for C16H21NO2 (259.35): C, 74.09; H, 8.16; N,
5.4%; IR (KBr) 3425 (OH), 1733 (C-3-(O)), 1582 cm−1 (CwN);
1H NMR (CDCl3) δ 1.33, 1.46 (2 × 9H, 2s, C(CH3)3), 6.05 (1H, s,
C-2-H), 6.87 (1H, s, C-5-H), 10.24 (1H, sω, –OH, exchangeable
with D2O); 13C NMR δ 31.3, 32.6 (2 × C(CH3)), 34.5, 35.4 (2 ×
C(CH3)3), 122.8 (C-5), 133.1 (C-2-H), 138.5 (C-9), 142.6 (C-4),
145.9 (C-6), 149.6 (C-8), 151.4 (C-7-OH), 171.3 (C-3-(O)); MS
m/z (%) 259 (M+, 100), 258 (4), 231 (16), 205 (3), 186 (11).
(B) Preparation of 9b and 11: A stirred solution of 1b (0.8 g,
3.4 mmol) and (methoxycarbonylmethylene)triphenylphospho-
rane (2b) (2.3 g, 6.8 mmol) in dry CHCl3 (20 mL) was boiled un-
der reflux for 15 h (TLC). The product mixture was worked up ac-
cording to the above-described procedure for ylide 2a, yielding
compounds 9b and 11.
high melting points). Structure 19 was assigned from an ele-
mental analysis and the spectral properties. Obviously, the
highly reactive ylide 15A is unlikely to react at the oxoimino
nitrogen atom of 1b and is much more likely to remove a pro-
ton from the OH group, to generate cation 17. An attack of
the oxygen anion 16 on 17 yields the ylide 18, which would
then undergo a Wittig reaction giving the final product 19.
Noteworthy, an analogous mechanism was previously reported
for the reaction of vinylphosphonium salt with α-imino ke-
tones.11
In summary, the present and previous studies4g clearly show
that the α-imino carbonyl substrates 1a,b react with alkyli-
denephosphoranes exclusively in the phenolic form, and not in
the tautomeric o-quinone-imine structure, at least under the
prevailing experimental conditions. Although the initial step
in the reactions of 1b with 2 or 12 involves a nucleophilic at-
tack by the nitroso-oxygen atom on the phosphonium center of
the reagent, the consequences of the initial step vary markedly
according to the nature of the α-substituent of the ylidic car-
bon atom. Finally, the N-heterocycles prepared in the present
work, might to be biologically active compounds based on
known drug skeletons.
Experimental
All of the melting points are uncorrected. IR spectra were re-
corded on a Perkin-Elmer spectrophotometer model 297 (Grating)
1
using a KBr disc. The H and 13C NMR spectra were run on a
Varian Gemini 200 (200 MHz) instrument using TMS as an inter-
nal reference. The mass spectra were taken at 70 eV on an MS-50
Kratos (A.E.I.) spectrometer provided with a data system. Appro-
priate precautions in handling moisture-sensitive compounds were
observed. Light petroleum refers to the 40–60 °C fraction.
ꢀ. Reaction of 3,5-Di-tert-butyl-1,2-benzoquinone 1-Oxime
(1b) with Ester Ylides 2a,b: (A) Preparation of Compounds 9a
and 11. A stirred solution of monoxime 1b (0.8 g, 3.4 mmol) and
(ethoxycarbonylmethylene)triphenylphosphorane (2a) (2.4 g, 6.8
mmol) in dry chloroform (25 mL) was boiled under reflux for 18
Elution with hexane/CHCl3 (9:1, v/v) yielded yellow crystals
of methyl 6,8-di-tert-butyl-2-oxo-1H-1,4-benzoxazine-3-acetate
(9b) (490 mg, 49%), mp 138–140 °C (CH2Cl2); Anal. Found: C,
68.74; H, 7.67; N, 4.18%. Calcd for C19H25NO4 (331.42): C,
68.85; H, 7.60; N, 4.23%; IR (KBr) 1772 (CwO, lactone), 1718
(CwO, ester), 1598 cm−1 (CwN); 1H NMR (CDCl3) δ 1.24, 1.28 (2

2484 Bull. Chem. Soc. Jpn., 75, No. 11 (2002)
o-Quinonimines in N-Heterocyclic Synthesis
× 9H, 2s, C(CH3)3), 2.58 (2H, s, CH2-), 3.84 (3H, s, OCH3), 6.24,
6.79 (2 × 1H, 2d, JHH = 4.2 Hz, Ar-H); 13C NMR δ 28.3 (CH2-),
31.4, 32.8 (2 × C(CH3)3], 34.3, 35.5 (2 × C(CH3)3), 54.5 (s,
OCH3), 123.4, 125.4 (C-5 & C-7), 129.8 (C-4a), 133.3 (C-3),
141.8 (C-6), 146.4 (C-8), 150.8 (C-8a), 161.5 (C(O), ester), 173.6
(C-2-(O)); MS m/z (%) 331 (M+, 48), 316 (4), 300 (17), 272 (27),
271 (100), 246 (20), 186 (8).
Elution with hexane/CHCl3 (8:2, v/v) afforded yellow leaflets
of 3H-indol-3-one 11 (195 mg, 22%), mp 155–157 °C (benzene),
and were shown to be identical to material prepared as described
above by using 2a.
(C) A reaction between equimolar amounts of 1b and 2a or 2b
in CHCl3 was carried out, and the reaction mixture was worked up
according to the above-described procedure for 2a,b. The product
mixture gave (with 2a) 9a (21%) and 11 (18%) and (with 2b) 9b
(20%) and 11 (14%). Unreacted oxime 1b was also isolated
(~25%) in each case.
(D) A reaction between 1b and 2 molar amounts of 2a,b was
repeated in dry toluene. The reaction mixture was heated under
reflux for 40 h and afforded, after the usual working up, com-
pounds 9a,b (~28%) and 11 (~17), respectively.
ꢁ. Reactions of 1b with Keto Ylides 12a,b: Preparation of
13a,b and 14a,b: A mixture of 1b (0.8 g, 3.4 mmol) and benzoyl-
12a or acetyl-12b methylenetriphenylphosphorane (4 mmol) in
dry toluene (20 mL) was refluxed for 40 h. The product mixture
was chromatographed on silica gel using hexane/chloroform (8:2,
v/v) as the eluent to give 13a or 13b, respectively.
2-Benzoyl-5,7-di-tert-butyl-2,3-dihydrobenzoxazole (13a) was
obtained as pale-yellow flakes (722 mg, 63%), mp 118–120 °C
(cyclohexane); Anal. Found: C, 78.35; H, 8.14; N, 4.20%. Calcd
for C22H27NO2 (337.46): C, 78.30; H, 8.06; N, 4.15%; IR (KBr)
3345 (NH), 1666 cm−1 C(O)Ph; 1H NMR (CDCl3) δ 1.23, 1.26 (2
× 9H, 2s, C(CH3)3], 3.68 (C-2-H), 6.23 (1H, d, JHH = 4.2 Hz, C-
4-H), 6.81 (1H, d, JHH = 4.2 Hz, C-6-H), 7.35–7.77 (5H, m, Ph-
H), 11.3 (1H, s, NH, exchangeable with D2O); 13C NMR δ 31.2,
32.6 (2 × C(CH3)3), 34.1, 35.5 (2 × C(CH3)3), 51.3 (C-2), 123.4,
124.4 (C-4 & C-6), 142.7 (C-5), 147.4 (C-7), 195.5 (C(O), ben-
zoyl); MS m/z (%) 337 (M+, 33), 335 (55), 307 (10), 232 (29), 230
(100), 186 (6).
2-Acetyl 5,7-di-tert-butyl-2,3-dihydrobenzoxazole (13b) was
obtained as pale yellow needles (475 mg, 51%), mp 108–109 °C
(pentane); Anal. Found: C, 74.23; H, 9.09; N, 5.18%. Calcd for
C17H25NO2 (275.39): C, 74.14; H, 9.15; N, 5.08%; IR (KBr) 3330
(NH), 1675 cm−1 (C(O)CH3); 1H NMR (CDCl3) δ 1.24, 1.26 (2 ×
9H, 2s, C(CH3)3), 2.55 (3H, s, (O)CH3), 3.88 (C-2-H), 6.22 (1H, d,
JHH = 4.2 Hz, C-4-H), 6.76 (1H, d, JHH = 4.2 Hz, C-6-H), 10.68
(1H, s, NH, exchangeable with D2O); 13C NMR δ 30.8, 31.3, 32.8
(C(O)CH3 & 2 × C(CH3)3), 34.6, 35.2 (2 × C(CH3)3), 48.8 (C-
2),123.8, 125.9 (C-4 & C-6), 142.3 (C-5), 146.4 (C-7), 192.5
(C(O), acetyl); MS m/z (%) 275 (M+, 22), 273 (38), 258 (11), 245
(9), 230 (100), 186 (8).
Conversion of 13a,b to 14a,b: N-Bromosuccinimide (NBS)
(54 mg, 0.3 mmol) and benzoyl peroxide (7 mg, 0.04 mmol) were
added to a solution of 13a (100 mg, 0.3 mmol) or 13b (82 mg, 0.3
mmol) in 20 mL of dry CCl4. The mixture was refluxed for 2 h
and filtered while hot. Evaporation of the solvent left a residue,
which was triturated with a small amount of light petroleum to
give the dehydrogenated derivative, 14a or 14b.
(335.45): C, 78.77; H, 7.51; N, 4.17%; IR (KBr) 1667 (C(O)Ph),
1
1605 cm−1 (CwN); H NMR (CDCl3) δ 1.23, 1.25 (2 × 9H, 2s,
C(CH3)3], 6.23, 6.83 (2 × 1H, 2d, JHH = 4.2 Hz, C-4-H & C-6-H),
7.35–7.77 (5H, m, Ph-H); MS m/z (%) 335 (M+, 28), 307 (13),
231 (66), 230 (100), 185 (3).
2-Acetyl-5,7-di-tert-butylbenzoxazole (14b) was obtained as
yellow crystals (57 mg, 70%), mp 89–90 °C (light petroleum);
Anal. Found: C, 74.62; H, 8.58; N, 5.06%. Calcd for C17H23NO2
(273.38): C, 74.69; H, 8.48; N, 5.12%; IR (KBr) 1675 (C(O)Me),
1
1598 cm−1 (CwN); H NMR (CDCl3) δ 1.22, 1.24 [2 × 9H, 2s,
C(CH3)3], 2.57 (3H, s, (O)CH3), 6.22, 6.79 (2 × 1H, 2d, JHH = 4.2
Hz, C-4-H & C-6-H); MS m/z (%) 273 (M+, 43), 258 (14), 245
(8), 230 (100), 186 (8).
ꢂ. Reaction of Monoxime 1b with Allylidenetriphenylphos-
phorane (16): Preparation of 19: A solution of allyltriphen-
ylphosphonium bromide (1.4 g, 3.6 mmol) and the monoxime 1b
(0.8 g, 3.4 mmol) in chloroform (40 mL) was stirred by a magnet-
ic stirrer. Freshly prepared aqueous lithium hydroxide (0.5 M, 15
mL, 1 M = 1 mol dm−3) was added in one portion to the mixture,
and the two- phase system was stirred at room temperature for 1 h,
then refluxed for 4 h. The product mixture was then extracted
with CHCl3 (2 × 50 mL) and dried; the solvent was removed un-
der reduced pressure. The residue was chromatographed on silica
gel using hexane/CHCl3 7:3, v/v to give 6,8-di-tert-butyl-2-meth-
yl-2H-1,4-benzoxazine (19) (425 mg, 48%), mp 174–175 °C (ace-
tonitrile); Anal. Found: C, 78.77; H, 9.67; N, 5.32%. Calcd for
C17H25NO (259.39): C, 78.71; H, 9.71; N, 5.40%; IR (KBr) 1600
cm−1 (CwN); 1H NMR (CDCl3) δ 1.24, 1.28 (2 × 9H, 2s,
C(CH3)3), 1.68 (3H, d, JHH = 8.2 Hz, C-2-CH3), 3.84 (1H, d of q,
JHH = 5.8 Hz, C-2-H), 6.25 (1H, d, JHH = 2.4 Hz, C-5-H), 6.87–
6.95 (2H, m, C-3-H & C-7-H); 13C NMR δ 22.2 (C-2-CH3), 31.1,
32.4 (2 × C(CH3)3), 34.3, 35.3 (2 × C(CH3)3), 44.7 (C-2), 122.6,
123.3, 125.2 (C-3, C-5 & C-7), 129.8 (C-4a), 142.4 (C-6), 146.6
(C-8), 150.4 (C-8a); MS m/z (%) 259 (M+, 57), 244 (100), 228
(21), 226 (11), 199 (7), 186 (10).
In the next fractions several polymeric unidentified products
with mp > 300 °C were eluted.
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4
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