Formation of xanthone oxime and related compounds using a combination of tert-butyl nitrite and potassium hexamethyldisilazide

Article abstract of DOI:10.3987/COM-13-S(S)110

Synthesis of xanthone oxime and related compounds via nitrosation of the dibenzylic position using a combination of tert-butyl nitrite and potassium hexamethyldisilazide is described. The reaction conditions are effective for the synthesis of xanthone oxime as well as thioxanthone, acridone, and anthrone oximes, which have been difficult to synthesize from the corresponding ketones by conventional dehydrative condensation with hydroxylamine.

Full text of DOI:10.3987/COM-13-S(S)110

HETEROCYCLES, Vol. 88, No. 2, 2014
1433
HETEROCYCLES, Vol. 88, No. 2, 2014, pp. 1433 - 1444. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 12th August, 2013, Accepted, 11th September, 2013, Published online, 17th September, 2013
DOI: 10.3987/COM-13-S(S)110
FORMATION OF XANTHONE OXIME AND RELATED COMPOUNDS
USING A COMBINATION OF tert-BUTYL NITRITE AND POTASSIUM
†
HEXAMETHYLDISILAZIDE
a
a
a
a,b
Yusuke Iwama, Takahiro Noro, Kentaro Okano, Hidetsura Cho,* and
a
Hidetoshi Tokuyama*
a
b
Graduate School of Pharmaceutical Sciences and Graduate School of Science,
Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan
E-mail: tokuyama@mail.pharm.tohoku.ac.jp, hcho@mail.pharm.tohoku.ac.jp
Abstract – Synthesis of xanthone oxime and related compounds via nitrosation of
the dibenzylic position using a combination of tert-butyl nitrite and potassium
hexamethyldisilazide is described. The reaction conditions are effective for the
synthesis of xanthone oxime as well as thioxanthone, acridone, and anthrone
oximes, which have been difficult to synthesize from the corresponding ketones
by conventional dehydrative condensation with hydroxylamine.
INTRODUCTION
Xanthone, thioxanthone, acridone, and anthrone oximes are highly attractive synthetic precursors for
1
2
nitrogen-containing heterocycles since Beckmann rearrangement or other ring-expansion reactions
provide the corresponding medicinally attractive nitrogen-containing tricyclic compounds. But despite
their potential utility, there is no efficient method for preparation of these oximes. Thus, the conventional
dehydrative condensation of the corresponding ketones and hydroxylamine is inefficient due to the low
reactivity of the carbonyl group caused by the resonance effects of a heteroatom. Although several
examples of dehydrative condensation with hydroxylamine have been documented in the literature, yields
3
of the corresponding oximes were not reported in most cases. As an alternative route, a two-step method
including conversion of ketone to more reactive thione followed by condensation with hydroxylamine
1
d,4
was developed. In addition to the classical dehydrative condensation of ketones and hydroxylamine,
5
oximes have also been synthesized by several other methods. For example, nitrosation of alkane under
†
This paper is dedicated to Professor Dr. Victor Snieckus, Queen’s University on the occasion of his 77th
birthday.

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HETEROCYCLES, Vol. 88, No. 2, 2014
radical conditions and subsequent tautomerization of the resultant nitroso compound gives the
5
c
6
corresponding oxime; however, radicalic conditions under photo irraditation or using a combination of
7
tert-butyl nitrite (t-BuONO) and N-hydroxyphthalimide, have a limited substrate scope. Nitrosation of
8
enolizable methylene, such as the !-position of carbonyl or cyano groups, takes place under acidic
conditions. Typical conditions such as nitrite salts and strong aqueous acids, however, promote
9
electrophilic nitrosation on an aromatic ring and are inappropriate for the electron-rich aromatic
compounds employed in this study.
With this background, we investigated oximation of 1 to xanthone oxime 2a and related compounds
8
a,10
2
b-2e via nitroso compound 3 (Scheme 1).
Herein we report a formation of oxime using a
combination of t-BuONO and potassium hexamethyldisilazide (KHMDS).
Scheme 1. Formation of Oxime via Tautomerization of Nitroso Compound
RESULTS AND DISCUSSION
At the outset of our research, we carefully investigated the conventional condensation of ketones and
hydroxylamine (Table 1). Disappointingly, the reaction rate was slow to provide the corresponding
oximes in low to moderate yields with recovery of the starting ketones 4a and 4b (entries 1 and 2).
N-Boc acridone 4c was completely consumed in 12 h even at 80 °C; however, the desired oxime 2c was
isolated in 21%. Instead, removal of the Boc group took place to provide acridone in 78% yield (entry 3).
Reaction using N-methylacridone 4d resulted in recovery of 4d (entry 4), and on the other hand, reaction
of anthorone 4e provided a complex mixture (entry 5).
Having confirmed the infeasibility of the conventional condensation for preparation of the desired oximes,
1
1
we investigated our working hypothesis, using xanthene 1a as a substrate (Table 2). First, we examined
a variety of bases (2.0 equiv.) using 2.0 equiv. of t-BuONO as a nitrosation reagent. While the use of
1
0b,10c
KOt-Bu
provided oxime 2a in 78% yield with recovery of 6% starting xanthene 1a, more basic NaH
gave none of the desired product 2a (entries 1 and 2). Alkyllithium, such as MeLi, n-BuLi, and t-BuLi,
also provided minute amounts of the oxime with recovery of ca. 90% of the starting xanthene 1a (entries
3
–5), which indicated that t-BuONO reacted with a base. To circumvent the undesired reaction, we used

HETEROCYCLES, Vol. 88, No. 2, 2014
1435
Table 1. Formation of Oxime by Condensation of Ketones and Hydroxylamine
a
entry
1
substrates
products
reaction time [h] yield [%]
b
24
24
44 (56 )
b
2
26 (69 )
c
d
e
3
12
24
21 (78 )
f
b
4
5
– (96 )
d
f,g
2
–
a
b
c
d
Isolated yield. Recovery of starting ketone. The reaction was carried out at 80 °C. Starting
e
f
g
material were completely consumed. Yield of acridone. Not observed. Complex mixture.
hindered bases such as LDA and LiHMDS, and found that hexamethyldisilazide was the better base
entries 6 and 7). During the investigations, we observed a significant effect of counter ion of
hexamethyldisilazide. Thus, the use of KHMDS improved the yield of the oxime up to 85% (entries 7–9).
(

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HETEROCYCLES, Vol. 88, No. 2, 2014
Finally, the desired oxime 2a was obtained in excellent yield even with the decreased amount (1.2 equiv.)
of KHMDS and t-BuONO (entry 10).
Table 2. Effects of a Base on Oximation of Xanthene 1a
entry
Base
[equiv.])
KOt-Bu (2.0)
t-BuONO
[equiv.]
2.0
temp.
[°C]
rt
recovery of 1a
yield of 2a
a
a
(
[%]
6
[%]
78
1
2
3
4
5
6
7
8
9
NaH (2.0)
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.2
rt
0
0
0
0
0
0
0
0
88
90
87
90
86
77
48
-
-
MeLi (2.0)
-
n-BuLi (2.0)
t-BuLi (2.0)
LDA (2.0)
4
4
2
LiHMDS (2.0)
NaHMDS (2.0)
KHMDS (2.0)
KHMDS (1.2)
8
32
85
90
1
0
-
a
Isolated yields.
ꢀ
We then focused on feasibility of the established optimal conditions for formation of the variety of
1
1
oximes (Table 3). In addition to xanthene 1a, thioxanthene 1b and N-Boc-dihydroacridine 1c were
successfully converted to oximes 2b or 2c in excellent yields respectively using 1.2 equiv. of t-BuONO
1
2
and KHMDS (entries 2 and 3). In the case of N-methyldihydroacridine 1d, 2.0 equiv. of t-BuONO and
KHMDS were necessary for complete consumption of 1d to provide oxime 2d in 54% yield (entry 4).
1
1
While dihydroanthracene 1e did not gave the desired oxime 2e under the optimal conditions using
KHMDS, the use of n-BuLi provided oxime 2e in moderate yield.

HETEROCYCLES, Vol. 88, No. 2, 2014
1437
Table 3. Scope and Limitations of Oximation using t-BuONO and KHMDS
a
entry
1
substrates
products
yield [%]
b
90 (94 )
2
3
4
97
93
c
54
d
5
47
a
d
b
c
Isolated yield. t-BuONO: 1.5 equiv., KHMDS: 1.5 equiv. t-BuONO: 2.0 equiv., KHMDS: 2.0 equiv.
To a solution of substrate in THF were added n-BuLi (2.0 equiv.) followed by t-BuONO (2.0 equiv.) at
78 °C, and the reaction mixture was stirred for 0.5 h at –78 °C.
–
In summary, we have established an efficient synthesis of oximes via nitrosation of dibenzylic position by
using a combination of t-BuONO and KHMDS. This method would be an effective choice for oximation
of xanthone, thioxanthone, acridone derivatives, and anthrone, which were difficult to be converted to the
corresponding oximes by the conventional condensation of ketones with hydroxylamine.

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HETEROCYCLES, Vol. 88, No. 2, 2014
EXPERIMENTAL
General Remarks: Materials were obtained from commercial suppliers and used without further
purification unless otherwise mentioned. All reactions were carried out in oven-dried glassware under a
slight positive pressure of argon unless otherwise noted. Anhydrous THF was purchased from Kanto
Chemical Co. Inc. Anhydrous pyridine was dried and distilled according to the standard protocols. Flash
column chromatography was performed on Silica Gel 60N (Kanto, spherical neutral, 40–50 µm) using the
indicated eluent. Preparative TLC and analytical TLC were performed on Merck 60 F254 glass plates
precoated with a 0.25 mm thickness of silica gel. IR spectra were measured on a SHIMADZU FTIR-8300
spectrometer or a JASCO FT/IR-4100 spectrometer. NMR spectra were recorded on a GX500
1
spectrometer and JNM-AL400 spectrometer. For H NMR spectra, chemical shifts are expressed in parts
1
3
3
per million downfield from internal tetramethylsilane (" 0) or relative internal CHCl (" 7.26). For C
NMR spectra, chemical shifts are expressed in ppm downfield from relative internal CDCl (" 77.0).
3
Mass spectra were recorded on a JEOL JMS-DX-303 spectrometer (EI), a JMS-T100GC spectrometer
(EI), or a Bruker micrOTOF II (ESI). Elemental analyses were performed by a Yanaco CHN CORDER
MT-5.
tert-Butyl 9-oxoacridine-10(9H)-carboxylate (4c): A 30-mL two-necked round-bottomed flask
equipped with a magnetic stirring bar, a rubber septum, and a three-way stopcock was charged with
2
acridone (402.0 mg, 2.06 mmol) and anhydrous MeCN (6.8 mL). To the solution was added Boc O
(761.9 mg, 3.49 mmol), followed by DMAP (753.7 mg, 6.17 mmol). The resulting mixture was stirred for
4
h, after which time TLC (hexanes-EtOAc = 4:1) indicated complete consumption of acridone. To the
O, and the mixture was extracted with EtOAc three times. The combined
organic extracts were washed with saturated aqueous NH Cl and brine, dried over anhydrous sodium
resulting mixture was added H
2
4
sulfate, and filtered. The organic solvents were removed under reduced pressure to give crude
N-Boc-acridone 4c, which was purified by flash silica gel column chromatography (hexanes-EtOAc =
4
:1) to afford N-Boc-acridone 4c (565.3 mg, 1.91 mmol, 93%) as a colorless solid. The analytical data
1
13
13
(
HRMS, H and C NMR) were identical with those reported in the literature.
R
f
= 0.45
–
1
(
hexanes-EtOAc = 4:1); IR (neat, cm ): 3446, 1743, 1636, 1604, 1488, 1459, 1369, 1360, 1246, 1178,
1
142, 1121, 937, 840, 749, 670, 610, 554.
1
0-Methylacridin-9(10H)-one (4d): A 30-mL flame-dried round-bottomed flask equipped with a
magnetic stirring bar, a rubber septum, and a three-way stopcock was charged with acridone (398.0 mg,
2
0
.04 mmol) and anhydrous DMF (6.8 mL). To the solution was added NaH (164.0 mg, 4.10 mmol) at
°C and the resulting mixture was stirred at room temperature for 30 min. To the resulting mixture was

HETEROCYCLES, Vol. 88, No. 2, 2014
1439
added MeI (255 µL, 4.10 mmol) dropwise at 0 °C. The resulting mixture was stirred for 4 h, after which
time TLC (hexanes-EtOAc = 1:1) indicated complete consumption of acridone. The reaction mixture was
quenched with H
2
O, and the mixture was extracted with EtOAc three times. The combined organic
O and brine, dried over anhydrous sodium sulfate, and filtered. The organic
extracts were washed with H
2
solvents were removed under reduced pressure to give crude N-methylacridone 4d, which was purified by
flash silica gel column chromatography (hexanes-EtOAc = 4:1) to afford N-methylacridone 4d (410.8 mg,
1
13
1
.96 mmol, 96%) as a pale yellow solid. The analytical data (IR, HRMS, H and C NMR) were identical
1
4
f
with those reported in the literature. R = 0.44 (hexanes-EtOAc = 1:1).
Procedure for dehydrative condensation of benzophenones and hydroxylamine.
H-Xanthen-9-one oxime (2a): A 10-mL flame-dried screw-top test tube equipped with a magnetic
stirring bar was charged with xanthone 4a (100.5 mg, 0.512 mmol), NH OH!HCl (107.1 mg, 1.54 mmol)
and anhydrous pyridine (0.51 mL). The resulting mixture was stirred at 110 °C for 24 h. To the resulting
mixture was added H O, and the mixture was extracted with EtOAc three times and CH Cl once. The
9
2
2
2
2
combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and filtered.
The organic solvents were removed under reduced pressure to give crude xanthone oxime 2a. Residual
pyridine was azeotropically removed with toluene. The residue was purified by flash silica gel column
3
chromatography (CHCl ) to afford xanthone oxime 2a (48.0 mg, 0.227 mmol, 44%) as a colorless solid
with recovery of xanthone 4a (56.5 mg, 0.288 mmol, 56%).
9
H-Thioxanthen-9-one oxime (2b): A 10-mL flame-dried screw-top test tube equipped with a magnetic
stirring bar was charged with thioxantone 4b (101.0 mg, 0.476 mmol), NH OH!HCl (99.0 mg, 1.42
mmol) and anhydrous pyridine (0.48 mL). The resulting mixture was stirred at 110 °C for 24 h. To the
resulting mixture was added H O, and the mixture was extracted with CH Cl three times. The combined
2
2
2
2
organic extracts were washed with brine, dried over anhydrous sodium sulfate, and filtered. The organic
solvents were removed under reduced pressure to give crude thioxanthone oxime 2b. Residual pyridine
was azeotropically removed with toluene. The residue was purified by flash silica gel column
3 2
chromatography (CHCl to toluene-Et O = 3:2) to afford thioxanthone oxime 2b (27.9 mg, 0.123 mmol,
2
6%) as a yellow solid with recovery of thioxanthone 4b (69.6 mg, 0.328 mmol, 69%).
tert-Butyl acridine-10(9H)-carboxylate oxime (2c): A 10-mL flame-dried screw-top test tube equipped
with a magnetic stirring bar was charged with N-Boc-acridone 4c (105.6 mg, 0.358 mmol), NH OH!HCl
75.1 mg, 1.08 mmol) and anhydrous pyridine (0.36 mL). The resulting mixture was stirred at 80 °C for
2
(
1
2 h after which time TLC (hexanes-EtOAc = 4:1) indicated complete consumption of N-Boc-acridone 4c.

1440
HETEROCYCLES, Vol. 88, No. 2, 2014
2 2 2
To the resulting mixture was added H O, and the mixture was extracted with THF twice and CH Cl three
times. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and
filtered. The organic solvents were removed under reduced pressure to give crude N-Boc-acridone oxime
2
c. Residual pyridine was azeotropically removed with toluene. The residue was purified by flash silica
gel column chromatography (hexanes-EtOAc = 4:1 to CHCl -MeOH = 9:1) to afford N-Boc acridone
3
oxime 2c (23.6 mg, 0.076 mmol, 21%) as a colorless solid with recovery of acridone (54.4 mg, 0.279
mmol, 78%).
A 10-mL flame-dried screw-top test tube equipped with a magnetic stirring bar was charged with
N-methylacridone (4d) (100.7 mg, 0.481 mmol), NH OH!HCl (99.6 mg, 1.43 mmol) and anhydrous
2
pyridine (0.48 mL). The resulting mixture was stirred at 110 °C for 24 h. To the resulting mixture was
2 2 2
added H O, and the mixture was extracted with CH Cl three times. The combined organic extracts were
washed with brine, dried over anhydrous sodium sulfate, and filtered. The organic solvents were removed
under reduced pressure to give crude material. Residual pyridine was azeotropically removed with
3
toluene. Purification by flash silica gel column chromatography (CHCl ) resulted in only recovery of
N-methylacridone 4d (94.6 mg, 0.452 mmol, 94%).
General procedure for constructing oxime via electrophilic nitrosation: A flame-dried 30-mL
two-necked round-bottomed flask equipped with a magnetic stirring bar was charged with starting
material (100 mg) and anhydrous THF (0.1 M). To the solution was added 1.2 equiv. of t-BuONO at 0 °C,
followed by 1.2 equiv. of KHMDS dropwise at 0 °C. The resulting solution was stirred for 30 min, after
which time TLC indicated complete consumption of starting material. The reaction was quenched with
4 2
saturated aqueous NH Cl, and the aqueous layer was extracted three times with Et O. The combined
organic extracts were washed with brine, dried over anhydrous sodium sulfate, and filtered. The organic
solvents were removed under reduced pressure to give a crude material. The residue was purified by flash
silica gel column chromatography to afford the desired oxime.
–
1
9
H-Xanthen-9-one oxime (2a): a colorless solid. R
f
= 0.48 (hexanes-EtOAc = 4:1); IR (neat, cm ): 3179,
1
3
033, 2916, 1623, 1594, 1454, 1341, 1257, 998, 932, 738; H NMR (400 MHz, CDCl
3
): " 9.01 (dd, 1H, J
=
8.4, 1.2 Hz), 8.44 (brs, 1H), 8.00 (dd, 1H, J = 8.4, 1.2 Hz), 7.49 (ddd, 1H, J = 8.4, 7.2, 1.2 Hz), 7.42
1
3
(
ddd, 1H, J = 8.4, 7.2, 1.2 Hz), 7.36-7.14 (m, 4H); C NMR (100 MHz, CDCl
3
): " 152.8, 151.5, 141.4,
1
31.9, 131.6, 130.7, 124.0, 123.8, 122.8, 119.1, 117.3, 117.0, 116.1; HRMS (ESI) Calcd. for C13H10NO
2
+
(
M+H ), 212.0706; Found: 212.0711; Anal. Calcd for C13
9 2
H NO : C, 73.92; H, 4.29; N, 6.63; Found: C,
7
3.99; H, 4.39; N, 6.59.

HETEROCYCLES, Vol. 88, No. 2, 2014
1441
–
1
9
H-Thioxanthen-9-one oxime (2b): a colorless solid. R
f
= 0.47 (hexanes-EtOAc = 4:1); IR (neat, cm ):
1
3
174, 3042, 2906, 1587, 1435, 992, 923, 755, 727; H NMR (400 MHz, CDCl
3
): " 8.57 (brs, 1H), 8.41
(dd, 1H, J = 8.0, 2.4 Hz), 7.84 (dd, 1H, J = 8.0, 1.6 Hz), 7.51 (dd, 1H, J = 7.6, 2.4 Hz), 7.43 (dd, 1H, J =
1
3
7
.6, 1.6 Hz), 7.40–7.28 (m, 4H); C NMR (100 MHz, CDCl ): " 149.0, 134.1, 132.6, 131.4, 131.0, 129.4,
3
1
28.8, 126.7, 126.5, 125.8, 125.6, 125.4 (one carbon is missing due to overlap); HRMS (ESI) Calcd. for
+
C
13
H
10NOS (M+H ), 228.0478; Found: 228.0483; Anal. Calcd for C13
H
9
NOS: C, 68.70; H, 3.99; N, 6.16;
Found: C, 68.87; H, 4.10; N, 6.15.
tert-Butyl acridine-10(9H)-carboxylate (1c): A two-necked 20-mL round-bottomed flask equipped with
a magnetic stirring bar was charged with acridone (195 mg, 1.00 mmol), and THF (2.5 mL). To the
3
solution was added BH !THF (1.08 M in THF, 1.3 mL, 1.4 mmol) at room temperature. The reaction
mixture was heated to reflux for 4 h, after which time TLC (hexanes-EtOAc = 3:1) indicated complete
consumption of acridone. The reaction was quenched with brine and 2 M aqueous NaOH, and the mixture
2
was extracted with Et O three times. The combined organic extracts were washed with saturated aqueous
NaHCO , dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under
3
reduced pressure to afford the crude dihydroacridine as a colorless solid, which was used for the next
reaction without further purification.
A 50-mL round-bottomed flask equipped with a magnetic stirring bar was charged with dihydroacridine,
Boc
mmol) at 0 °C. The solution was stirred for 11 h at room temperature, after which time TLC
hexanes-EtOAc = 9:1) indicated complete consumption of dihydroacridine. The reaction was diluted
with Et O. The mixture was washed with saturated aqueous NH Cl and brine, dried over anhydrous
2
O (766 mg, 3.51 mmol), and MeCN (3.3 mL). To the solution was added DMAP (203 mg, 1.66
(
2
4
sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel
column chromatography (hexanes-EtOAc = 9:1) to afford N-Boc-dihydroacridine 1c (226 mg, 0.803
–
1
mmol, 80%) as colorless crystals; R
f
= 0.47 (hexanes-EtOAc = 9:1); IR (neat, cm ): 1706, 1476, 1328,
1
1
269, 1253, 1151, 760; H NMR (400 MHz, CDCl
3
): " 7.63 (d, 2H, J = 8.0 Hz), 7.36–7.17 (m, 4H), 7.12
1
3
(
d, 2H, J = 7.2 Hz), 3.80 (s, 2H), 1.54 (s, 9H); C NMR (125 MHz, CDCl
25.9, 125.04, 124.96, 33.8, 28.2, 27.9; HRMS (ESI): Calcd. for C14
Found: 226.0878; Anal. Calcd for C18
.01.
3
): " 152.5, 138.8, 133.0, 126.9,
+
1
H
12NO
2
[(M–t-Bu) ], 226.0863;
H
2
19NO : C, 76.84; H, 6.81; N, 4.98; Found: C, 76.64; H, 6.83; N,
5
tert-Butyl 9-(hydroxyimino)acridine-10(9H)-carboxylate oxime (2c): a colorless solid. R
f
= 0.35
–
1
(
hexanes-EtOAc = 4:1); IR (neat, cm ): 3071, 2974, 2928, 1716, 1598, 1463, 1322, 1251, 1159, 955, 923,

1442
HETEROCYCLES, Vol. 88, No. 2, 2014
1
7
55; H NMR (400 MHz, CDCl
3
): " 8.42 (dd, 1H, J = 8.0, 1.2 Hz), 8.23 (brs, 1H), 7.79 (d, 1H, J = 8.0
Hz), 7.78 (d, 1H, J = 8.0 Hz), 7.72 (dd, 1H, J = 8.0, 1.2 Hz), 7.41 (ddd, 1H, J = 8.0, 8.0, 1.2 Hz), 7.39
(ddd, 1H, J = 8.0, 8.0, 1.2 Hz), 7.27 (dd, 1H, J = 8.0, 8.0 Hz), 7.24 (dd, 1H, J = 8.0, 8.0 Hz), 1.53 (s, 9H);
1
3
C NMR (100 MHz, CDCl
3
): " 152.0, 146.4, 138.5, 137.5, 129.2, 129.0, 128.3, 128.2, 125.47, 125.42,
+
1
3
24.7, 124.6, 124.3, 124.2, 82.9, 28.1; HRMS (ESI) Calcd. for C H N O (M+H ), 311.1390; Found:
1
8
19
2
3
18 2 3
11.1386; Anal. Calcd for C18H N O : C, 69.66; H, 5.85; N, 9.03; Found: C, 69.79; H, 5.81; N, 8.94.
1
0-Methylacridin-9(10H)-one oxime (2d): a yellow solid. R
f
= 0.28 (hexanes-EtOAc = 4:1); IR (neat,
–
1
1
cm ): 3004, 2891, 1593, 1464, 1362, 1265, 1175, 989, 918, 744; H NMR (400 MHz, CDCl
3
): " 8.81 (d,
1
7
1
H J = 8.4 Hz), 7.95 (dd, 1H, J = 8.4, 1.6 Hz), 7.46 (ddd, 1H, J = 8.4, 7.2, 1.6 Hz), 7.43 (ddd, 1H, J = 8.4,
1
3
3
.2, 1.6 Hz), 7.22–7.05 (m, 4H), 3.57 (s, 3H); C NMR (100 MHz, CDCl ): " 145.5, 142.3, 140.7, 131.2,
13 2
30.8, 129.8, 124.7, 121.3, 120.6, 119.6, 116.8, 113.4, 113.1, 34.0; HRMS (ESI) Calcd. for C14H N O
+
(
M+H ), 225.1022; Found: 225.1018; Anal. Calcd for C14
H
12
N
2
O: C, 74.98; H, 5.39; N, 12.49; Found: C,
7
4.89; H, 5.45; N, 12.27.
Anthracen-9(10H)-one oxime (2e): A two-necked 30-mL round-bottomed flask equipped with a
magnetic stirring bar was charged with dihydroanthracene 1e (100.2 mg, 0.556 mmol) and anhydrous
THF (5.6 mL). To the solution was added n-BuLi (1.51 M in n-hexane, 0.736 mL, 1.11 mmol) dropwise
at –78 °C. The resulting suspension was stirred for 5 min. To the mixture was added t-BuONO (0.132 mL,
1
.11 mmol) at –78 °C. After the resulting solution was stirred for 30 min, the reaction was quenched with
saturated aqueous NH Cl, and the aqueous layer was extracted three times with Et O. The combined
4
2
organic extracts were washed with brine, dried over anhydrous sodium sulfate, and filtered. The organic
solvents were removed under reduced pressure to give a crude material, which was purified by flash silica
gel column chromatography (hexanes-acetone = 6:1) to afford oxime 2e (54.5 mg, 0.260 mmol, 47%) as a
–
1
colorless solid. R
f
= 0.43 (hexanes-EtOAc = 4:1); IR (neat, cm ); 3063, 2917, 1450, 1331, 1160, 995,
1
9
28, 722, 711; H NMR (400 MHz, CDCl
3
): " 8.53 (dd, 1H, J = 6.8, 2.0 Hz), 8.12 (brs, 1H), 7.86 (d, 1H,
1
3
J = 6.8 Hz), 7.44–7.28 (m, 6H), 4.01 (s, 2H); C NMR (100 MHz, CDCl
3
): " 149.4, 138.1, 135.9, 132.9,
1
30.6, 129.6, 128.7, 127.9, 127.9, 127.4, 126.9, 126.0, 124.8, 35.5; HRMS (ESI) Calcd. for C14H12NO
+
(
M+H ), 210.0913; Found: 209.0910; Anal. Calcd for C14
H11NO: C, 80.36; H, 5.30; N, 6.69; Found: C,
8
0.13; H, 5.36; N, 6.60.
ACKNOWLEDGMENTS
This work was financially supported by the Ministry of Education, Culture, Sports, Science, and
Technology, Japan; the KAKENHI, a Grant-in-Aid for Scientific Research (B) (20390003) and (C)

HETEROCYCLES, Vol. 88, No. 2, 2014
1443
(23590001); the Cabinet Office, Government of Japan through its “Funding Program for Next Generation
World-Leading Researchers (LS008)”; JSPS predoctoral fellowship for Y.I.; Tohoku University Global
COE program ‘International Center of Research and Education for Molecular Complex Chemistry’.
REFERENCES AND NOTES
1
.
(a) L. G. Donaruma and W. Z. Heldt, Org. React., 1960, 11, 1; (b) R. E. Gawley, Org. React., 1988,
5, 1; (c) R. H. Williams and H. R. Snyder, J. Org. Chem., 1973, 38, 809; (d) K. Nagarajan, C. L.
3
Kulkarni, and A. Venkateswarlu, Ind. J. Chem., 1974, 12, 247; (e) A. K. Sinha and S. Nizamuddin,
Ind. J. Chem. Sect. B, 1984, 23, 165.
2
.
(a) Y. Girault, M. Decouzon, and M. Azzaro, Bull. Soc. Chim. Fr., 1975, 385; (b) K. Hattori, Y.
Matsumura, T. Miyazaki, K. Maruoka, and H. Yamamoto, J. Am. Chem. Soc., 1981, 103, 7368; (c) S.
Sasatani, T. Miyazaki, K. Maruoka, and H. Yamamoto, Tetrahedron Lett., 1983, 24, 4711; (d) J.
Fujiwara, H. Sano, K. Maruoka, and H. Yamamoto, Tetrahedron Lett., 1984, 25, 2367; (e) K.
Maruoka and H. Yamamoto, Angew. Chem., Int. Ed. Engl., 1985, 24, 668; (f) Y. Torisawa, T. Nishi,
and J. Minamikawa, Bioorg. Med. Chem. Lett., 2002, 12, 387; (g) N. Willand, T. Beghyn, G.
Nowogrocki, J.-C. Gesquiere, and B. Deprez, Tetrahedron Lett., 2004, 45, 1051; (h) M.
Ortiz-Marciales, L. D. Rivera, M. De Jesús, S. Espinosa, J. A. Benjamin, O. E. Casanova, I. G.
Figueroa, S. Rodríguez, and W. Correa, J. Org. Chem., 2005, 70, 10132; (i) P. P. Mukhopadhyay, O.
Miyata, and T. Naito, Synlett, 2007, 1403; (j) O. Miyata, T. Ishikawa, M. Ueda, and T. Naito, Synlett,
2
006, 2219; (k) H. Cho, K. Murakami, H. Nakanishi, H. Isoshima, K. Hayakawa, and I. Uchida,
Heterocycles, 1998, 48, 919; (l) H. Cho, K. Murakami, H. Nakanishi, A. Fujisawa, H. Isoshima, M.
Niwa, K. Hayakawa, Y. Hase, I. Uchida, H. Watanabe, K. Wakitani, and K. Aisaka, J. Med. Chem.,
2004, 47, 101; (m) H. Cho, Y. Iwama, K. Sugimoto, E. Kwon, and H. Tokuyama, Heterocycles, 2009,
78, 1183; (n) H. Cho, Y. Iwama, K. Sugimoto, S. Mori, and H. Tokuyama, J. Org. Chem., 2010, 75,
627; (o) H. Cho, Y. Iwama, N. Mitsuhashi, K. Sugimoto, K. Okano, and H. Tokuyama, Molecules,
2012, 17, 7348; (p) H. Cho, Y. Iwama, K. Okano, and H. Tokuyama, Synlett, 2013, 813.
3
.
(a) T. Kurihara and H. Niwa, Yakugaku Zasshi 1953, 73, 1378 [Chem. Abstr., 1955, 313]; (b) N.
Campbell, S. R. McCallum, and D. J. Mackenzie, J. Chem. Soc., 1957, 1922; (c) J. Lalevee, X.
Allonas, F. Louerat, J.-P. Fouassier, H. Tachi, A. Izumitani, M. Shirai, and M. Tsunooka, Phys. Chem.
Chem. Phys., 2001, 3, 2721; (d) Y. S. Or, Y. Sun, and Z. Wang, WO2007 146695 A1; (e) Y. Sun, D.
Niu, G. Xu, Y. S. Or, and Z. Wang, US2007 0281884 A1; (f) Y. Sun, Y. S. Or, and Z. Wang, US2008
1
87516 A1.
4
.
(a) F. G. Mann and J. H. Turnbull, J. Chem. Soc., 1951, 757; (b) V. A. Prabhu, R. G. Brown, and J. N.
Delgado, J. Pharm. Sci., 1981, 70, 558.

1444
HETEROCYCLES, Vol. 88, No. 2, 2014
5
.
(a) R. H. Williams and H. R. Snyder, J. Org. Chem., 1971, 36, 2327; (b) M. Hafiz and G. A. Taylor, J.
Chem. Soc., Perkin Trans. 1, 1980, 1700; (c) R. SanMartín, R. Olivera, E. M. de Marigorta, and E.
Domínguez, Tetrahedron, 1995, 51, 5361; (d) M. Yonekawa, Y. Koyama, S. Kuwata, and T. Takata,
Org. Lett. 2012, 14, 1164.
6.
7.
8.
(a) E. V. Lynn, J. Am. Chem. Soc., 1919, 41, 368; (b) E. V. Lynn and O. Hilton, J. Am. Chem. Soc.,
1
922, 44, 645; (c) E. V. Lynn and H. L. Arkley, J. Am. Chem. Soc., 1923, 45, 1045.
(a) T. Hirabayashi, S. Sakaguchi, and Y. Ishii, Angew. Chem. Int. Ed., 2004, 43, 1120; (b) Y. Ishii, S.
Sakaguchi, and T. Iwahama, Adv. Synth. Catal., 2001, 343, 393.
(a) O. Touster, Org. React., 1953, 7, 327; (b) J. Beger and C. Thielemann, J. Prakt. Chem., 1981, 323,
1
37; (c) J. Beger and C. Thielemann, J. Prakt. Chem., 1981, 323, 337; (d) R. N. Loeppky, J. Shi, C.
L. Barnes, and S. Geddam, Chem. Res. Toxicol., 2008, 21, 295.
9
1
.
(a) E. Bosch and J. K. Kochi, J. Org. Chem., 1994, 59, 5573; (b) R. J. Maleski, M. Kluge, and D.
Sicker, Synth. Commun., 1995, 25, 2327; (c) M. González-Jiménez, J. Arenas-Valgañón, E. Calle,
and J. Casado, Org. Biomol. Chem., 2011, 9, 7680.
0. (a) A. D. Dunn and K. I. Kinnear, J. Heterocycl. Chem., 1985, 22, 311; (b) M. Le Rudulier and C.
Moinet, J. Organomet. Chem., 1988, 352, 337; (c) M. C. Senechal-Tocquer, D. Senechal, J. Y. Le
Bihan, D. Gentric, B. Caro, M. Gruselle, and G. Jaouen, J. Organomet. Chem., 1992, 433, 261.
1. Xanthene 1a, thioxanthene 1b, and dihydroanthracene 1e are commercially available compounds.
2. N-Methyldihydroacridine 1d was prepared from known procedure, which is described in following
paper; Á. Pintér, A. Sud, D. Sureshkumar, and M. Klussmann, Angew. Chem. Int. Ed., 2010, 49,
1
1
5
004.
3. A. A. Kulago, E. M. Mes, M. Klok, A. Meetsma, A. M. Brouwer, and B. L. Feringa, J. Org. Chem.,
010, 75, 666.
4. X.-A. Li, H.-L. Wang, and S.-D. Yang, Org. Lett., 2013, 15, 1794.
1
1
2