Novel methods of synthesizing naphtho[1,2-c]furan-1,3-dione and benzo[e]isoindole-1,3-dione

Article abstract of DOI:10.3987/COM-05-S(T)78

Convenient methods of synthesizing naphtho[1,2-c]furan-1,3-dione and benzo[e]isoindole-1,3-dione from phenylbutyric acid derivatives have been established. Naphtho[1,2-c]furan-1,3-dione and benzo[e]isoindole-1,3-dione were obtained respectively from 4,5-d

Full text of DOI:10.3987/COM-05-S(T)78

HETEROCYCLES, Vol. 67, No. 2, 2006
807
HETEROCYCLES, Vol. 67, No. 2, 2006, pp. 807 - 814. © The Japan Institute of Heterocyclic Chemistry
Received, 1st September, 2005, Accepted, 27th October, 2005, Published online, 28th October, 2005. COM-05-S(T)78
NOVEL METHODS OF SYNTHESIZING NAPHTHO[1,2-c]FURAN-1,3-
DIONE AND BENZO[e]ISOINDOLE-1,3-DIONE
Masahiro Mizuno* and Mitsuhisa Yamano
Chemical Development Laboratories, Pharmaceutical Production Division,
Takeda Pharmaceutical Company Limited, 17-85, Jusohonmachi 2-chome,
Yodogawa-ku, Osaka, 532-8686, Japan; E-mail: Mizuno_Masahiro@takeda.co.jp
Dedicated to Professor Barry M. Trost on the occasion of his 65th birthday
Abstract – Convenient methods of synthesizing naphtho[1,2-c]furan-1,3-dione
and benzo[e]isoindole-1,3-dione from phenylbutyric acid derivatives have been
established. Naphtho[1,2-c]furan-1,3-dione and benzo[e]isoindole-1,3-dione were
obtained respectively from 4,5-dihydronaphtho[1,2-c]furan-1,3-dione and 4,5-
dihydrobenzo[e]isoindole-1,3-dione by aromatization with 10% Pd-C in AcOH
under mild conditions. In addition, benzo[e]isoindole-1,3-dione derivatives were
obtained from 4,5-dihydronaphtho[1,2-c]furan-1,3-dione by imidation and
simultaneous aromatization with primary amine in AcOH in one pot.
INTRODUCTION
Naphtho[1,2-c]furan-1,3-dione and benzo[e]isoindole-1,3-dione are useful intermediates for medicines,
agrochemicals and chemicals, e.g. 6-methacryloxyethyl 1,2,6-naphthalenetricarboxylic cyclic anhydride,
1
which is used as a dental adhesive, and 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-
benzo[e]isoindoline-1,3-dione, which reduces levels of TNFα and inhibits PDE IV in mammals. 2
Conventionaly, several methods have been reported for the synthesis of naphtho[1,2-c]furan-1,3-dione.
For example, ethyl 3-carboethoxy-2-oxo-5-phenylpentanate, derived from phenylbutyric acid, was
cyclized to obtain 4,5-dihydronaphtho[1,2-c]furan-1,3-dione, then aromatized by heating at 250oC with
sulfur to obtain naphtho[1,2-c]furan-1,3-dione. 3 α-Bromostylene was cyclized with maleic anhydride to
afford 1,2-dihydronaphtho[1,2-c]furan-1,3-dione, then aromatized by heating at 250oC with sulfur to give
4
naphtho[1,2-c]furan-1,3-dione.
1-Chloromethyl-2-methylnaphthalene, derived from 2-
methylnaphthalene, was heated at 240oC under elevated pressure with sodium bichromate to yield

808
HETEROCYCLES, Vol. 67, No. 2, 2006
1,2-naphthalenedicarboxylic acid, 5 then reacted with acetic anhydride to give naphtho[1,2-c]furan-1,3-
o
dione. However, all of these methods require extremely high temperatures (ca. 240-250 C), so they are
difficult to use in the case of unstable compounds.
Several methods have been developed for aromatization by dehydrogenation, 6 e.g. using sulfur, selenium,
platinum, palladium, aluminum chloride, ammonium ceric nitrate (CAN), chloranil, 2,3-dichloro-5,6-
dicyanobenzoquinone (DDQ), trityl tetrafluoroborate, diphenylpicrylhydrazyl, etc. Hence, we planned the
development of novel methods to obtain naphtho[1,2-c]furan-1,3-dione and benzo[e]isoindole-1,3-dione,
which in normally produced by amidation, under mild and convenient conditions.
RESULTS AND DISCUSSION
1. Synthesis of 4,5-dihydronaphtho[1,2-c]furan-1,3-dione
Among several methods of synthesizing naphtho[1,2-c]furan-1,3-dione, we focused on that via
4,5-dihydronaphtho[1,2-c]furan-1,3-dione, because of its inexpensive starting material and reagents. 7-
Bromo-4,5-dihydronaphtho[1,2-c]furan-1,3-dione (4), a new compound, was prepared from 4-(3-
aminophenyl)butanoic acid hydrochloride (1) as shown in Scheme 1. Ethyl 4-(3-bromophenyl)butanoate
(3) was reacted with diethyl oxalate and base, then acid was added to the reaction mixture to give 4.
EtOH, H2SO4
HNO2, CuBr
CO2H
CO2Et
H2N
HCl
H2N
78%
95%
1
2
O
1) (CO2Et)2, NaOEt, 100oC
2) H2SO4, 80oC
O
O
CO2Et
Br
Br
66%
3
4
Scheme 1. Synthesis of 7-bromo-4,5-dihydronaphtho[1,2-c]furan-1,3-dione
2. Aromatization to naphtho[1,2-c]furan-1,3-dione and benzo[e]isoindole-1,3-dione using 10% Pd-C
To avoid the extremely high temperature needed for aromatization using sulfur, we studied DDQ and
10% Pd-C to obtain 7-bromonaphtho[1,2-c]furan-1,3-dione (6) from 4. In the case of DDQ, the products
were complex mixtures. In the case of 10% Pd-C, the reaction proceeded under mild conditions.
Consequently, we determined the conditions for the reaction of 4 with 10% Pd-C (50%wet) (4 times the
weight of 4) in AcOH at 120oC, and obtained 6 in 79% yield as shown in Scheme 2.
Similarly, 7-bromo-2-methyl-1H-benzo[e]isoindole-1,3(2H)-dione (7) was obtained in 76% yield from 7-
bromo-2-methyl-4,5-dihydro-1H-benzo[e]isoindole-1,3(2H)-dione (5), which was obtained in 81% yield
by the reaction of 4 with 2eq. of 40% methylamine (MeOH solution) in AcOH, by the same reaction as 4
to 6.

HETEROCYCLES, Vol. 67, No. 2, 2006
809
Me
N
O
O
O
O
MeNH2, AcOH
O
Br
Br
81%
4
5
10% Pd-C,
AcOH
10% Pd-C,
AcOH
76%
Me
79%
O
O
O
N
O
O
Br
Br
6
7
Scheme 2. Aromatization using 10% Pd-C
This method of aromatization using 10% Pd-C is a mild and convenient way of synthesizing
naphtho[1,2-c]furan-1,3-dione and benzo[e]isoindole-1,3-dione derivatives.
Table 1. Reaction from 4 to 5 and/or 7
Me
Me
O
O
O
MeNH2, additive
N
O
N
+
O
O
O
AcOH
Br
Br
Br
5
7
4
Entry MeNH2 (eq.) Additive (eq.) Conditions Ratio by HPLC b
5
120oC – 4 h 95
120oC – 4 h 77
24 h 53
7
1
2
2
none
none
5
10
23
48
64
96
77
99.9
80
98
98
100
90
100
55
94
3
4
5
6
7
8
25
50
2
none
120oC – 4 h 36
24 h 4
none
120oC – 4 h 23
24 h 0.1
Et3N (8)
Et3N (23)
Et3N (15)
120oC – 4 h 20
24 h 2
2
120oC – 4 h 2
24 h ND c
10
10
120oC – 4 h 10
24 h ND
AcONa (15) 120oC – 4 h 45
24 h 6
a 300 eq. of AcOH was used as solvent. b Determined at 220nm. c ND = Not detected.

810
HETEROCYCLES, Vol. 67, No. 2, 2006
3. One-pot imidation and aromatization to benzo[e]isoindole-1,3-dione using primary amine
In the course of our studies of the conversion of 4 to 5, we noticed that the ratio of the aromatized
compound (7) increased depending on the equivalent of methylamine as shown in Table 1. (Entries 1-4)
Furthermore, this reaction was accelerated by addition of triethylamine. (Entries 5-7)
Consequently, using only methylamine and base in refluxing AcOH, 7 was obtained in 81% yield by
imidation and simultaneous aromatization by oxidation in one-pot starting from 4 as shown in Scheme 3.
Using the same procedure, several benzo[e]isoindole-1,3-dione derivatives (9, 11, 12, 13) were obtained
in good yield by imidation and simultaneous aromatization by oxidation in one pot from 4,5-
dihydronaphtho[1,2-c]furan-1,3-dione derivatives (4, 8, 10).
R
O
O
RNH2, (Et3N)
AcOH
O
N
Y
X
O
Y
X
O
7 (R=Me, X=Br, Y=H); 81% a
9 (R=Me, X=H, Y=H); 71% a
11 (R=Me, X=H, Y=OMe); 49% a
12 (R=Bn, X=Br, Y=H); 56% a
13 (R=Ph, X=Br, Y=H); 87% a
a isolated yield
4 (X=Br, Y=H)
8 (X=H, Y=H)
10 (X=H, Y=OMe)
Scheme 3. One pot imidation and aromatization using primary amine
CONCLUSION
In conclusion, we achieved the synthesis of naphtho[1,2-c]furan-1,3-dione and benzo[e]isoindole-1,3-
dione in acetic acid with 10% Pd-C under mild conditions. Unexpectedly, benzo[e]isoindole-1,3-dione
was obtained by imidation and simultaneous aromatization by oxidation in refluxing acetic acid with
primary amine in two steps, one pot.
EXPERIMENTAL
Melting points were determined based on differential scanning calorimetry (DSC). IR spectra were
recorded on a Thermo Electron Nicolet 4700 spectrophotometer. NMR spectra were recorded on a Bruker
1
DPX300 spectrometer. H and 13C NMR chemical shifts were referenced to the internal deuterated
solvent or tetramethylsilane. HPLC was performed with a Hitachi L-6200, Hitachi L-4000 UV
spectrophotometric detector at 220 nm, and YMC ODS-Pack A-302 150 mm×4.6 mm i.d. column. DSC,
MS spectra and elemental analyses were performed at Takeda Analytical Research Laboratories, Ltd.. All
commercial chemicals and solvents were of reagent grade and used without further purification.
Ethyl 4-(3-aminophenyl)butanoate (2). To a suspension of 4-(3-aminophenyl)butanoic acid
hydrochloride (1; 4.31 g, 20 mmol) in EtOH (10 mL) was added conc. H2SO4 (0.4 mL), and the resulting

HETEROCYCLES, Vol. 67, No. 2, 2006
811
mixture was refluxed for 1 h. After cooling, AcOEt (20 mL) and 1N-NaOH (40 mL) were added to the
reaction mixture and separated. The organic extract was washed with 1N-NaOH (30 mL) and H2O (30
mL x 2) and concentrated in vacuo to give 2 (3.93 g, 94.7%) as a pale brown liquid; HPLC(50 mM
1
KH2PO4-MeCN= 50:50) tR: 2.1(1), 5.4(2); H-NMR(300 MHz, CDCl3): δ 1.24(t, J=7.1 Hz, 3H),
1.92(quint, J=7.4 Hz, 2H), 2.30(t, J=7.4 Hz, 2H), 2.55(t, J=7.4 Hz, 2H), 3.62(br, 2H), 4.12(q, J=7.1 Hz,
13
2H), 6.49-6.58(m, 3H), 7.02-7.08(m, 1H); C-NMR(75 MHz, CDCl3): δ 14.2, 26.3, 33.6, 35.0, 60.1,
112.7, 115.2, 118.7, 129.2, 142.6, 146.4, 173.5.
Ethyl 4-(3-bromophenyl)butanoate (3). To a solution of 2 (207 mg, 1 mmol) and 48% HBr (1 mL) was
added an H2O (0.5 mL) solution of sodium nitrite (69 mg, 1 mmol), and the resulting mixture was added
to a solution of copper(I) bromide (143 mg, 1 mmol) and 48% HBr (0.2 mL) in acetone (2 mL). After the
resulting mixture was stirred for 1 h, AcOEt (6 mL) and H2O (4 mL) were added to the reaction mixture
and separated. The organic extract was washed with 1N-NaOH (4 mL x 2) and H2O (4 mL x 2) and
concentrated in vacuo to give 3 (210 mg, 77.5%) as an orange liquid; HPLC(50 mM KH2PO4-MeCN=
1
30:70) tR: 2.8(2), 7.4(3); H-NMR(300 MHz, CDCl3): δ 1.26(t, J=7.1 Hz, 3H), 1.94(quint, J=7.4 Hz,
2H), 2.31(t, J=7.4 Hz, 2H), 2.62(t, J=7.4 Hz, 2H), 4.13(q, J=7.1 Hz, 2H), 7.10-7.19(m, 2H), 7.30-7.33(m,
2H); 13C-NMR(75 MHz, CDCl3): δ 14.2, 26.2, 33.5, 34.7, 60.3, 122.4, 127.1, 129.1, 129.9, 131.5,
143.7, 173.2.
7-Bromo-4,5-dihydronaphtho[1,2-c]furan-1,3-dione (4). To a suspension of sodium ethoxide (61 mg,
0.9 mmol) in THF (1 mL) were added diethyl oxalate (105 mg, 0.72 mmol) and 3 (163 mg, 0.6 mmol),
and the resulting mixture was stirred at 100oC for 1 h. After cooling, 80% H2SO4 (4 mL) was added to the
mixture at 0oC, and the resulting mixture was stirred at 80oC for 30 min. After cooling, the resulting
precipitates were collected by filtration, washed with H2O (2 mL x 3) and dried in vacuo to give 4 (110
mg, 65.9%) as a pale yellow crystalline powder; HPLC(50 mM KH2PO4-MeCN= 30:70) tR: 7.4(3),
1
4.9(4); mp 181.9oC (AcOH); IR(KBr): 1833.9, 1755.0, 1262.3, 876.6 cm-1; H-NMR(300 MHz, CDCl3):
δ 2.79(t, J=8.5 Hz, 2H), 3.09(t, J=8.5 Hz, 2H), 7.46(s, 1H), 7.49(dd, J=8.1 Hz, 1.9 Hz, 1H), 7.91(d,
J=8.1 Hz, 1H); 13C-NMR(75 MHz, CDCl3): δ 18.5, 26.7, 124.0, 126.7, 127.7, 130.8, 131.8, 138.7,
138.8, 139.8, 162.8, 163.9; MS(EI): m/z 278[M]+; Anal. Calcd for C12H7O3Br: C, 51.64; H, 2.53. Found:
C, 51.96; H, 2.74.
7-Bromo-2-methyl-4,5-dihydro-1H-benzo[e]isoindole-1,3(2H)-dione (5). To a suspension of 4 (279
mg, 1 mmol) in AcOH (17 mL) was added 40% methylamine (methanol solution) (0.16 mL, 2 mmol) at
0oC, and the resulting mixture was stirred at 120oC for 4 h. After cooling, the resulting precipitates were
collected by filtration, washed with MeOH (4 mL x 3) and dried in vacuo to give 5 (235 mg, 80.5%) as a
yellow crystalline powder; HPLC(50 mM KH2PO4-MeCN= 30:70) tR: 4.8(4), 5.9(5); mp 169.1oC

812
HETEROCYCLES, Vol. 67, No. 2, 2006
1
(AcOH); IR(KBr): 1759.7, 1696.0, 1435.4, 1382.9 cm-1; H-NMR(300 MHz, CDCl3): δ 2.67(t, J=8.4
Hz, 2H), 2.99(t, J=8.4 Hz, 2H), 3.05(s, 3H), 7.38(s, 1H), 7.42(dd, J=8.2 Hz, 1.9 Hz, 1H), 7.96(d, J=8.2
Hz, 1H); 13C-NMR(75 MHz, CDCl3): δ 17.9, 23.6, 27.0, 124.6, 125.6, 127.1, 130.3, 131.4, 135.4,
138.1, 138.7, 169.4, 170.1; MS(EI): m/z 291[M]+; Anal. Calcd for C13H10NO2Br: C, 53.45; H, 3.45; N,
4.79. Found: C, 53.71; H, 3.43; N, 4.89.
7-Bromonaphtho[1,2-c]furan-1,3-dione (6). To a suspension of 4 (28 mg, 0.1 mmol) in AcOH (1 mL)
was added 10% Pd-C (50% wet) (112 mg), and the resulting mixture was stirred at 120oC for 6 h. After
cooling, Pd-C was filtered off and washed with AcOEt, and the mother solution was concentrated in
vacuo to give 6 (22 mg, 78.6%) as a white crystalline powder; HPLC(50 mM KH2PO4-MeCN= 30:70) tR:
1
4.9(4), 5.0(6); mp 211.6oC (AcOH); IR(KBr): 1840.4, 1759.2, 1281.6, 882.1 cm-1; H-NMR(300 MHz,
DMSO-d6): δ 8.04(dd, J=8.8 Hz, 2.0 Hz, 1H), 8.07(d, J=8.6 Hz, 1H), 8.48(d, J=8.4 Hz, 1H), 8.55(d,
J=9.0 Hz, 1H), 8.58(d, J=1.8 Hz, 1H); 13C-NMR(75 MHz, DMSO-d6): δ 120.8, 123.7, 125.6, 125.8,
127.8, 131.4, 131.5, 133.6, 136.4, 137.4, 163.2(2C); MS(EI): m/z 276[M]+; Anal. Calcd for C12H5O3Br: C,
52.02; H, 1.82. Found: C, 52.14; H, 2.07.
7-Bromo-2-methyl-1H-benzo[e]isoindole-1,3(2H)-dione (7) from 5 using 10% Pd-C. To a suspension
of 5 (29 mg, 0.1 mmol) in AcOH (1 mL) was added 10% Pd-C (50% wet) (116 mg), and the resulting
mixture was stirred at 120oC for 10 h. After cooling, Pd-C was filtered off and washed with AcOEt, and
the mother solution was concentrated in vacuo to give 7 (22 mg, 75.9%) as a white crystalline powder;
HPLC(50 mM KH2PO4-MeCN= 30:70) tR: 5.9(5), 6.2(7); mp 238.7 oC (AcOH); IR(KBr): 1758.0, 1707.5,
1697.9, 1379.8cm-1; 1H-NMR(300 MHz, CDCl3): δ 3.22(s, 3H), 7.78(dd, J=9.0 Hz, 1.9 Hz, 1H), 7.88(d,
J=8.3 Hz, 1H), 8.05(d, J=8.3 Hz, 1H), 8.12(d, J=1.8 Hz, 1H), 8.80(d, J=9.0 Hz, 1H); 13C-NMR(75
MHz, CDCl3): δ 23.9, 119.6, 123.4, 126.3, 126.5, 127.9, 130.7, 131.6, 132.9, 133.7, 137.5, 168.7,
169.3; MS(EI): m/z 289[M]+; Anal. Calcd for C13H8NO2Br.0.4H2O: C, 52.52; H, 2.98; N, 4.71. Found: C,
52.60; H, 2.94; N, 4.67.
7 from 4 using methylamine and triethylamine. To a suspension of 4 (70 mg, 0.25 mmol) in AcOH
(4.3 mL) were added 40% methylamine (methanol solution) (0.04 mL, 0.5 mmol) and triethylamine (582
mg, 5.75 mmol) at 0oC, and the resulting mixture was stirred at 120oC for 24 h. After cooling, the
resulting precipitates were collected by filtration, washed with MeOH (1 mL x 3) and dried in vacuo to
give 7 (59 mg, 80.8%) as a yellow crystalline powder; HPLC(50 mM KH2PO4-MeCN= 30:70) tR: 4.8(4),
5.9(5), 6.2(7).
2-Methyl-1H-benzo[e]isoindole-1,3(2H)-dione (9). To a suspension of 4,5-dihydronaphtho[1,2-c]-
furan-1,3-dione (8; 60 mg, 0.3 mmol) in AcOH (3 mL) was added 40% methylamine (methanol solution)
(1.2 mL, 15 mmol) at 0oC, and the resulting mixture was stirred at 120oC for 48 h. After cooling, the
resulting precipitates were collected by filtration, washed with MeOH (1 mL x 3) and dried in vacuo to

HETEROCYCLES, Vol. 67, No. 2, 2006
813
give 9 (45 mg, 71.4%) as a pale yellow crystalline powder; HPLC(50 mM KH2PO4-MeCN= 65:35) tR:
31.4(8), 30.3(9); mp 167.4oC (AcOH); IR(KBr): 1706.7, 1694.6, 1437.1, 1378.8 cm-1; 1H-NMR(300 MHz,
CDCl3): δ 3.19(s, 3H), 7.59-7.71(m, 2H), 7.79(d, J=8.2 Hz, 1H), 7.90(d, J=8.1 Hz, 1H), 8.09(d, J=8.2
Hz, 1H), 8.87(d, J=8.3 Hz, 0.8 Hz, 1H); 13C-NMR(75 MHz, CDCl3): δ 23.7, 118.3, 124.8, 127.4, 127.8,
128.6(2C), 129.3, 131.3, 134.7, 136.4, 168.9, 169.6; MS(ESI): m/z 212[M+H]+; Anal. Calcd for
C13H9NO2: C, 73.92; H, 4.29; N, 6.63. Found: C, 73.80; H, 4.19; N, 6.64.
8-Methoxy-2-methylbenzo[e]isoindole-1,3-dione (11). To a suspension of 8-methoxy-4,5-dihydro-
naphtho[1,2-c]furan-1,3-dione (10; 115 mg, 0.5 mmol) in AcOH (8.5 mL) were added 40% methylamine
(methanol solution) (0.08 mL, 1 mmol) and triethylamine (1.16 g, 11.5 mmol) at 0oC, and the resulting
mixture was stirred at 120oC for 24 h. After cooling, the resulting precipitates were collected by filtration,
washed with MeOH (2 mL x 3) and dried in vacuo to give 11 (59 mg, 48.8%) as a pale yellow crystalline
powder; HPLC(50 mM KH2PO4-MeCN= 30:70) tR: 3.7(10), 4.3(11); mp 173.8 oC (AcOH); IR(KBr):
1753.3, 1708.5, 1695.9, 1377.8 cm-1; 1H-NMR(300 MHz, CDCl3): δ 3.19(s, 3H), 3.99(s, 3H), 7.23(dd,
J=9.1 Hz, 2.6 Hz, 1H), 7.64(d, J=8.1 Hz, 1H), 7.76(d, J=9.1 Hz, 1H), 7.98(d, J=8.1 Hz, 1H), 8.14(d,
J=2.4 Hz, 1H); 13C-NMR(75 MHz, CDCl3): δ 23.6, 55.6, 102.0, 116.1, 122.1, 125.5, 129.6, 130.0,
131.7, 132.3, 134.3, 160.5, 169.1, 170.0; MS(ESI): m/z 242[M+H]+; Anal. Calcd for C14H11NO3.0.1H2O:
C, 68.73; H, 4.61; N, 5.73. Found: C, 68.74; H, 4.50; N, 5.77.
2-Benzyl-7-bromobenzo[e]isoindole-1,3-dione (12). To a suspension of 4 (84 mg, 0.3 mmol) in AcOH
(5.1 mL) were added benzylamine (64 mg, 0.6 mmol) and triethylamine (698 mg, 6.9 mmol) at 0oC, and
the resulting mixture was stirred at 120oC for 24 h. After cooling, the resulting precipitates were collected
by filtration, washed with MeOH (1.5 mL x 3) and dried in vacuo to give 12 (61 mg, 55.5%) as an orange
crystalline powder; HPLC(50 mM KH2PO4-MeCN= 30:70) tR: 4.8(4), 13.0(12); mp 157.9 oC (AcOH);
IR(KBr): 1697.7, 1397.3, 1387.9, 1352.8 cm-1; 1H-NMR(300 MHz, CDCl3): δ 4.88(s, 2H),
7.24-7.35(m, 3H), 7.45-7.48(m, 2H), 7.75(dd, J=9.0 Hz, 1.9 Hz, 1H), 7.85(d, J=8.3 Hz, 1H), 8.01(d,
J=8.3 Hz, 1H), 8.08(d, J=1.7 Hz, 1H), 8.77(d, J=9.0 Hz, 1H); 13C-NMR(75 MHz, CDCl3): δ 41.6,
119.7, 123.5, 126.3, 126.5, 127.7, 127.8, 128.6(2C), 128.7(2C), 130.7, 131.4, 132.9, 133.8, 136.4, 137.5,
168.2, 168.8; MS(ESI): m/z 366[M+H]+; Anal. Calcd for C19H12NO2Br: C, 62.32; H, 3.30; N, 3.82.
Found: C, 62.24; H, 3.36; N, 3.96.
7-Bromo-2-phenylbenzo[e]isoindole-1,3-dione (13). To a suspension of 4 (84 mg, 0.3 mmol) in AcOH
(5.1 mL) were added phenylamine (56 mg, 0.6 mmol) and triethylamine (698 mg, 6.9 mmol) at 0oC, and
the resulting mixture was stirred at 120oC for 24 h. After cooling, the resulting precipitates were collected
by filtration, washed with MeOH (1.5 mL x 3) and dried in vacuo to give 13 (92 mg, 86.8%) as a yellow
crystalline powder; HPLC(50 mM KH2PO4-MeCN= 30:70) tR: 4.8(4), 9.2(13); mp 292.2 oC (AcOH);

814
HETEROCYCLES, Vol. 67, No. 2, 2006
1
IR(KBr): 1716.1, 1502.2, 1384.9, 749.8 cm-1; H-NMR(300 MHz, CDCl3): δ 7.37-7.56(m, 5H),
7.84(dd, J=9.0 Hz, 1.9 Hz, 1H), 7.99(d, J=8.3 Hz, 1H), 8.15(d, J=8.3 Hz, 1H), 8.18(d, J=1.9 Hz, 1H),
13
8.89(d, J=9.0 Hz, 1H); C-NMR(75 MHz, CDCl3): δ 120.0, 123.8, 126.57, 126.61(2C), 126.7, 128.1,
129.1, 129.2(2C), 130.9, 131.2, 131.6, 133.2, 134.3, 137.8, 167.5, 168.1; MS(ESI): m/z 352[M+H]+; Anal.
Calcd for C18H10NO2Br: C, 61.39; H, 2.86; N, 3.98. Found: C, 61.39; H, 2.92; N, 4.07.
ACKNOWLEDGEMENTS
The authors thank Dr. Kiminori Tomimatsu and Mr. Yuzuru Saito for helpful discussions.
REFERENCES
1. I. Harashima, T. Hirasawa, K. Tomioka, and J. Okada, Dent. Mater. J., 1988, 7, 141.
2. G. W. Muller and H-w. M., WO0025777.
3. L. F. Fieser and E. B. Hershberg, J. Am. Chem. Soc., 1936, 58, 2314.
4. M. S. Newman, B. Dhawan, M. M. Hashem, V. K. Khanna, and J. M. Springer, J. Org. Chem., 1976,
41, 3925.
5. J. Szadewski, Przem. Chem., 1972, 51, 227.
6. P. F. Peter and G. H. Ronald, Chem. Rev., 1978, 78, 317.