Synthesis of 2,4-disubstituted isoquinolin-1(2H)-ones based on reactions of α-substituted 2-lithio-β-methoxystyrenes with isocyanates

Article abstract of DOI:10.3987/COM-07-11304

An efficient method for the preparation of 2,4-disubstituted isoquinolin-1(2H)-ones is described. The reaction of α-substituted 2-lithio-β-methoxystyrenes, generated by treating α-substituted 2-bromo-β-methoxystyrenes with butyilithium, with isocyanates yields the corresponding α-substituted 2-(2-methoxyvinyl)benzamide derivatives, which in turn are transformed into 2,4-disubstituted isoquinolin-1(2H)-ones on treatment with a catalytic amount of concentrated hydriodic acid.

Full text of DOI:10.3987/COM-07-11304

HETEROCYCLES, Vol. 75, No. 5, 2008
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HETEROCYCLES, Vol. 75, No. 5, 2008, pp. 1225 - 1231. © The Japan Institute of Heterocyclic Chemistry
Received, 14th December, 2007, Accepted, 1st February, 2008, Published online, 5th February, 2008. COM-07-11304
SYNTHESIS OF 2,4-DISUBSTITUTED ISOQUINOLIN-1(2H)-ONES
BASED ON REACTIONS OF α-SUBSTITUTED 2-LITHIO-β-
METHOXYSTYRENES WITH ISOCYANATES
Kazuhiro Kobayashi,* Kazutaka Hayashi, Changeng Nam, Shuhei Fukamachi,
and Hisatoshi Konishi
Department of Materials Science, Faculty of Engineering, Tottori University,
4-101 Koyama-minami, Tottori 680-8552, Japan
Abstract - An efficient method for the preparation of 2,4-disubstituted
isoquinolin-1(2H)-ones is described. The reaction of α-substituted 2-lithio-
β-methoxystyrenes, generated by treating α-substituted 2-bromo-β-
methoxystyrenes with butyllithium, with isocyanates yields the corresponding
α-substituted 2-(2-methoxyvinyl)benzamide derivatives, which in turn are
transformed into 2,4-disubstituted isoquinolin-1(2H)-ones on treatment with a
catalytic amount of concentrated hydriodic acid.
In a recent paper,1 we demonstrated that α-substituted 2-lithio-β-methoxystyrenes, generated by a
treatment of α-substituted 2-bromo-β-methoxystyrenes with butyllithium, reacted with various nitriles to
give directly 1,4-disubstituted isoquinolines. As part of studies on the utility of these lithium products
for organic synthesis, we have been interested in the reaction with isocyanates, which should give
2,4-disubstituted isoquinolin-1(2H)-ones. In this paper, we wish to report a convenient synthesis of
2,4-disubstituted isoquinolin-1(2H)-ones (3) from α-substituted 2-bromo-β-methoxystyrenes (1). We
found that the reaction of α-substituted 2-lithio-β-methoxystyrenes with isocyanates gave only
α-substituted 2-(2-methoxyvinyl)benzamide derivatives (2). However, these benzamides (2) could be
converted into 2,4-disubstituted isoquinolin-1(2H)-ones (3) upon treatment with a catalytic amount of
concentrated hydriodic acid. Recently, a number of efficient methods for the preparation of
isoquinolin-1(2H)-one derivatives have been reported,2 because of their biological activities.3 Moreover,
some of them have been utilized as precursors for the synthesis of more complex and useful molecules.4
However, to date, there have been only a limited report on the synthesis of isoquinolin-1(2H)-one
derivatives bearing substituents both at the 2- and 4-positions.5
Our two-step preparation of 2,4-disubstituted isoquinolin-1(2H)-ones (3) from α-substituted 2-bromo-
β-methoxystyrenes (1) was conducted as illustrated in Scheme 1. The first step involves the reaction of

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HETEROCYCLES, Vol. 75, No. 5, 2008
α-substituted 2-lithio-β-methoxystyrenes, generated by the treatment of 1 with butyllithium in diethyl
ether at 0 ˚C as described previously,1 with various isocyanates, affording the corresponding α-substituted
2-(2-methoxyvinyl)benzamide derivatives (2). As summarized in Table 1, the yields of 2 are generally
fair to good, though those using t-butyl isocyanate are somewhat lower (Entries 7 and 9). These lower
yields are considered to arise from the less reactivity of this isocyanate due to the bulkiness of the t-butyl
group. Compounds (2) were obtained as mixtures of stereoisomers, and the ratios were determined by
1
their H NMR spectra (see Experimental). However, the stereochemistry of each isomer could not be
determined in every case.
R2
R2
Br
R2
R1
R1
OMe
R1
OMe
1. n-BuLi,Et2O, 0 ˚C, 1 h
2. R3NCO, 0 ˚C, 0.5 h
conc. HI (cat.)
0 ˚C to rt, 1.5 h
NR3
CONHR3
O
2
3
1
Scheme 1
Table 1. Preparation of Isoquinolin-1(2H)-ones (3) via 2-Vinylbenzamides (2)
Entry
1
R3 in RNCO
Ph
o-Tol
4-ClC6H4
Ph
4-ClC6H4
3-MeOC6H4
t-Bu
4-ClC6H4
t-Bu
Ph
2 (Yield/%)a,b
2a (73)
2b (74)
2c (69)
2d (71)
2e (62)
2f (73)
3 (Yield/%)a
3a (67)
3b (61)
3c (75)
3d (66)
3e (73)
3f (68)
1
2
3
4
5
6
7
8
9
10
1a (R1 = H, R2 = Ph)
1a
1a
1b (R1 = H, R2 = 4-ClC6H4)
1b
1b
1b
2g (51)
2h (65)
2i (55)
3g (64)
3h (71)
3i (69)
1c (R1 = H, R2 = Me)
1c
1d (R1 = OMe, R2 = Ph)
2j (88)
3j (63)
aIsolated yields. bMixtures of stereoisomers.
Subsequent intramolecular replacement of the methoxy substituent in the methoxyvinyl moiety with the
amide nitrogen atom of 2 was easily achieved upon treatment of a catalytic amount of concentrated
hydriodic acid in acetonitrile at 0 ˚C to room temperature to result in the formation of 3 in generally fair
yields, independent of the substituents both at the 2-and 4-positions. These results are also summarized in
Table 1.
In summary, we have shown that α-substituted 2-(2-methoxyvinyl)benzamide derivatives, which are
readily prepared by reactions of α-substituted 2-lithio-β-methoxystyrenes with isocyanates, cyclize on
treatment with concentrated hydriodic acid to afford 2,4-disubstituted isoquinoline-1(2H)-ones. Since
these isoquinolinones derivatives are hard to obtain by conventional methods, the present new and simple
method may find some value in organic synthesis. Further investigations on the development of methods

HETEROCYCLES, Vol. 75, No. 5, 2008
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for the synthesis of heterocycles utilizing reactions of these lithium compounds with various electrophiles
are now in progress in our laboratory, and results will be reported in near future.
EXPERIMENTAL
The melting points were determined on a Laboratory Devices MEL-TEMP II melting-point apparatus and
1
are uncorrected. The IR spectra were recorded on a Shimadzu FTIR-8300 spectrometer. The H NMR
spectra were determined using SiMe4 as an internal reference with a JEOL ECP500 FT NMR
13
spectrometer operating at 500 MHz. The C NMR spectra were determined in CDCl3 using TMS as an
internal reference with a JEOL ECP500 FT NMR spectrometer operating at 125 MHz. Low-resolution
mass spectra (EI) were recorded on a JEOL AUTOMASS 20 spectrometer. Thin-layer chromatography
(TLC) was carried out on Merck Kieselgel 60 PF254. Column chromatography was performed using
Merck Kieselgel 60 (0.063–0.200 mm). All of the solvents used were dried over appropriate drying
agents and distilled under argon prior to use.
Starting Materials. 2-Bromostyrene derivatives (1a),1 (1b),1 (1c),6 and (1d)1 were prepared by
appropriate reported procedures. All other chemicals used in this study were commercially available.
Typical Procedure for the Preparation of 2-(2-Methoxyvinyl)benzamides (2). 2-(2-Methoxy-1-
phenylethenyl)-N-phenylbenzamide (2a). To a stirred solution of 1a (0.29 g, 1.0 mmol) in Et2O (4 mL)
at 0 ˚C was added dropwise n-BuLi (1.6M in hexane; 1.0 mmol). After 1 h, PhNCO (0.12 g, 1.0 mmol)
was added and stirring was continued for an additional 30 min. The mixture was quenched with saturated
aqueous NH4Cl (15 mL) and extracted with Et2O three times (10 mL each). The combined extracts were
dried over anhydrous Na2SO4 and evaporated. The residue was purified by column chromatography on
silica gel to afford 2a (0.24 g, 73%); a pale-yellow viscous oil; Rf 0.40 (1:5 AcOEt–hexane); a mixture of
stereoisomers (ca. 9:1); IR (neat) 3323, 1649, 1636, 1603 cm–1; 1H NMR δ 3.71 (0.3H, s), 3.77 (2.7H, s),
6.40 (0.9H, s), 6.69 (0.1H, s), 7.04 (0.9H, tt, J = 7.3, 1.4 Hz), 7.07 (0.1H, tt, J = 7.3, 1.4 Hz), 7.13–7.29
(7H, m), 7.35 (0.9H, d, J = 8.2 Hz), 7.36 (0.1H, d, J = 8.2 Hz), 7.42–7.51 (4H, m), 7.67 (0.9H, br s), 7.85
(1H, dd, J = 7.8, 1.8 Hz), 7.88 (0.1H, br s). Anal. Calcd for C22H19NO2: C, 80.22; H, 5.81; N, 4.25. Found:
C, 80.08; H, 5.85, N, 4.47.
2-(2-Methoxy-1-phenylethenyl)-N-(2-methylphenyl)benzamide (2b): a pale-yellow viscous oil; Rf 0.14
1
(1:3 AcOEt–hexane); a mixture of stereoisomers (ca. 5:5); IR (neat) 3288, 1668, 1634 cm–1; H NMR δ
1.93 (1.5H, s), 2.04 (1.5H, s), 3.70 (1.5H, s), 3.78 (1.5H, s), 6.42 (0.5H, s), 6.70 (0.5H, s), 6.99–7.05 (1H,
m), 7.07–7.19 (4H, m), 7.22–7.26 (3H, m), 7.28 (0.5H, dd, J = 7.8, 1.4 Hz), 7.34 (0.5H, d, J = 7.3 Hz),
7.42–7.55 (2H, m), 7.57 (0.5H, br s), 7.66 (0.5H, d, J = 7.8 Hz), 7.71 (0.5H, br s), 7.82 (0.5H, d, J = 8.2
Hz), 7.87 (0.5H, dd, J = 8.2, 1.8 Hz), 7.89 (0.5H, d, J = 7.8 Hz). Anal. Calcd for C23H21NO2: C, 80.44; H,
6.16; N, 4.08. Found: C, 80.31; H, 6.17; N, 3.99.
N-(4-Chlorophenyl)-2-(2-methoxy-1-phenylethenyl)benzamide (2c): a pale-yellow viscous oil; Rf 0.14

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1
(1:5 AcOEt–hexane); a mixture of stereoisomers (ca. 8:2); IR (neat) 3223, 1645, 1628 cm–1; H NMR δ
3.70 (2.4H, s), 3.78 (0.6H, s), 6.39 (0.2H, s), 6.69 (0.8H, s), 7.08–7.51 (12H, m), 7.66 (0.2H, br s), 7.82
(1H, d, J = 7.3 Hz), 7.88 (0.8H, br s). Anal. Calcd for C22H18ClNO2: C, 72.62; H, 4.99; N, 3.85. Found: C,
72.47; H, 5.27; N, 3.86.
2-[1-(4-Chlorophenyl)-2-methoxyethenyl]-N-phenylbenzamide (2d): a pale-yellow viscous oil; Rf 0.21
1
(1:4 AcOEt–hexane); a mixture of stereoisomers (ca. 7:3); IR (neat) 3288, 1652, 1636 cm–1; H NMR δ
3.71 (0.9H, s), 3.79 (2.1H, s), 6.43 (0.7H, s), 6.65 (0.3H, s), 7.04–7.51 (12H, m), 7.59 (0.7H, br s), 7.79
(0.3H, br s), 7.82 (1H, d, J = 7.8 Hz). Anal. Calcd for C22H18ClNO2: C, 72.62; H, 4.99; N, 3.85. Found: C,
72.49; H, 5.01, N, 3.71.
N-(4-Chlorophenyl)-2-[1-(4-chlorophenyl)-2-methoxyethenyl]benzamide (2e): a white solid; mp
140–160 ˚C; a mixture of stereoisomers (ca. 9:1); IR (neat) 3320, 1654, 1631, 1601 cm–1; 1H NMR δ 3.71
(0.3H, s), 3.80 (2.7H, s), 6.42 (0.9H, s), 6.65 (0.1H, s), 7.14–7.22 (6H, m), 7.31–7.36 (3H, m), 7.44–7.51
(2H, m), 7.58 (0.9H, br s), 7.72 (0.1H, br s), 7.79 (1H, d, J = 7.3 Hz). Anal. Calcd for C22H17Cl2NO2: C,
66.34; H, 4.30; N, 3.52. Found: C, 66.24; H, 4.30, N, 3.49.
2-[1-(4-Chlorophenyl)-2-methoxyethenyl]-N-(3-methoxyphenyl)benzamide (2f): a pale-yellow vis-
cous oil; Rf 0.13 (1:4 AcOEt–hexane); a mixture of stereoisomers (ca. 5:5); IR (neat) 3300, 1659, 1634,
1605 cm–1; 1H NMR δ 3.75 (1.5H, s), 3.78 (3H, s), 3.79 (1.5H, s), 6.18 (0.5H, s), 6.42 (0.5H, s), 6.59–7.50
(11H, m), 7.58 (0.5H, br s), 7.78–7.82 (1.5H, m). Anal. Calcd for C23H20ClNO3: C, 70.14; H, 5.12; N,
3.56. Found: C, 70.10; H, 5.26, N, 3.38.
2-[1-(4-Chlorophenyl)-2-methoxyethenyl]-N-(1,1-dimethylethyl)benzamide (2g): a pale-yellow oil; Rf
0.21 (1:3 AcOEt–hexane); a mixture of stereoisomers (ca.7:3); IR (neat) 3400, 1653, 1634 cm–1; 1H NMR
δ 1.13 (6.3H, s), 1.23 (2.7H, s), 3.74 (0.9H, s), 3.83 (2.1H, s), 5.71 (0.7H, br s), 5.93 (0.3H, br s), 6.34
(0.7H, s), 6.71 (0.3H, s), 7.05 (0.6H, d, J = 8.7 Hz), 7.18–7.25 (2.4H, m), 7.36–7.43 (4H, m), 7.67–7.71
(1H, m). Anal. Calcd for C20H22NO4: C, 65.51; H, 7.90; N, 4.77. Found: C, 65.48; H, 7.94, N, 4.76.
N-(4-Chlorophenyl)-2-(2-methoxy-1-methylethenyl)benzamide (2h): a pale-yellow oil; Rf 0.40 (1:30
1
THF–benzene); a mixture of stereoisomers (ca. 7:3); IR (neat) 3263, 3229, 1655, 1645 cm–1; H NMR δ
1.88 (0.9H, d, J = 1.4 Hz), 1.94 (2.1H, d, J = 0.9 Hz), 3.59 (0.9H, s), 3.72 (2.1H, s), 6.12 (0.3H, q, J = 1.4
Hz), 6.26 (0.7H, q, J = 0.9 Hz), 7.23–7.55 (7H, m), 7.76 (0.3H, d, J = 7.3 Hz), 7.81 (0.7H, dd, J = 7.3, 1.4
Hz), 7.99 (0.7H, br s), 8.21 (0.3H, br s). Anal. Calcd for C17H16ClNO2: C, 67.66; H, 5.34; N, 4.64. Found:
C, 67.41; H, 5.40; N, 4.59.
N-(1,1-Dimethylethyl)-2-(2-methoxy-1-methylethenyl)benzamide (2i): a pale-yellow solid; mp 65–70
1
˚C; a mixture of stereoisomers (ca. 7:3); IR (KBr) 3267, 1666, 1626 cm–1; H NMR δ 1.415 (2.7H, s),
1.420 (6.3H, s), 1.85 (0.9H, d, J = 1.4 Hz), 1.94 (2.1H, d, J = 1.4 Hz), 3.57 (0.9H, s), 3.69 (2.1H, s), 5.97
(0.7H, br s), 6.05 (0.3H, q, J = 1.4 Hz), 6.14 (0.7H, q, J = 1.4 Hz), 6.27 (0.3H, br s), 7.13–7.17 (1H, m),
7.28–7.39 (2H, m), 7.64 (0.7H, dd, J = 7.3, 1.4 Hz), 7.67 (0.3H, dd, J = 7.8, 1.4 Hz). Anal. Calcd for

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C15H21NO2: C, 72.84; H, 8.56; N, 5.66. Found: C, 72.59; H, 8.42; N, 5.53.
4-Methoxy-2-(2-methoxy-1-phenylethenyl)-N-phenylbenzamide (2j): a pale-yellow solid; mp 45–60
1
˚C; a mixture of stereoisomers (ca. 5:5); IR (KBr) 3223, 1649, 1636 cm–1; H NMR δ 3.71 (1.5H, s),
3.748 (1.5H, s), 3.754 (1.5H, s), 3.76 (1.5H, s), 6.10 (0.5H, s), 6.48 (0.5H, s), 6.57 (0.5H, dd, J = 8.7, 2.7
Hz), 6.60 (0.5H, d, J = 2.7 Hz), 6.71 (0.5H, d, J = 2.7 Hz), 6.74 (0.5H, dd, J = 8.7, 2.7 Hz), 6.96–7.32
(10H, m), 7.41–7.45 (2H, m). Anal. Calcd for C23H21NO3: C, 76.86; H, 5.89; N, 3.90. Found: C, 76.83; H,
5.95; N, 3.99.
Typical Procedure for the Preparation of Isoquinolinone Derivatives (3). 2,4-Diphenylisoquinolin-
1(2H)-one (3a).5 To a stirred solution of 2a (0.24 g, 0.72 mmol) in MeCN (7 mL) at 0 ˚C was added a
drop of concentrated HI. The mixture was allowed to warm to rt, and stirring was continued for 1.5 h
before saturated aqueous NaHCO3 (10 mL) was added. The organic materials were extracted with Et2O
(20 mL), and the extract was washed with brine and dried over anhydrous Na2SO4. Evaporation of the
solvent gave a residue, which was purified by preparative TLC on silica gel to afford 3a (0.14 g, 67%); a
1
white solid; mp 133–134 ˚C (hexane–Et2O) (lit.,5 mp 132–133 ˚C). The IR and H NMR data for this
product were identical to those reported previously.5
2-(2-Methylphenyl)-4-phenylisoquinolin-1(2H)-one (3b): a white solid; mp 135–137 ˚C (hexane–Et2O);
IR (KBr) 1662, 1624, 1603 cm–1; 1H NMR δ 2.24 (3H, s), 7.03 (1H, s), 7.29–7.37 (5H, m), 7.39–7.47 (4H,
13
m), 7.56 (1H, ddd, J = 8.2, 6.9, 1.4 Hz), 7.63–7.68 (2H, m), 8.58 (1H, d, J = 7.8 Hz); C NMR δ 17.84,
119.57, 124.79, 126.39, 127.11, 127.57, 127.73, 128.64 (two overlapped C’s), 128.67, 128.86, 129.96
(two overlapped C’s), 131.11, 132.40, 135.42, 136.10, 136.58, 140.40, 161.20; MS m/z 311 (M+, 89), 294
(100). Anal. Calcd for C22H17NO: C; 84.86; H, 5.50; N, 4.50. Found: C, 84.67; H, 5.54; N, 4.46.
2-(4-Chlorophenyl)-4-phenylisoquinolin-1(2H)-one (3c):5 a white solid; mp 148–150 ˚C (hexane–Et2O)
(lit.,2 mp 148–149 ˚C); IR (KBr) 1661, 1628, 1601 cm–1; 1H NMR δ 7.13 (1H, s), 7.41–7.50 (9H, m), 7.57
(1H, ddd, J = 8.2, 6.9, 1.4 Hz), 7.60 (1H, d, J = 8.2 Hz), 7.66 (1H, ddd, J = 8.2, 6.9, 1.4 Hz), 8.57 (1H, dd,
J = 8.2, 1.4 Hz).
4-(4-Chlorophenyl)-2-phenylisoquinolin-1(2H)-one (3d): a white solid; mp 145–147 ˚C (hexane–Et2O);
IR (KBr) 1661, 1626 cm–1; 1H NMR δ 7.17 (1H, s), 7.40 (2H, d, J = 8.2 Hz), 7.43–7.58 (9H, m), 7.66 (1H,
13
td, J = 7.3, 1.4 Hz), 8.58 (1H, dd, J = 7.3, 1.4 Hz); C NMR δ 118.44, 124.46, 126.39, 126.83, 127.38,
128.22, 128.81, 128.91, 129.34, 131.24 (two overlapped C’s), 132.60, 133.82, 134.58, 136.15, 141.13,
161.49; MS m/z 331 (M+, 100). Anal. Calcd for C21H14ClNO: C; 76.36; H, 3.94; N, 4.24. Found: C, 76.17;
H, 4.19; N, 4.08.
2,4-Bis(4-chlorophenyl)isoquinolin-1(2H)-one (3e): a white solid; mp 180–183 ˚C (hexane–AcOEt); IR
1
(KBr disk) 1657, 1622 cm–1; H NMR δ 7.11 (1H, s), 7.38 (2H, d, J = 8.7 Hz), 7.43 (2H, d, J = 8.7 Hz),
7.45 (2H, d, J = 8.7 Hz), 7.48 (2H, d, J = 8.7 Hz), 7.53 (1H, d, J = 8.2 Hz), 7.58 (1H, ddd, J = 8.2, 7.3, 1.4
Hz), 7.67 (1H, ddd, J = 8.2, 7.3, 1.4 Hz), 8.56 (1H, dd, J = 8.2, 1.4 Hz); MS m/z 365 (M+, 100). Anal.

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Calcd for C21H13Cl2NO: C, 68.87; H, 3.58; N, 3.82. Found: C, 68.93; H, 3.70; N, 3.73.
4-(4-Chlorophenyl)-2-(3-methoxyphenyl)isoquinolin-1(2H)-one (3f): a pale-yellow solid; mp 121–124
˚C (Et2O); IR (KBr) 1665, 1628, 1605 cm–1; 1H NMR δ 3.85 (3H, s), 6.97 (1H, ddd, J = 8.2, 2.8, 0.9 Hz),
7.02–7.06 (2H, m), 7.16 (1H, s), 7.38–7.42 (3H, m), 7.45 (2H, d, J = 8.2 Hz), 7.54 (1H, d, J = 8.2 Hz),
7.57 (1H, ddd, J = 8.2, 7.3, 0.9 Hz), 7.66 (1H, ddd, J = 8.2, 7.3, 1.4 Hz), 8.58 (1H, dd, J = 8.2, 0.9 Hz);
MS m/z 361 (M+, 100). Anal. Calcd for C22H16ClNO2: C, 73.03; H, 4.46; N, 3.87. Found: C, 73.07; H,
4.14; N, 3.84.
4-(4-Chlorophenyl)-2-(1,1-dimethylethyl)isoquinolin-1(2H)-one (3g): a white solid; mp 183–185 ˚C
(hexane–Et2O); IR (KBr) 1643, 1616 cm–1; 1H NMR δ 1.76 (9H, s), 7.30 (1H, s), 7.36 (2H, d, J = 8.2 Hz),
7.44–7.46 (3H, m), 7.49 (1H, ddd, J = 7.8, 7.3, 0.9 Hz), 7.58 (1H, ddd, J = 8.2, 7.3, 1.4 Hz), 8.51 (1H, dd,
J = 8.2, 0.9 Hz); MS m/z 311 (M+, 22), 255 (100). Anal. Calcd for C19H18ClNO: C, 73.19; H, 5.82; N, 4.49.
Found: C, 72.99; H, 5.86; N, 4.32.
2-(4-Chlorophenyl)-4-methylisoquinolin-1(2H)-one (3h): a white solid; mp 168–170 ˚C (hexane–
1
Et2O); IR (KBr) 1665, 1628, 1612 cm–1; H NMR δ 2.32 (3H, s), 6.98 (1H, s), 7.39 (2H, d, J = 8.7 Hz),
7.47 (2H, d, J = 8.7 Hz), 7.56 (1H, dd, J = 7.8, 7.3 Hz), 7.65 (1H, d, J = 7.8 Hz), 7.75 (1H, dd, J = 7.8, 7.3
Hz), 8.51 (1H, d, J = 7.8 Hz); MS m/z 269 (M+, 100). Anal. Calcd for C16H12ClNO: C; 71.38; H, 4.46; N,
5.20. Found: C, 71.32; H, 4.34; N, 5.04.
2-(1,1-Dimethylethyl)-4-methylisoquinolin-1(2H)-one (3i): a pale-yellow oil; Rf 0.41 (1:4 AcOEt–
hexane); IR (neat) 1651, 1626, 1603 cm–1; 1H NMR δ 1.75 (9H, s), 2.28 (3H, d, J = 1.4 Hz), 7.19 (1H, q, J
= 1.4 Hz), 7.47 (1H, ddd, J = 7.8, 7.3, 0.9 Hz), 7.55 (1H, d, J = 7.8 Hz), 7.66 (1H, ddd, J = 7.8, 7.3, 1.4
Hz), 8.46 (1H, dd, J = 7.8, 0.9 Hz); MS m/z 215 (M+, 18), 159 (100). Anal. Calcd for C14H17NO: C, 78.10;
H, 7.96; N, 6.51. Found: C, 78.16; H, 8.05; N, 6.29.
6-Methoxy-2,4-diphenylisoquinolin-1(2H)-one (3j): a white solid; mp 153–155 ˚C (hexane–Et2O); IR
(KBr disk) 1722, 1636, 1605 cm–1; 1H NMR δ 3.81 (3H, s), 6.78 (1H, d, J = 2.3 Hz), 7.09 (1H, dd, J = 8.7,
2.3 Hz), 7.24 (1H, s), 7.39–7.41 (4H, m), 7.45–7.51 (6H, m), 8.33 (1H, d, J = 8.7 Hz); MS m/z (%) 327
(M+, 13), 251 (94), 223 (100). Anal. Calcd for C22H17NO2: C, 80.71; H, 5.23; N, 4.28. Found: C, 80.68; H,
5.41; N, 4.46.
ACKNOWLEDGEMENTS
We would like to thank Mrs. Miyuki Tanmatsu of this Faculty for determining mass spectra and
performing combustion analyses.
REFERENCES AND NOTES
1. K. Kobayashi, K. Hayashi, K. Miyamoto, O. Morikawa, and H. Konishi, Synthesis, 2006, 2934.
2. a) Z. Xiang, T. Luo, K. Lu, J. Cui, X. Shi, R. Fathi, J, Chen, and Z. Yang, Org. Lett., 2004, 6, 3155.

HETEROCYCLES, Vol. 75, No. 5, 2008
1231
b) K. Cherry, A. Duchene, J. Thibonnet, J.-L. Parrain, and M. Abarbi, Synthesis, 2005, 2349. c) N.
Coskun, and Y. Kizikusak, Synth. Commun., 2005, 35, 2435. d) J. F. Guastavino, S. M. Barolo, and
R. A. Rossi, Eur. J. Org. Chem., 2006, 3898. e) Z. He and A. K. Yudin, Org. Lett., 2006, 8, 5829.
3. a) C. Y. Watson, W. J. D. Whish, and M. D. Threadgill, Bioorg. Med. Chem., 1998, 6, 721. b) T. N.
Li and W.-J. Cho, Chem. Pharm. Bull., 2005, 53, 118. c) R. Fujita, T. Yoshisuji, S. Wakayanagi, H.
Wakamatsu, and H. Matsuzaki, Chem. Pharm. Bull., 2006, 54, 204. d) R. Fujita, S. Wakayanagi, H.
Wakamatsu, and H. Matsuzaki, Chem. Pharm. Bull., 2006, 54, 209. e) D. Brookings, R. J. Davenport,
J. Davis, F. C. A. Galvin, S. Lloyd, S. R. Mark, R. Owens, V. Sabin, and J. Wynn, Bioorg. Med.
Chem. Lett., 2007, 17, 562.
4. a) M. Treus, J. C. Estévez, L. Castedo, and R. Estévez, Tetrahedron Lett., 2002, 43, 5323. b) T. N.
Le, S. G. Gang, and W.-J. Cho, J. Org. Chem., 2004, 69, 2768. c) Z. Ma and D. Y. W. Lee,
Tetrahedron Lett., 2004, 45, 6721. d) S. Peukert, U. Schwahn, S. Güssregen, H. Schreuder, and A.
Hofmeister, Synthesis, 2005, 1550. e) E. R. Walker, S. Y. Leung, and A. G. Barrett, Tetrahedron
Lett., 2005, 46, 6537.
5. D. J. Dodsworth, M. Pia-Calcagno, U. Ehrmann, A. M. Quesada, O. Nuñez S., and P. G. Sammes, J.
Chem. Soc., Perkin Trans. 1, 1983, 1453.
6. B. Wuensch, G. Hoefner, and G. Bauschke, Arch. Pharm., 1993, 326, 513.