Photochemical synthesis of benzoxazolo[3,2-b]isoquinolin-11-one and isoquinolino[3,2-b][1,3]benzoxazin-11-one under basic conditions

Article abstract of DOI:10.1016/j.tet.2005.02.068

Irradiation of N-phenyl substituted isoquinolines in acetonitrile containing 1 M NaOH in a multilamp reactor (MLR) furnished benzoxazolo[3,2-b] isoquinolin-11-ones. In contrast, irradiation of the N-benzyl substituted isoquinoline derivative under the sam

Full text of DOI:10.1016/j.tet.2005.02.068

Tetrahedron 61 (2005) 4213–4220
Photochemical synthesis of benzoxazolo[3,2-b]isoquinolin-11-one
and isoquinolino[3,2-b][1,3]benzoxazin-11-one under
basic conditions
*
A. Senthilvelan, D. Thirumalai and V. T. Ramakrishnan
Department of Organic Chemistry, School of Chemical Sciences, University of Madras, Guindy Campus, Chennai 600 025, India
Received 1 December 2004; revised 2 February 2005; accepted 24 February 2005
Available online 17 March 2005
Abstract—Irradiation of N-phenyl substituted isoquinolines in acetonitrile containing 1 M NaOH in a multilamp reactor (MLR) furnished
benzoxazolo[3,2-b]isoquinolin-11-ones. In contrast, irradiation of the N-benzyl substituted isoquinoline derivative under the same conditions
afforded the hydrolysed N-benzylbenzamide derivative. The isoquinolinobenzoxazine was obtained by irradiating the N-benzyl substituted
isoquinoline derivative at higher basic conditions. The required isoquinolines were synthesized under solvent-free, solid supported
microwave conditions.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
have reported the first photochemical synthesis of isoquino-
line-fused benzoxazole and benzoxazine derivatives. In this
paper, we wish to report the systematic study on the thermal
and microwave assisted synthesis of tetrahydroisoquinolines
and their photolysis under base-mediated conditions.
Isoquinoline fused alkaloids play an important role in the
field of medicine as antihypertensive agents and anti-
depressant agents.1,2 Tetrahydroisoquinolines are the
building blocks for the syntheses of various isoquinolino-
alkaloids.3,4 Oxazoles and oxazines are known to exhibit a
broad spectrum of biological activities.5,6 Recently, the
synthesis of benzoxazoles7 and benzoxazines8 has been
reported. Microwave-assisted organic synthesis is a new and
growing area in synthetic organic chemistry. The combi-
nation of supported reagents and microwave irradiation can
be used to carry out a wide range of reactions in short times
with high conversions, without the need for solvents.9
2. Results and discussion
2.1. Synthesis of isoquinolines
The isoquinolines were synthesized by a direct one-step
process under thermal and solvent-free, solid supported
microwave conditions. In the thermal conditions, refluxing a
mixture of homophthalic acid (1 equiv), substituted aniline
(1 equiv) and p-toluenesulfonic acid (catalytic amount) in
dry toluene using a Dean–Stark apparatus for 22–24 h
furnished the corresponding tetrahydroisoquinoline-1,3-
dione 1a–g (Scheme 1) in good yield in one-step. In the
In continuation of our interest on the photochemistry of
heterocycles, we have reported the photochemical synthesis
of benzothiazoles,10,11 triazolobenzothiazoles,12 and triazo-
lobenzothiazines.13,14 In a preliminary communication,15 we
Scheme 1.
Keywords: Isoquinolines; Cyclization; Benzoxazoles; Benzoxazine.
*
Corresponding author. Tel.: C91 44 2235 1269x213; fax: C91 44 2235 2494; e-mail: vtrk28@yahoo.com
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.02.068

4214
A. Senthilvelan et al. / Tetrahedron 61 (2005) 4213–4220
Table 1. Synthesis of tetrahyroisoquinoline-1,3-dione 1a–g under thermal and microwave condition
1
X
R1
R2
R3
R4
Microwave condition
Thermal condition
Time (h) Yield (%)
22 70
Time (min)
Yield (%)
1a
1b
1c
1d
1e
1f
Cl
Cl
Cl
Cl
Cl
Br
Br
H
Cl
H
H
H
H
H
H
H
Cl
H
H
H
H
H
Cl
H
H
H
H
H
H
H
Cl
H
H
25
25
30
30
40
30
35
67
73
58
62
65
78
69
24
23
24
24
24
24
68
62
66
70
75
72
CH3
H
1g
microwave conditions, the synthetic procedure generally
involved impregnating the solid support with homophthalic
acid with the substituted anilines in methylene chloride
solution, evaporating the solvent, and heating the solid
residue in a microwave oven. Preliminary optimization of
reaction conditions was carried out using solid supports like
neutral alumina, anhydrous sodium sulfate, anhydrous
magnesium sulfate and acidic silica gel. Among different
supports tested, the expected isoquinolines 1a–g were
formed in higher yields when acidic silica gel was used
(Scheme 1). Optimal conditions for the synthesis were
found to be 25–40 min reaction time, with a cut-off of the
MW irradiation after every 5 min (to monitor the progress of
the reaction), using microwave irradiation power of 800 W.
No reaction was observed in the absence of MW irradiation
or when the solid support was omitted from the reaction
mixture.
carbonyl group around 1600 cmK1. In the 1H NMR spectra
of compounds 1b and 1g, geminal coupling was observed
for C4-CH2 protons with JZ22.5 Hz around d 4, while for
compounds 1a,c,d,f the J value could not be determined,
because the splitting pattern was not resolved. In the case of
compound 1e, due to the symmetrical substituents in the
N-aryl ring, no geminal coupling of C4-CH2 protons was
observed. The C8-ArH of compounds 1a–h showed doublet
around d 8 due to the deshielding effect of the C1-carbonyl
group. The structure of the compounds 1b,f,h were further
confirmed by XRD analysis.16
2.2. Irradiation studies
An acetonitrile solution (150 mL) of the isoquinoline 1a
(0.3 g, 1.1 mmol), containing 30 mL of aqueous 1 M NaOH,
was flushed with nitrogen for 1 h and irradiated at 254 nm in
an Applied Photophysics multilamp reactor (MLR) for 12 h.
Usual work-up and chromatographic purification furnished
the benzoxazolo[3,2-b]isoquinolin-11-one 2a in 41% yield
(Scheme 3). Similarly, irradiation of compounds 1b–f, in
acetonitrile containing 1 M NaOH in a multilamp reactor for
8–12 h, furnished the corresponding substituted benzoxa-
zolo[3,2-b]isoquinolin-11-ones 2b–f (Table 2). Photolysis
of the bromo analogue 1g also afforded 2a, which was
confirmed by mp, mixture mp and superimposable IR
spectrum with that obtained under the same conditions from
1a.
Under classical thermal conditions using high boiling
solvent such as toluene in the presence of p-toluenesulfonic
acid (PTSA), a much longer reaction time (22–24 h) was
required. In contrast, with microwave irradiation, the time
did not exceed 40 min for completion of the reaction. The
comparative data is shown in Table 1. Likewise, the reaction
of homophthalic acid with 2-chlorobenzylamine in the
presence of p-toluenesulfonic acid required 24 h under
thermal condition, but only 40 min for the solid-supported
MW irradiation condition, to afford the N-(2-chlorobenzyl)-
tetrahydroisoquinoline-1,3-dione 1h (Scheme 2).
The photosubstitution reaction described here has to involve
replacement of the halogen atom present in the N-phenyl
moiety of the isoquinoline-1,3-diones 1a–g by the carbonyl
oxygen (C3-CO) intramolecularly. A dark experiment
The products 1a–h were characterized by spectral and
analytical data. The IR spectra of compounds 1a–h showed
the C3-carbonyl group around 1700 cmK1 and the C1-
Scheme 2.
Scheme 3.

A. Senthilvelan et al. / Tetrahedron 61 (2005) 4213–4220
Table 2. Photolysis of isoquinoline 1a–g to benzoxazolo isoquinoline 2a–f
4215
1
X
R1
R2
R3
R4
Irradiation
time (h)
2
Yield of 2 (%)
1a
1b
1c
1d
1e
1f
Cl
Cl
Cl
Cl
Cl
Br
Br
H
Cl
H
H
H
H
H
H
H
Cl
H
H
H
H
H
Cl
H
H
H
H
H
H
H
Cl
H
H
12
7
8
9
10
7
2a
2b
2c
2d
2e
2f
41
43
48
46
40
52
50
CH3
H
1g
8
2a
(without irradiation) of 1a for 30 h did not produce any
product. Thus the formation of benzoxazolo[3,2-b]iso-
quinolin-11-one is not due to the thermal reaction, but due
to the photoinduced substitution reaction.
detected in the reaction conditions. From these results, it
is viewed that the photosubstitution reaction is more likely
occurring by the intramolecular SN(ET)Ar* mechanism and
not the SN2Ar*mechanism.
In presence of base such as NaOH, the UV–Vis absorption
(lmax) behavior of the isoquinoline 1a in acetonitrile was
changed from 247 to 314 nm. The species at 314 nm is
believed to be the enolate. Thus anionic species are
probably formed in solution, which induces the photo-
substitution. One possible explanation is that the enolate
oxygen intramolecularly displaces the halogen of the
haloarene in the singlet excited state (SN2Ar*).17 Another
possibility is that a radical anion intramolecularly sub-
stitutes the halogen of the haloarene (SN(ET)Ar*).17
The probable mechanistic pathway is described in Scheme 5.
The light absorption of enolate anion populates the
intramolecular charge transfer (CT) singlet excited state,
which produces a cyclohexadienyl anion radical by
intramolecular addition of the oxygen radical of the enolate
to the anionic halophenyl moiety in the charge transfer
excited state, which in turn yields the benzoxazolo[3,2-
b]isoquinoline 2 by the ejection of the halide ion.
A similar intramolecular electron-transfer mechanism has
been proposed for 2-(pyridinyl)benzoxazoles.18 The intra-
molecular electron transfer mechanism for the formation of
benzothiazoles from the photoreaction of o-halothio-
acetanilide, by observing the Cl%2K anion radical at
lmaxw345 nm in laser flash and steady state experiments
has been proposed for the first time from our
laboratory.12
The photosubstitution reactivity depends on the leaving
ability of the halide ion. Bromoanalogue 1g is more
reactive, which is reflected in the formation of the
photosubstituted product 2a in higher yield and in a shorter
reaction time compared to the chloro analogue 1a (Table 2).
Thus the rate-determining step of the reaction is the leaving
halide anion. Moreover, if the SN2Ar* mechanism is
operative, a phenolic-type product could be formed from
intermolecular substitution of the halide ion with the
hydroxyl group (Scheme 4). Such a product was not
The structure of photoproducts 2a–f were consistent with
the spectroscopic data. The IR spectra showed the
disappearance of the C3-CO group of isoquinoline 1a–g
around 1700 cmK1. It showed the C11-CO group around
1650 cmK1. The 1H NMR spectra showed the C6-CH proton
of 2a–f around d 6.5, which indicates the disappearance of
the C4–CH2 proton of isoquinolines 1a–g. The 13C NMR
spectra also confirmed the presence of C6-CH carbon and
C11-CO carbon, which appear around d 82 and d 159,
respectively. Furthermore, the structure of compound 2c
was confirmed by XRD.19
Scheme 4.
Scheme 5.

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A. Senthilvelan et al. / Tetrahedron 61 (2005) 4213–4220
Scheme 6.
2.3. Irradiation of the isoquinoline 1h
3. Conclusions
The irradiation of isoquinoline-1,3-dione 1h (1.0 mmol) for
15 h in acetonitrile containing 1 M NaOH (30 mL) was
carried out (after flushing with nitrogen for 1 h) in a
multilamp reactor (254 nm). After completion of the
reaction, usual work-up and chromatographic separation
afforded the hydrolysed N-(2-chlorobenzyl)-2-methyl-
benzamide 3 (Scheme 6) instead of the expected
isoquinolinobenzoxazine.
The tetrahydroisoquinoline-1,3-diones 1a–h were syn-
thesized in comparable yield, under solid supported
solvent-free microwave conditions in shorter reaction time
(!1 h) compared to the classical thermal conditions.
Irradiation of tetrahydroisoquinoline 1a–g under base
mediated conditions (CH3CN/1 M NaOH) in a multilamp
reactor (MLR) afforded the respective benzoxazolo[3,2-
b]isoquinolin-11-one 2a–f in good yield. Photolysis of
isoquinoline 1h in CH3CN/1 M NaOH using a multilamp
reactor furnished the hydrolysed N-(2-chlorobenzyl)-2-
methylbenzamide 3, whereas irradiation at higher basic
conditions such as acetonitile containing 3 M NaOH
afforded the expected product isoquinolino[3,2-b][1,3]-
benzoxazin-11-one 4.
The hydrolysis product 3 was confirmed by spectroscopic
and analytical data. The IR spectrum of compound 3 showed
–NH peak at 3296 cmK1 and carbonyl peak at 1641 cmK1
.
The 1H NMR spectrum showed the –CH3 protons at d 2.41,
–CH2 protons at d 4.68 as a doublet with coupling constant
JZ6 Hz and –NH proton at d 6.25 as a broad singlet. The
13C NMR of the compound 3 indicated the presence of
–CH3 carbon at d 19.7, –CH2 carbon at d 41.8 and CO
carbon at d 169.8. Furthermore, the compound 3 was
confirmed by mp, mixture mp and superimposable IR
spectra with the authentic sample prepared from 2-methyl
benzoylchloride and 2-chlorobenzylamine in dry benzene.
4. Experimental
4.1. General
All the melting points are uncorrected. UV spectra were
recorded with Shimadzu 1601 spectrophotometer. IR
spectra were recorded on Shimadzu FTIR-8300 spectro-
The formation of hydrolysis product is probably due to
ineffective population of the enolate of 1h in 1 M NaOH and
the molecular flexibility of the N-benzyl substituent, which
causes the base mediated hydrolysis followed by photo-
decarboxylation of 1h to 3. Light induced decarboxylation
of (o-acylphenyl)acetic acids has been reported.20
1
photometer. H and 13C NMR spectra were recorded with
Brucker-DPX 200 (200 MHz) and Jeol-GSX 400
(400 MHz) instruments with TMS as internal standard
(chemical shift in d ppm). The mass spectra were recorded
with Jeol-JMS-DX 303 HF (EI, 70 eV) and GCMS QP 5000
Shimadzu instruments. Chromatographic separations were
done using silica gel (ACME sample). Thin layer chroma-
tography (TLC) was performed using glass plates coated
with silica gel (ACME sample) of 0.25 mm thickness. Spots
were visualized using iodine vapour. The photochemical
reactions were carried out in quartz vessel of different
capacity in Applied Photophysics multilamp reactor
(254 nm, 12 lamps). Microwave reactions were carried out
in Kenstar-India microwave oven (800 W).
In order to effect the photosubstitution reaction, we carried
out the photolysis of 1h under higher basic conditions.
Hence, irradiation of 1h (1.0 mmol) in acetonitrile contain-
ing 3 M NaOH (30 mL) was carried out for 12 h (after
flushing with nitrogen for 1 h) in a multilamp reactor. The
expected product isoquinolino[3,2-b][1,3]benzoxazin-11-
one 4 was isolated.
The compound 4 was confirmed by spectroscopic and
analytical data. The IR spectrum of 4 shows the dis-
appearance of C3-CO group of 1h and shows the C11-CO
4.2. General procedure for the synthesis of substituted
tetrahydroisoquinoline-1,3-diones 1a–h
1
group at 1689 cmK1. The H NMR spectrum of 4 showed
the C13-CH2 proton at d 5.16, the C6-CH proton at d 6.21 and
the C4-aromatic proton at d 8.33 as a doublet with coupling
constant JZ7.8 Hz. The remaining seven aromatic protons
appeared as a multiplet at d 7.12–7.60. The 13C NMR also
indicated the C13-CH2 carbon at d 40.7, the C6-CH carbon at
d 87.8 and the C11-CO carbon at d 161.9.
The tetrahydroisoquinolines were synthesized from the
corresponding homophthalic acid and substituted anilines
and benzylamine by a direct one-step procedure under
thermal and solvent-free solid supported microwave
conditions.

A. Senthilvelan et al. / Tetrahedron 61 (2005) 4213–4220
4217
(i) Thermal conditions. A mixture of homophthalic acid
(1 equiv), substituted amine (1 equiv) and p-toluenesulfonic
acid (catalytic amount) was refluxed in dry toluene using a
Dean–Stark apparatus for 22–24 h. After completion of the
reaction, monitored by TLC, the reaction mixture was
cooled to room temperature, extracted with ethyl acetate and
the organic layer washed with H2O, dil. HCl and dil.
NaHCO3. The ethyl acetate layer was dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The solid
obtained was filtered and recrystallized from ethyl acetate–
hexane mixture, to furnish the corresponding tetrahydro-
isoquinoline-1,3-dione 1a–h in good yield.
acid in dry toluene (120 mL) was refluxed for 24 h. After
completion of the reaction, usual work-up furnished 1b.
Yield: 2.87 g (68%); mp 198–200 8C; UV: 242 nm
(CH3CN); IR (KBr): 1728 (C3-CO), 1679 (C1-CO) cmK1
;
1H NMR (CDCl3, 400 MHz): d 4.20 (d, JZ22.5 Hz, 1H, C4-
Ha), 4.28 (d, JZ22.5 Hz, 1H, C4-Hb), 7.18–7.68 (m, 6H,
Ar–H), 8.24 (d, JZ7.8 Hz, 1H, C8-H); 13C NMR (CDCl3,
100 MHz): d 36.8, 124.9, 127.4, 127.7, 127.9, 128.6, 129.5,
131.0, 131.7, 134.1, 134.1, 134.3, 134.8, 164.1 (C1-CO),
168.9 (C3-CO). MS: m/z (%): (305 (MC), 307-trace), 270
(100) [272 (33)], 269 (2), 242 (46) [244 (15)], 214 [216],
213 [215], 152 [154], 118 (15), 117 (4), 104 (2), 90 (58), 89
(58), 63 (16).The structure of the compound was further
confirmed by XRD.16
(ii) Microwave conditions. A thoroughly ground mixture of
homophthalic acid (1 equiv) and acidic silica gel (3–5 g)
was mixed with a methylene chloride solution of substituted
amine (1 equiv). The solvent was removed under reduced
pressure; the solid residue was placed in a (Kenstar-India)
microwave oven (800 W), irradiated for 5 min, cooled, and
again irradiated for 5 min. The procedure was continued for
a total MW irradiation time of 25–40 min. After completion
of the reaction, checked by TLC, it was cooled to room
temperature. The mixture was extracted with ethyl acetate
and filtered. The filtrate was washed with water, dil. HCl,
and dil. NaHCO3, dried over anhydrous Na2SO4 and
concentrated. The solid obtained was filtered and
recrystallized from ethyl acetate–hexane mixture. The
isoquinolines thus formed were compared by mp, mixture
mp and superimposable IR spectra with 1a–h obtained
under thermal conditions.
A mixture of homophthalic acid (0.3 g, 1.6 mmol), 2,3-
dichloroaniline (0.27 g, 1.6 mmol) and acidic silica gel (3 g)
was heated in the microwave oven for 25 min. Usual work-
up afforded 1b (yieldZ73%).
4.2.3. N-(2,4-Dichlorophenyl)-1,2,3,4-tetrahydroiso-
quinoline-1,3-dione 1c. A mixture of homophthalic acid
(4 g, 22.2 mmol), 2,4-dichloroaniline (3.6 g, 22.2 mmol)
and p-toluenesulfonic acid in dry toluene (150 mL) was
refluxed for 23 h; the usual work-up afforded 1c. Yield:
4.21 g (62%); mp 160–162 8C; UV: 240 nm (CH3CN); IR
(KBr): 1732 (C3-CO), 1678 (C1-CO) cmK1 1H NMR
;
(CDCl3, 200 MHz): d 4.20 (bs, 2H, C4-CH2), 7.16K7.68
(m, 6H, Ar–H), 8.22 (d, JZ7.8 Hz, 1H, C8-H). 13C NMR
(CDCl3, 50 MHz): d 36.8, 124.9, 127.5, 128.0, 128.1, 129.5,
130.2, 131.3, 131.9, 133.6, 134.2, 134.3, 135.5, 164.1 (C1-
CO), 169.0 (C3-CO). MS: m/z (%): (305 (MC), 307-trace),
270 (100) [272 (33)], 269 (2), 242 (46) [244 (14)], 214
[216], 213 [215], 152 [154], 118 (14), 117 (5), 104 (4), 90
(60), 89 (60), 63 (20). Anal. Calcd for C15H9NO2Cl2
(306.143): C, 58.84; H, 2.96; N, 4.57. Found: C, 58.62; H,
3.11; N, 4.72.
4.2.1. N-(2-Chlorophenyl)-1,2,3,4-tetrahydroisoquino-
line-1,3-dione 1a. A mixture of homophthalic acid
(1 g, 5.0 mmol), o-chloroaniline (0.7 g, 5.0 mmol) and
p-toluenesulfonic acid (catalytic amount) in toluene
(50 mL) was refluxed using a Dean–Stark apparatus for
22 h. After completion of the reaction, usual work-up as
mentioned above furnished 1a. Yield: 1.05 g (70%); mp
110–112 8C; UV 246 nm (CH3CN); IR (KBr): 1720 (C3-
CO), 1679 (C1-CO) cmK1; 1H NMR (CDCl3, 200 MHz): d
4.28 (bs, 2H, C4-CH2), 7.23–7.67 (m, 7H, Ar–H), 8.24 (d,
JZ7.7 Hz, 1H, C8-H). 13C NMR (CDCl3, 50 MHz): d 36.8,
125.1, 127.5, 127.8, 127.9, 129.5, 130.2, 130.4, 132.7,
133.2, 134.1, 134.2, 164.3 (C1-CO), 169.1 (C3-CO). MS:
m/z (%): (271 (MC), 273-trace), 236 (100), 235 (3), 208
(38), 180 (5), 179 (4), 118 (12), 117 (6), 104 (6), 90 (37), 89
(32), 63 (12). Anal. Calcd for C15H10NO2Cl (271.698): C,
66.30; H, 3.70; N, 5.15; Found: C, 66.52; H, 3.51; N, 5.40.
Microwave irradiation of a mixture of homophthalic acid
(0.4 g, 2.2 mmol), 2,4-dichloroaniline (0.36 g, 2.2 mmol)
and acidic silica gel (4 g) for 30 min furnished 1c (yieldZ
58%), after usual work-up.
4.2.4. N-(2,5-Dichlorophenyl)-1,2,3,4-tetrahydroiso-
quinoline-1,3-dione 1d. Refluxing a mixture of homo-
phthalic acid (4 g, 22.2 mmol), 2,5-dichloroaniline (3.6 g,
22.2 mmol) and p-toluenesulfonic acid in dry toluene
(150 mL) for 24 h, followed by usual work-up furnished
1d. Yield: 4.48 g (66%); mp 158–160 8C; UV: 240 nm
(CH3CN); IR (KBr): 1728 (C3-CO), 1679 (C1-CO) cmK1
;
A mixture of homophthalic acid (0.3 g, 1.6 mmol),
o-chloroaniline (0.21 g, 1.6 mmol) and acidic silica gel
(3 g) was irradiated in the microwave oven for 25 min. After
completion of the reaction, usual work up as mentioned
above afforded 1a (yieldZ67%). Refluxing a mixture of
homophthalic anhydride (1 g, 6.2 mmol), o-chloroaniline
(0.78 g, 6.2 mmol) and p-toluenesulfonic acid in dry toluene
(100 mL) using a Dean–Stark apparatus for 24 h, followed
by usual work up, afforded 1a (yieldZ0.33 g, 20%).
1H NMR (CDCl3, 200 MHz): d 4.23 (bs, 2H, C4-CH2),
7.27–7.70 (m, 6H, Ar–H), 8.23 (dd, JZ7.8, 1.1 Hz, 1H, C8-
H). 13C NMR (CDCl3, 50 MHz): d 37.2, 125.3, 127.9,
128.5, 130.0, 130.5, 130.8, 131.1, 131.4, 131.7, 133.6,
134.6, 134.8, 164.5 (C1-CO), 169.3 (C3-CO). MS: m/z (%):
(305 (MC), 307-trace), 270 (100) [272 (33)], 269 (2), 242
(32) [244 (10)], 214 [216], 213 [215], 152 [154], 118 (9),
117 (6), 104 (2), 90 (30), 89 (28), 63 (8). Anal. Calcd for
C15H9NO2Cl2 (306.143): C, 58.84; H, 2.96; N, 4.57. Found:
C, 58.63; H, 3.13; N, 4.68.
4.2.2. N-(2,3-Dichlorophenyl)-1,2,3,4-tetrahydroiso-
quinoline-1,3-dione 1b. Following the general procedure,
a mixture of homophthalic acid (2.5 g, 13.8 mmol), 2,3-
dichloroaniline (2.25 g, 13.8 mmol) and p-toluenesulfonic
A mixture of homophthalic acid (0.3 g, 1.6 mmol), 2,5-
dichloroaniline (0.27 g, 1.6 mmol) and acidic silica gel (3 g)

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A. Senthilvelan et al. / Tetrahedron 61 (2005) 4213–4220
was heated in the microwave oven for 30 min. After
completion of the reaction, usual work-up afforded 1d
(yieldZ62%).
trace), 236 (100), 235 (2), 208 (48), 180 (6), 179 (4), 118
(12), 117 (2), 104 (8), 90 (38), 89 (33), 63 (10). Anal. Calcd
for C15H10NO2Br (316.15): C, 56.98; H, 3.18; N, 4.43.
Found: C, 56.77; H, 3.29; N, 4.58.
4.2.5. N-(2,6-Dichlorophenyl)-1,2,3,4-tetrahydroiso-
quinoline-1,3-dione 1e. A toluene (150 mL) solution of
homophthalic acid (4 g, 22.2 mmol), 2,6-dichloro aniline
(3.6 g, 22.2 mmol) and p-toluenesulfonic acid was refluxed
for 24 h; usual work-up afforded 1e. Yield: 4.75 g (70%);
mp 170–172 8C; UV: 244 nm (CH3CN); IR (KBr): 1720
Microwave irradiation of a mixture of homophthalic acid
(0.4 g, 2.2 mmol) and 2-bromoaniline (0.38 g, 2.2 mmol) in
acidic silica gel (4 g) for 35 min, furnished 1g (yieldZ
69%).
(C3-CO), 1674 (C1-CO) cmK1
;
1H NMR (CDCl3,
4.2.8. N-(2-Chlorobenzyl)-1,2,3,4-tetrahydroisoquino-
line-1,3-dione 1h. Following the general procedure, a
mixture of homophthalic acid (3 g, 16.6 mmol), 2-chloro-
benzylamine (2.35 g, 16.6 mmol) and p-toluenesulfonic
acid was refluxed in dry toluene (120 mL) for 24 h. After
completion of the reaction, usual work- up furnished 1h.
Yield: 3.36 g (71%); mp 122–124 8C; UV: 244 nm
200 MHz): d 4.24 (s, 2H, C4-CH2), 7.27–7.68 (m, 6H, Ar–
H), 8.26 (d, JZ7.8 Hz, 1H, C8-H).13C NMR (CDCl3,
50 MHz): d 37.2, 125.3, 128.0, 128.4, 129.0, 130.0, 130.6,
131.0, 134.8, 135.0, 134.8, 164.5 (C1-CO), 168.8 (C3-CO).
MS: m/z (%): (305 (MC), 307-trace), 270 (100) [272 (33)],
242 (38) 213 [215], 152 [154], 118 (25), 117 (4), 104 (2), 90
(68), 63 (30). Anal. Calcd for C15H9NO2Cl2 (306.14): C,
58.84; H, 2.96; N, 4.57. Found: C, 58.72; H, 3.17; N, 4.77.
(CH3CN); IR (KBr): 1718 (C3-CO), 1670 (C1-CO) cmK1
;
1H NMR (CDCl3, 200 MHz): d 4.18 (s, 2H, C4-CH2), 5.28
(s, 2H, N–CH2), 7.02–7.64 (m, 7H, Ar–H), 8.20 (d, JZ
7.7 Hz, 1H, C8-H). 13C NMR (CDCl3, 50 MHz): d 36.5,
41.3, 125.1, 126.8, 127.2, 127.3, 127.9, 128.3, 129.4, 129.6,
133.0, 133.9, 134.0, 134.1, 164.7 (C1-CO), 169.8 (C3-CO).
MS: m/z (%): (285 (MC), 287-trace), 250 (100), 249 (1),
222 (13), 194 (2), 166 (4), 132 (2), 125 (6), 118 (12), 104
(3), 90 (20), 89 (22), 63 (2). Anal. Calcd for C16H12NO2Cl
(285.725): C, 67.25; H, 4.23; N, 4.90. Found: C, 67.17; H,
4.42; N, 5.12. Further the compound was confirmed by
XRD.16
A mixture of homophthalic acid (0.4 g, 2.2 mmol), 2,3-
dichloroaniline (0.36 g, 2.2 mmol) and acidic silica gel (4 g)
was heated in the microwave oven for 40 min; usual work-
up afforded 1e (yieldZ65%).
4.2.6. N-(2-Bromo-4-methylphenyl)-1,2,3,4-tetrahydro-
isoquinoline-1,3-dione 1f. Following the general
procedure,
a mixture of homophthalic acid (4 g,
22.2 mmol), 2-bromo-4-methylaniline (4.13 g, 22.2 mmol)
and p-toluenesulfonic acid in dry toluene (150 mL) was
refluxed for 24 h. After completion of the reaction, usual
work-up furnished 1f. Yield: 5.47 g (75%); mp 162–164 8C;
UV: 245 nm (CH3CN); IR (KBr): 1722 (C3-CO), 1679 (C1-
Heating a mixture of homophthalic acid (0.5 g, 2.7 mmol),
2-chlorobenzylamine (0.38 g, 2.7 mmol) and acidic silica
gel (5 g) in microwave oven for 40 min, followed by usual
work-up furnished 1h (yieldZ65%).
1
CO) cmK1; H NMR (CDCl3, 200 MHz): d 2.36 (bs, 3H,
CH3), 4.18 (s, 2H, C4-CH2), 7.09–7.63 (m,6H, Ar–H), 8.21
(d, JZ7.7 Hz, 1H, C8-H). 13C NMR (CDCl3, 50 MHz): d
21.5, 37.4, 123.0, 125.7, 128.0, 128.3, 129.8, 129.9, 130.4,
132.6, 134.3, 134.6, 134.8, 141.4, 164.8 (C1-CO), 169.7
(C3-CO). MS: m/z (%): (329 (MC), 331-trace), 250 (100),
249 (2), 222 (42), 194 (2), 193 (2), 132 (10), 118 (8), 117
(3), 104 (5), 90 (40), 89 (39), 63 (12). Anal. Calcd for
C16H12NO2Br (330.176): C, 58.20; H, 3.66; N, 4.24. Found:
C, 58.46; H, 3.57; N, 4.42. Further the structure was
confirmed by XRD.16
4.3. Irradiation of the tetrahydroisoquinolines 1a–g
4.3.1. Benzoxazolo[3,2-b]isoquinolin-11-one 2a. An
acetonitrile solution (150 mL) of N-(2-chlorophenyl)-
1,2,3,4-tetrahydroisoquinoline-1,3-dione 1a (0.3 g,
1.1 mmol) containing 30 mL of aqueous 1 M NaOH was
flushed with nitrogen for 1 h and irradiated at 254 nm in an
Applied Photophysics multilamp reactor for 12 h. The
reaction was monitored by TLC until the disappearance of
the starting material. After completion of the reaction, the
solvent was evaporated under reduced pressure from the
two-phase mixture and it was extracted with ethyl acetate.
The ethyl acetate layer was separated, the aqueous layer was
neutralized with dil. HCl, and then was extracted with ethyl
acetate. The ethyl acetate portions were combined together,
dried over anhydrous Na2SO4, and concentrated. The
residue was chromatographed over a column of silica gel;
elution with ethyl acetate-petroleum ether (15:85) furnished
the respective benzoxazolo[3.2-b]isoquinolin-11-one 2a. It
was recrystallized from ethyl acetate-hexane mixture.
Yield: 0.106 g (41%); mp 200–202 8C (lit.21 mp 204–
206 8C); UV: 234 nm (CH3OH); IR (KBr): 1685, 1625,
Heating a mixture of homophthalic acid (0.5 g, 2.7 mmol),
2-bromo-4-methylaniline (0.52 g, 2.7 mmol) and acidic
silica gel (5 g) in microwave oven for 30 min, followed by
usual work-up furnished 1f (yieldZ78%).
4.2.7. N-(2-Bromophenyl)-1,2,3,4-tetrahydroisoquino-
line-1,3-dione 1g. A mixture of homophthalic acid (3 g,
16.6 mmol), 2-bromoaniline (2.86 g, 16.6 mmol) and
p-toluenesulfonic acid in dry toluene (120 mL) was refluxed
for 24 h. After completion of the reaction, usual work-up
afforded 1g. Yield: 3.76 g (72%); mp 126–128 8C; UV:
242 nm (CH3CN); IR (KBr): 1712 (C3-CO), 1676 (C1-CO)
cmK1; 1H NMR (CDCl3, 400 MHz): d 4.19 (d, JZ22.5 Hz,
1H, C4-Ha), 4.28 (d, JZ22.5 Hz, 1H, C4-Hb), 7.25K7.73
(m, 7H, Ar–H), 8.24 (d, JZ7.3 Hz,1H,C8-H). 13C NMR
(CDCl3, 100 MHz): d 36.8, 122.8, 125.1, 127.4, 127.9,
128.4, 129.5, 130.3, 130.4, 133.3, 134.1, 134.2, 134.8, 164.2
(C1-CO), 169.1 (C3-CO). MS: m/z (%): (315 (MC), 317-
1
1606, 1473 cmK1; H NMR (CDCl3, 200 MHz): d 6.45 (s,
1H, C6-CH), 7.19–7.51 (m, 4H, ArH), 7.51–7.85 (m, 2H,
ArH), 8.29–8.75 (m, 2H, ArH). 13C NMR (CDCl3,
50 MHz): d 81.9 (C6-CH), 109.9, 116.4, 119.6, 121.5,
124.2, 124.3, 125.9, 126.2, 127.8, 132.8, 137.7, 147.2,
149.9, 159.3 (C11-CO). MS: m/z (%): 235 (MC, 100), 234

A. Senthilvelan et al. / Tetrahedron 61 (2005) 4213–4220
4219
(12), 207 (6), 206 (5), 179 (2), 178 (6), 177 (2), 151 (5), 125
(2), 117.5 (MCC), 115 (2), 101 (2), 89 (12).
4.3.5. 1-Chlorobenzoxazolo [3,2-b] isoquinolin-11-one 2e.
The irradiation of N-(2,6-dichlorophenyl)-1,2,3,4-tetra-
hydroisoquinoline-1,3-dione 1e (0.3 g, 1.0 mmol) in aceto-
nitrile (150 mL) containing 1 M NaOH (30 mL) for 10 h,
using multilamp reactor, followed by usual work-up as
mentioned above and chromatographic separation,
furnished 2e.Yield: 0.108 g (40%); mp 183–185 8C; UV:
Irradiation of N-(2-bromophenyl)-1,2,3,4-tetrahydroiso-
quinoline-1,3-dione 1g (0.3 g, 3.1 mmol) in acetonitrile
(150 mL) containing 1 M NaOH (30 mL) for 8 h, using
multilamp reactor (MLR), followed by usual work-up and
chromatographic separation, afforded 2a (yieldZ50%),
which was confirmed by mp, mixture mp and super-
imposable IR with that obtained under the same conditions
from 1a.
240 nm (CH3OH); IR (KBr): 1680, 1641, 1600, 1468 cmK1
;
1H NMR (CDCl3, 400 MHz): d 6.37 (s, 1H, C6-CH), 7.26–
7.67 (m, 4H, ArH), 7.82–8.00 (m, 2H, ArH), 8.46–8.54 (m,
1H, ArH). 13C NMR (CDCl3, 100 MHz): d 81.6 (C6-CH),
108.6, 124.1, 124.7, 125.3, 126.9, 127.5, 128.5, 128.6,
131.5, 133.1, 134.6, 137.0, 150.0, 159.9 (C11-CO). MS: m/z
(%): 269 (MC, 100), 271 (MC2, 33), 241 (16) [243 (6)],
234 (25), 213 (5) [215 (2)], 206 (18), 178 (25), 177 (16), 151
(10), 134.5 (MCC, 6), 125 (3), 115 (4), 101 (8), 89 (28).
Anal. Calcd for C15H8NO2Cl (269.68): C, 66.80; H, 2.98; N,
5.19. Found: C, 66.57; H, 3.17; N, 5.39.
4.3.2. 4-Chlorobenzoxazolo[3,2-b]isoquinolin-11-one 2b.
Irradiation of N-(2,3-dichlorophenyl)-1,2,3,4-tetrahydro-
isoquinoline-1,3-dione 1b (0.3 g, 1.0 mmol) in acetonitrile
(150 mL) containing 1 M NaOH (30 mL) for 7 h, using
multilamp reactor, followed by usual work-up as mentioned
above and chromatographic separation, furnished 2b.Yield:
0.113 g (43%); mp 188–190 8C; UV: 242 nm (CH3OH); IR
1
(KBr): 1678, 1642, 1604, 1468 cmK1; H NMR (CDCl3,
4.3.6. 3-Methylbenzoxazolo[3,2-b]isoquinolin-11-one 2f.
The compound 2f was obtained on irradiation of N-(2-
bromo-4-methylphenyl)-1,2,3,4-tetrahydroisoquinoline-
1,3-dione 1f (0.3 g, 0.9 mmol) in acetonitrile (150 mL)
containing 1 M NaOH (30 mL) for 7 h. Yield: 0.12 g (52%);
mp 200–202 8C; UV: 236 nm (CH3OH); IR (KBr): 1687,
400 MHz): d 6.54 (s, 1H, C6-CH), 7.26–7.88 (m, 5H, ArH),
8.42–8.50 (m, 2H, ArH); 13C NMR (CDCl3, 100 MHz): d
82.6 (C6-CH), 114.7, 115.4, 122.2, 124.9, 125.1, 126.5,
128.5, 129.1, 130.1, 133.2, 137.4, 146.1, 149.5, 159.2 (C11-
CO). MS: m/z (%): 269 (MC, 100), 271 (MC2, 30), 241
(15) [243 (6)], 234 (9), 213 (5) [215 (2)], 206 (22), 178 (30),
177 (17), 151 (8), 134.5 (MCC, 5), 125 (3), 115 (9), 101 (5),
89 (15). Anal. Calcd for C15H8NO2Cl (269.68): C, 66.80; H,
2.98; N, 5.19. Found: C, 66.67; H, 3.21; N, 5.37.
1
1641, 1601, 1464 cmK1; H NMR (CDCl3, 200 MHz): d
2.43 (s, 3H, CH3), 6.38 (s, 1H, C6-CH), 7.08–7.64 (m, 5H,
ArH), 8.34 (d, JZ8 Hz, 1H, C2-ArH), 8.45 (d, JZ8 Hz, 1H,
C1-ArH). 13C NMR (CDCl3, 50 MHz): d 22.1 (CH3), 82.2
(C6-CH), 110.8, 116.3, 121.9, 124.7, 125.1, 126.3, 128.1,
133.0, 137.1, 138.1, 147.8, 150.5, 159.5 (C11-CO). MS: m/z
(%): 249 (MC, 100), 221 (8), 220 (9), 193 (7), 192 (12), 178
(3), 177 (2), 165 (8), 151 (13), 125 (5), 124.5 (MCC), 115
(6), 101 (4), 89 (13). Anal. Calcd for C16H11NO2 (249.26):
C, 77.09; H, 4.44; N, 5.61. Found: C, 76.92; H, 4.33; N,
5.82.
4.3.3. 3-Chlorobenzoxazolo [3,2-b] isoquinolin-11-one 2c.
The compound 2c was obtained on irradiation of N-(2,4-
dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,3-dione
1c (0.3 g, 1.0 mmol) in acetonitrile (150 mL) containing
1 M NaOH (30 mL) for 8 h, using multilamp reactor. Yield:
0.126 g (48%); mp 205–207 8C; UV: 243 nm (CH3OH); IR
1
(KBr): 1683, 1643, 1606, 1475 cmK1; H NMR (CDCl3,
4.4. Irradiation of N-(2-chlorobenzyl)-1,2,3,4-tetra-
hydroisoquinoline-1,3-dione 1h
400 MHz): d 6.47 (s, 1H, C6-CH), 7.32–7.69 (m, 5H, ArH),
8.44 (d, JZ8.3 Hz, 1H, C1-ArH), 8.48 (d, JZ8.3 Hz, 1H,
C2-ArH). 13C NMR (CDCl3, 100 MHz): d 82.3 (C6-CH),
110.8, 116.7, 121.9, 124.4, 124.8, 126.1, 126.8, 127.8,
131.9, 133.0, 137.8, 147.8, 150.0, 159.5 (C11-CO). MS: m/z
(%): 269 (MC, 100), 271 (MC2, 36), 241 (8) [243 (3)], 234
(9), 213 (6) [215 (2)], 206 (22), 178 (16), 177 (8), 151 (8),
134.5 (MCC, 8), 125 (2), 115 (3), 101 (8), 89 (10). The
structure of the compound was further confirmed by XRD.19
4.4.1. N-(2-Chlorobenzyl)-2-methylbenzamide 3. The
irradiation of 1h (0.3 g, 1.0 mmol) in acetonitrile
(150 mL) containing 1 M NaOH (30 mL) was carried out
(after flushing with nitrogen for 1 h) for 15 h in a multilamp
reactor (254 nm). The completion of the reaction was
checked by TLC; usual work-up and chromatographic
separation using ethyl acetate-hexane mixture (1:9) afforded
N-(2-chlorobenzyl)-2-methylbenzamide 3 (yield: 0.18 g,
69%; mp 100–102 8C).
4.3.4. 2-Chlorobenzoxazolo [3,2-b] isoquinolin-11-one
2d. Irradiation of an acetonitrile (150 mL) solution of
N-(2,5-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1,3-
dione 1d (0.3 g, 1.0 mmol) containing 1 M NaOH (30 mL)
using multilamp reactor for 9 h, followed by usual work-up
and chromatographic separation, afforded 2d.Yield: 0.121 g
(46%); mp 213–215 8C (lit.21 mp 211–212 8C); UV: 242 nm
Further, the compound 3 was confirmed with the authentic
sample by mp, mixture mp and superimposable IR. The
authentic sample was prepared by the addition of a benzene
solution of 2-methylbenzoyl chloride (1.5 g, 9.7 mmol) to
2-chlorobenzyl amine (1.37 g, 9.7 mmol) in benzene
(40 mL) containing a few drops of pyridine (yieldZ1.6 g,
67%).
1
(CH3OH); IR (KBr): 1684, 1632, 1608, 1463 cmK1; H
NMR (CDCl3, 400 MHz): d 6.41 (s, 1H, C6-CH), 7.24–7.66
(m, 5H, ArH), 8.44 (d, JZ8.8 Hz, 1H, C4-ArH), 8.51 (d, JZ
2.0 Hz, 1H, C1-ArH). 13C NMR (CDCl3, 100 MHz): d 82.5
(C6-CH), 110.8, 116.9, 121.6, 125.0, 126.3, 128.1, 128.9,
129.8, 133.3, 137.8, 146.0, 150.2, 159.3 (C11-CO). MS: m/z
(%): 269 (MC, 100), 271 (MC2, 34), 241 (12) [243 (4)],
234 (4), 213 (6) [215 (2)], 206 (20), 178 (30), 177 (16), 151
(14), 134.5 (MCC, 6), 125 (6), 115 (5), 101 (6), 89 (24).
4.4.2. Isoquinolino[3,2-b[[1,3]benzoxazin-11-one 4.
Irradiation of 0.3 g (1.0 mmol) of 1h in acetonitrile
containing 3 M NaOH (30 mL) was carried out for 12 h
(after flushing with nitrogen for 1 h) in a multlamp reactor.
After completion of the reaction (checked by TLC),

4220
A. Senthilvelan et al. / Tetrahedron 61 (2005) 4213–4220
60, 131. (b) Petra, S.; Katja, T.; Danijel, K. Tetrahedron 2003,
59, 7123.
followed by usual work-up, the column chromatographic
separation using petroleum ether-ethyl acetate (4:1) as
eluant, afforded 4 (yield: 0.12 g, 47%; mp 210–212 8C). The
spectral data of compounds 3 and 4 were reported earlier.13
9. Varma, R. S. Green Chem. 1999, 43–55.
10. Paramasivam, R.; Palaniappan, P.; Ramakrishnan, V. T.
J. Chem. Soc., Perkin Trans. 1 1979, 260.
11. Jayanthi, G.; Muthusamy, S.; Ramakrishnan, V. T.
J. Photochem. Photobiol. 1998, 116, 103.
Acknowledgements
12. Jayanthi, G.; Muthusamy, S.; Ramakrishnan, V. T.;
Ramasamy, N. K.; Ramamurthy, P. J. Org. Chem. 1997, 62,
5766.
We wish to thank the University Grants Commission-
Special Assistance Program for financial assistance to the
Department of Organic Chemistry and CSIR, New Delhi,
India for providing research fellowship (A. S. V.).
13. Senthilvelan, A.; Ramakrishnan, V. T. Tetrahedron Lett. 2002,
43, 5119–5121.
14. Senthilvelan, A.; Thirumalai, D.; Ramakrishnan, V. T.
Tetrahedron 2004, 60, 851–860.
15. Senthilvelan, A.; Ramakrishnan, V. T. Tetrahedron Lett. 2002,
43, 8379–8381.
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