A novel synthesis of 1-substituted 2H-isoquinolin-3-ones

Article abstract of DOI:10.1002/jhet.5570410620

The intramolecular cyclization of 2-acylphenylacetonitriles 1 under strongly acidic conditions easily affords 1-substituted 2H-isoquinolin-3-ones 2 in excellent yields.

Full text of DOI:10.1002/jhet.5570410620

Nov-Dec 2004
979
A Novel Synthesis of 1-Substituted 2H-Isoquinolin-3-ones
Alicia S. Cánepa, Rodolfo D. Bravo*
Laboratorio de Estudio de Compuestos Orgánicos, Departamento de Química, Facultad de Ciencias Exactas,
Universidad Nacional de La Plata, Calle 47 y 115, 1900-La Plata, ARGENTINA
E-mail: rdb@exactas.unlp.edu.ar
Received March 1, 2004
The intramolecular cyclization of 2-acylphenylacetonitriles 1 under strongly acidic conditions easily
affords 1-substituted 2H-isoquinolin-3-ones 2 in excellent yields.
J. Heterocyclic Chem., 41, 979 (2004).
2H-Isoquinolin-3-ones are substances with interest due
to their pharmacological properties. For example 1-alkyl-
4-substituted derivatives were investigated and discussed
in connection with their cardiotonic and renal vasodilating
effects [1-3].
anthracene-2,7-diones in good yields [16].
The starting 2-acylphenylacetonitriles (1a-1f) were
obtained by reaction of 2-cyanomethylbenzoyl chloride
and Grignard reagents in the presence of cuprous iodide at
–5 ºC as previously described by us [18]. Compound 1g
was prepared from 4-chloro-2-methylbenzoic acid [19] via
formation of 4-chloro-2-methylbenzophenone (3) by
Friedel Crafts direct acylation with benzene [20].
Subsequent benzylic bromination with 1,3-dibromo-5,5-
dimethylhydantoin (DBH) and cyanation of the haloderiv-
ative afforded 2-benzoyl-5-chloro-phenylacetonitrile (1g).
For the preparation of 2H-isoquinolin-3-ones (2), the
keto nitrile 1 was stirred with the catalyst in 1,2-dichloro-
ethane for 3-6 h to give the product 2. We investigated the
synthesis of 2 using conventional strong acids such as
methanesulfonic and sulfuric acid and macroreticular ion
exchange resins Amberlyst 15 and Amberlyst XN 1010.
Different reaction temperatures and workup procedures
were necessary depending on the catalyst employed. The
yields of 2a-2g are summarized in Table 1. The products
Numerous methods are available for the synthesis of
2H-isoquinolin-3-ones [4]. The important ones include:
the cyclization of esters of o-acylphenylacetic acids with
ammonia, alkylamines or formamides [5-7], the
Pomeranz-Fritsch type cyclization of N-benzyl-diethoxy-
acetamides in sulfuric or polyphosphoric acid [8] and the
reaction of carboxylic acid or their derivatives with 2-
phenylethylamines, phenylacetamides, phenylacetonitriles
and N-acylphenylethylamines in polyphosphoric acid [9-
10]. Most of these methods, however, suffer from draw-
backs namely long reaction periods and are limited to the
presence of electron donating groups in the aromatic ring.
Alternatively, these products can be obtained by aromati-
zation of 1,4-dihydro-2H-isoquinolin-3-ones [11]
Recently, Hussain et al reported the synthesis of 2H-iso-
quinolin-3ones by reaction of azaallyllithiums derived
from imines of α-aminoesters with benzynes via 3+2
cycloaditions with moderate yields [12].
As far as we know, very few examples of 1-substituted
2H-isoquinolin-3-ones were reported [5,13-15].
Herein we describe a new effective method for the syn-
thesis of 1-substituted-2H-isoquinolin-3-ones (2) by
intramolecular cyclization of 2-acylphenylacetonitriles (1)
under strongly acidic conditions (Scheme 1).
This cyclization methodology for analogous transforma-
tions was previously reported in the literature [16,17]. For
example treatment of 1-cyanomethyl-anthraquinones
under strongly acidic conditions gave 3H-1-azabenzo[de]-
1
13
were identified using ir, H-nmr, C-nmr and elemental
analysis.
Very good yields were obtained when resins Amberlyst
15 and XN 1010 were used. The isoquinolinones 2 pre-
pared with these catalysts also have high purity because
the resins give a solid support to products 2 and make the
workup and isolation procedure quite simple. In this case,
when the reaction was complete, the resin was collected by
filtration, treated with aqueous sodium hydrogen carbon-
ate solution, water and then extracted with dichloro-
methane. The organic layer was dried, and the solvent
evaporated to give the isoquinolinones 2 with high purity.
There is no need to recrystallize the isolated products. In
the case of a reaction brought about in conventional strong
acid the yields were lower and the crude products were
obtained with less purity.
Scheme 1
Substrates 1 with aryl groups required a longer reaction
time with the use of Amberlyst resins. On the contrary, the
reaction time for substrates 1 with alkyl or aryl groups
remain unaltered with the use of mineral acids. On the
other hand, high yields using Amberlyst resins were only
found if higher temperatures than in the case of mineral
acids, were used. The resins can be easily regenerated and
reused without affecting the yields.

980
A. S. Cánepa, R. D. Bravo
Vol. 41
Table 1
Cyclization of 1 with Amberlyst Resins, Sulfuric Acid and Methanesulfonic Acid
1
2
Compound
R
R
A-15 [a]
Yield (%)/
Time (h)/
Temp (ºC)
A-XN 1010 [b]
Yield (%)/
Time (h)/
H SO
HMeSO
3
2
4
Yield (%)/
Time (h)/
Temp (ºC)
Yield (%)/
Time (h)/
Temp (ºC)
Temp (ºC)
1a
1b
1c
1d
1e
1f
CH CH
H
H
H
H
H
95 / 3/ 80
95 / 3/ 80
90 / 3/ 80
82 / 6/ 80
86 / 6/ 80
89 / 6/ 80
86 / 6/ 80
95 / 3/ 80
95 / 3/ 80
90 / 3/ 80
83 / 6/ 80
92 / 6/ 80
90 / 6/ 80
90 / 6/ 80
85 / 3/ 45
80 / 3/ 45
83 / 3/ 45
73 / 3 / 45
80 / 3/ 45
78 / 3/ 45
75 / 3/ 45
88 / 3/ 45
86 / 3/ 45
85 / 3/ 45
76 / 3/ 45
84 / 3/ 45
83 / 3/ 45
81 / 3/ 45
2
3
i-CH(CH )
3 2
CH C H
2
6
5
C H
6
5
4-ClC H
6
4
4-CH C H
H
5-Cl
3
6 4
1g
C H
6
5
[a] Amberlyst 15; [b] Amberlyst XN 1010.
sium cyanide (3.6 g, 56 mmol in 8 mL) was added. The reaction
mixture was stirred and boiled under reflux for 6 h, cooled to r.t.
and the solid removed by filtration. The resulting solution was
evaporated and the residue was poured onto water (26 mL). The
organic layer was separated, the aqueous layer was extracted
with chloroform (3 x 10 mL), and the combined organic layers
were washed with water (3 x 10 mL), 5 % aqueous sodium
hydrogen carbonate solution (10 mL) and water (10 mL). The
extracts were dried with sodium sulfate, concentrated in vacuo
and the residue purified by column chromatography in
toluene/dichloromethane (80/20) to afford 1g; yield: 12.5 g
In conclusion, we have found a short and high yield
route to 1-substituted 2H-isoquinolin-3-ones (2) by means
of intramolecular ciclyzation of 2-acylphenylacetonitriles
(1) under strongly acidic conditions, in particular with the
use of ion exchange resins Amberlyst 15 and Amberlyst
XN 1010.
EXPERIMENTAL
Mps were determined with a Buchi apparatus. Infrared spectra
were recorded with a Perkin Elmer FT-IR 1600 spectrophotome-
ter in potassium bromide. All nmr spectra were recorded on a
Brucker AC 250 MHz in deuteriochloroform and are reported in
ppm downfield from tetramethylsilane employed as an internal
standard (δ). The mass spectra were recorded in a Finnigan
Model 4500 Mass Spectrometer. Elemental analysis was carried
out at the Institut für Organische Chemie of the Stuttgart
University. Thin layer chromatography was performed on silica
-1
1
(49%); mp: 78-79 ºC; ir: 2238, 1658 cm ; H nmr: δ 4.00 (s, 2H,
CH CN), 7.39-7.44 (m, 2H, H-3', H-5'), 7.48-7.51 (m, 2H, H-4,
2
H-4'), 7.62-7.67 (m, 2H, H-3, H-6), 7.66 (dd, 1H J = 9.5, J
=
3-4
3-6
1.0, H-3); 7.76(dd, 2H, J
H-6'); C nmr (62.9 MHz) δ 21.7 (CH -), 117.1 (CN), 127.7 (C-
= J
= 8.3, J
=
= 1.26, H-2',
2'-3'
6'-5'
2'-4' 6'-4'
13
2
4), 128.7 (C-3', C-5'). 130.1 (C-6), 132.0 (C-3), 130,2 (C-2'-C-
6'),132.4 (C-1), 133.7 (C-4'), 134.9 (C-5), 136.9 (C-2), 138.0 (C-
1'), 196.0 (CO); ms: m/z 255,5 (M+, 44 %), 230 (32), 228 (100),
220, (32), 139 (27), 89 (11).
gel sheets 60 F
(Merck) with chloroform-methanol (90:10).
254
Anal. Calcd. for C
H NOCl (255.69): C, 70.48; H, 3.91; N,
15 10
Reagent grade solvents were used. Amberlyst 15 (Aldrich) was
dried at 60 °C under reduced pressure (5 mbar) for 15 minutes
and Amberlyst XN 1010 (Aldrich) was dried at 80 °C (5 mbar)
during 4 h.
5.48. Found: C, 70.46; H, 4.02; N, 5.30.
Cyclization of 2-acylphenylacetonitriles (1) to 2H-Isoquinolin-3-
ones (2).
The 2-acylphenilacetonitriles (1a-1f) were prepared applying a
known method from 2-cyanomethylphenylchloride by reaction
with Grignard reagents [18]. Compound 1g was prepared from 4-
chloro-2-methylbenzophenone (3) with benzylic bromination
and cyanation of the haloderivative.
General Procedure Using Amberlyst Resins.
A reaction flask equipped with a reflux condenser and mag-
netic bar, was charged with a solution of 2-acylphenylacetoni-
triles (1) (1 mmol) in 1,2-dichloroethane (4 mL) and the resin
(6.0 meq) [22]. Stirring was continued at 80 °C for the time indi-
cated (Table 1). The progress of the reaction was monitored by
thin layer chromatography. When the reaction was complete, the
resin was collected by filtration, washed with fresh 1,2-
dichloroethane and then was treated with 10% aqueous sodium
hydrogen carbonate solution and water. The resin was then
extracted three times with dichloromethane (2 mL). The com-
bined extracted was dried with sodium sulfate and concentrated
in vacuo to give the final products.
4-Chloro-2-methylbenzophenone (3).
This compound was prepared from 4-chloro-2-methylbenzoic
acid [19] by Friedel Crafts direct acylation with benzene accord-
ing to the literature procedure [20] in 62 % yield ; bp 140-142 ºC
,0.1 mm (lit [21] bp 143-144 ºC, 0.1 mm).
2-Benzoyl-5-chloro-phenylacetonitrile (1g).
A stirred mixture of 3 (13.8 g, 60 mmol) and DBH (10.2 g, 35
mmol) in carbon tetrachloride (120 mL) was heated under reflux
for 4 h while a 150-W bulb situated 2 cm away was shining on
the reaction flask. The cooled reaction mixture was filtered and
the solution evaporated to give a yellow oil (17.2 g), which was
dissolved in ethanol (60 mL) and an aqueous solution of potas-
General Procedure Using Sulfuric and Methanesulfonic Acid.
A reaction flask equipped with a magnetic bar and a Teflon
cap, was charged with a solution of 2-acylphenylacetonitriles (1)
(1 mmol) in 1,2-dichloroethane (4 mL) and the acid (1 mL). After

Nov-Dec 2004
A Novel Synthesis of 1-Substituted 2H-Isoquinolin-3-ones
981
3 h stirring at 45 ºC the mixture was quenched with water, neu-
tralized with 10% aqueous ammonium chloride solution and
extracted three times with dichloromethane (2 mL). The organic
layer was dried with sodium sulfate and concentrated in vacuo to
give a yellow solid that was recrystallized from ethanol.
(M,100%); 254 (6); 236 (4); 227 (53) ; 192 (8); 165 (11).
Anal. Calcd. for C NOCl (255.69): C, 70.48; H, 3.91; N,
5.48. Found: C, 70.59; H, 3.98; N, 5.41.
H
15 10
1-(p-Methylphenyl)-2H-isoquinolin-3-one (2f).
This compound was obtained as yellows prisms (ethanol), mp
1-Ethyl-2H-isoquinolin-3-one (2a).
-1 1
205-206 ºC; ir: 1536, 1642 cm ; H nmr: δ 2.45 (s, 3H, Ph-CH );
3
This compound was obtained as yellows prisms (ethanol), mp
6.89 (s, 1H, H-4); 7.11 (td, 1H, H-6'); 7.55 (d, 1H, J = 6.3, H-
5-6
-1
1
13
209-210 ºC; ir: 1557, 1651cm ; H nmr: δ 1.45(t, 3H, J= 7.5,
CH -CH ); 3.28 (q, 2H, J= 7.5, CH -CH ); 6.76 (H-4); 7.12 (ddd,
5); 7.77 (d, 1 H, J = 8.6, H-8); C nmr (62.9 MHz): δ 21.4
7-8
(CH ); 103.7 (C-4); 120.4 (C-9); 123.2 (C-7); 125.7 (C-8); 127.8
2
3
3
2
3
1H, J = 6.8, J = 8.8, J = 1.4, H-7); 7.41 (ddd, 1H, J = 6.8,
(C-5); 129.0 (C-3', C-5'); 129.9 (C-2', C-6'); 130.7 (C-6); 132.7
(C-1'); 139.2 (C-4'); 142.2 (C-10); 156.3 (C-1); 160.5 (C-3); ms:
m/z 235(M, 100%), 234 (9), 207 (54), 191 (4).
7-6
7-8
7-5
6-7
J
= 8.8, J = 1.2 , H-6); 7.47 (dd, J = 8.8, J = 1.4, H-5), 7.83
6-5
6-8 5-6 5-7
13
(dd, J = 8.8, J = 1.0, H-8); C nmr (62.9 MHz): δ 14.7(CH -
7-8
8-6
2
CH ); 25.0 (-CH -CH ); 104.4 (C-4); 117.7 (C-9); 122.5 (C-7);
Anal. Calcd. for C
N NO (235.28): C, 81.48; H, 5.66;
3
2
3
16 13
125.5 (C-8); 126.0 (C-5); 131.2 (C-6); 143.2 (C-10); 157.5 (C-1);
161.5 (C-3); ms: m/z 173(M, 100%); 172 (34);130 (90).
N,5.89. Found: C, 81.68; H, 5.57; N, 5.95.
7-Chloro-1-phenyl-2H-isoquinolin-3-one (2g).
This compound was obtained as yellows prisms (ethanol), mp
Anal. Calcd. for C H N (173.21): C,76.32; H, 6.35; N, 8.08.
11 11
Found: C, 76.32; H, 6.36; N, 8.00.
-1
1
235-237 ºC; ir: 1538, 1665 cm ; H nmr: δ 6.78 (s, 1H, H-4),
7.06 (dd, 1H, J = 9.1, J = 1.4, H-7); 7.54 (br, 6H, H-5, H-2',
1-(i-Propyl)-2H-isoquinolin-3-one (2b).
7-8
7-5
13
This compound was obtained as yellows prisms (ethanol), mp
H-3', H-4', H-5', H-6'), 7.72 (d, 1H, J = 9.1, H-8); C nmr
8-7
-1
1
(62.9 MHz): δ 102.9 (C-4); 120.0 (C-9); 124.5 (C-7); 125.0 (C-
8); 128.9 (C-3', C-5'); 130.0 (C-5), 130.2 (C-4'), 130.4 (C-2', C-
6'), 136.2 (C-1'); 137.9 (C-6); 142.9 (C-10); 157.9 (C-1); 161.1
(C-3); ms: m/z 255 (M, 100%), 236 (10), 227 (8), 150 (18).
151-152 ºC (Lit [13] mp: 151-152 ºC); ir: 1557, 1651 cm ; H
nmr: δ 1.53 (d, 6H J= 7.0, CH(CH ) ); 3.85 (sept., 1 H J= 7.0 ,
3 2
CH(CH ) ; 6.77 (s, 1H, H-4) 7.09 (ddd, 1 H, J = 7.9, J = 8.7,
3 2
7-6
7-8
J
= 1.4, H-7); 7.36(td, 1H, J = 7.9, J = 1.0, H-6), 7.45(d,
7-5
6-7 6-8
13
1H, J = 7.8, H-5); 7.89 (dd, 1H, J = 8.7, J = 1.0, H-8);
C
Anal. Calcd. for C H NOCl (255.69): C, 70.48; H, 3.91; N,
5-6
8-7
8-6
15 10
nmr (62.9 MHz) δ 21.3 ((CH ) -CH); 29.4 (-CH-(CH ) ); 104.6
5.48. Found: C, 70.51; H, 3.94; N, 5.52.
Acknowledgment.
3 2
3 2
(C-4); 117.1 (C-9); 122.3 (C-7); 125.0 (C-8); 126.1 (C-5); 130.9
(C-6); 143.2 (C-10); 160.5 (C-1); 161.0 (C-3); ms: m/z 187 (M,
100%); 186 (36); 172 (41); 159 (13); 144 (40).
The authors thank CIC (Pcia de Buenos Aires) for financial
support and Dr Pedro A. Colinas for valuable discussions.
1-Benzyl-2H-isoquinolin-3-one (2c).
This compound was obtained as yellows needles (ethanol), mp
REFERENCES AND NOTES
-1
1
194-195 ºC; ir: 1556, 1648 cm ; H nmr: δ 4.66 (s, 2H, CH Ph);
2
6.85 (s, 1H, H-4); 7.11-7.48 (m, 7H , H-6, H-7, H-2', H-3', H-4',
[1] W. E. Kreighbaum, W. F. Kavanaugh, W. T. Comer and D.
Deitchman, J. Med.Chem., 15, 1131 (1972).
[2] R. M. Kanojia, J. B. Press, O. W. Lever Jr., L. Williams, J. J.
McNally, A. J. Tobia, R. Falotico and J. B. Moore Jr., J. Med. Chem., 31,
1363 (1988).
[3] R. M. Kanojia, O. W. Lever, Jr., J. B. Press, L. Williams, H.
M. Werblood, E. C. Giardino, R. Falotico and A. J. Tobia, J. Med.
Chem., 32, 990 (1989).
H-5', H-6'); 7.51(d, 1H, J = 8.2, H-5); 7.92 (d, 1H, J = 8.8, H-
5-6
7-8
13
8); C nmr (62.9 MHz): δ 38.3 (-CH -Ph); 104.6 (C-4); 119.7
2
(C-9); 123.8 (C-7); 126.1 (C-8); 127.3 (C-5); 127.4 (C-2', C-6');
128.9 (C-4'); 129.0 (C-3', C-5'); 131.3 (C-6); 137.8 (C-1'); 143.6
(C-9); 154.6 (C-1); 161.6 (C-3); ms: m/z 235 (M, 100%); 234
(95); 216 (10); 207 (8).
Anal. Calcd. for C
H NO (235.27) : C, 81.72; H,5.53;
16 13
[4] L. Hazai, Adv. Heterocyclic. Chem., 52, 155 (1991).
[5] D. W. Jones, J. Chem. Soc. (C), 1729 (1969).
[6] I. W. Elliot, J. Heterocyclic Chem., 7, 1229, (1970).
[7] I. W. Elliot, J. Heterocyclic Chem., 9, 853 (1972).
[8] H. Fukumi and H. Kurihara, Heterocycles, 9, 1197 (1978).
[9] A. P. Venkov and I. I. Ivanov, Synthetic Comm., 24, 1145
(1994).
[10] A. P. Venkov and I. I. Ivanov, Tetrahedron, 52, 12299 (1996).
[11] N. G. Kundu, J. A. Wright, K. L. Perlman, W. Hallett and C.
Heidelberger, J. Med. Chem., 18, 395 (1975).
N,5.95. Found: C, 81.65; H, 5.51; N, 5.89.
1-Phenyl-2H-isoquinolin-3-one (2d).
This compound was obtained as yellows prisms (ethanol), mp
1
204-205 ºC (Lit. [5] m.p. 205-206 ºC. Spectral Data (ir, ms, H
13
nmr) are identical with those reported [5]; C nmr (62.9 MHz): δ
103.1 (C-4); 121.0 (C-9); 123.6 (C-7); 125.8 (C-8); 127.5 (C-5);
128.4 (C-2', C-6'); 129.2 (C-4'); 129.9 (C-3', C-5'); 130.7 (C-6);
136.3 (C-1'); 142.0 (C-10); 156.9 (C-1); 160.3 (C-3).
[12] H. Hussain, E. Kianmehr and T. Durst, Tetrahedron Lett., 42,
2245 (2001).
1-(p-Chlorophenyl)-2H-isoquinolin-3-one (2e).
[13] L. Arsenijevic and V. Arsenijevic, Bull. Soc. Chim. France, 8,
3403 (1968).
[14] Q. Lu, P. Bovonsombat and W. Agosta, Tetrahedron Lett., 36,
8941 (1995).
[15] Q. Lu, P. Bovonsombat and W. Agosta, J. Org. Chem., 61,
3729 (1996).
This compound was obtained as yellows prisms (ethanol), mp
-1
1
236-237 ºC; ir: 1550, 1630 cm ; H nmr: δ 6.96 (s, 1H, H-4);
7.21 (ddd, 1H, J = 8.5, J = 6.7, J = 1.4, H-7); 7.44-7.57 (m,
7-8
7-6
7-5
5H, H-6, H-2', H-3', H-5', H-6'); 7.65 (d, 1H, J = 8.5, H-5); 7.76
5-6
13
(dd, 1H, J = 8.5, J = 1.2, H-8); C nmr (62.9 MHz): δ 103.2
8-7
8-6
(C-4); 122.0 (C-9); 124.2 (C-7); 126.3 (C-8); 127.5 (C-5); 128.9
(C-3', C-5'); 131.0 (C-6); 131.6 (C-2', C-6'); 135.5 (C-4'); 135.7
(C-1'); 142.0 (C-10); 156.7 (C-1); 160.6 (C-3); ms: m/z 255.5
[16] M. V. Gorelik, S. P. Titova, M. A. Kanor, Zhurnal
Organicheskoi Khimii, 24, 1786 (1988).
[17] M. V. Gorelik, S. P. Titova, M. A. Kanor, Zhurnal

982
A. S. Cánepa, R. D. Bravo
Vol. 41
Organicheskoi Khimii, 28, 2301 (1992).
(1961).
[18] A. S. Cánepa and R. D. Bravo, Synthetic Comm., 34,579
(2004) .
[21] G. Goethals, J. P. Doucet, P. Baver and R. Uzan,
Espectrochim. Acta, 31A(9-10), 1501 (1975).
[19] Ad. Claus and E. Stapelberg, Ann. Chem., 274, 285 (1893).
[20] D. J. Reiding and W. Th. Nauta, Rec. Trav Chim., 80, 399
[22] Calculated with exchange capacity (4.7 meq./g for Amberlyst
15, 3.3 meq./g for Amberlyst XN 1010).