A convenient one-pot synthesis of 1-aryl-substituted 2H-isoquinolin-3-ones

Article abstract of DOI:10.1016/j.tetlet.2011.11.128

The synthesis of 1-aryl-substituted 2H-isoquinolin-3-ones is studied from 2-cyanomethylbenzoic acid and substituted benzenes via Friedel-Crafts acylation and intramolecular cyclization of 2-acylphenylacetonitriles formed in a one-pot method using sulfated zirconia as catalysts. Short reaction times, simplicity of operation, and easy work-up are some advantages of this method.

Full text of DOI:10.1016/j.tetlet.2011.11.128

Tetrahedron Letters 53 (2012) 688–690
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Tetrahedron Letters
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A convenient one-pot synthesis of 1-aryl-substituted 2H-isoquinolin-3-ones
Leticia J. Méndez a, Alicia S. Cánepa a, , M. Gloria González b, Rodolfo D. Bravo a
⇑
a Laboratorio de Estudio de Compuestos Orgánicos, Departamento de Química, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, 47 y 115, 1900 La Plata, Argentina
b CINDECA (CONICET-UNLP), Facultad de Ciencias Exactas, 47 No. 257, 1900 La Plata, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of 1-aryl-substituted 2H-isoquinolin-3-ones is studied from 2-cyanomethylbenzoic acid
and substituted benzenes via Friedel–Crafts acylation and intramolecular cyclization of 2-acylphenyl-
acetonitriles formed in a one-pot method using sulfated zirconia as catalysts. Short reaction times, sim-
plicity of operation, and easy work-up are some advantages of this method.
Received 8 October 2011
Revised 24 November 2011
Accepted 25 November 2011
Available online 2 December 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
1-Aryl-substituted 2H-isoquinolin-3-ones
One-pot synthesis
Sulfated zirconia
2-Acylphenylacetonitriles
Intramolecular cyclization
For many years isoquinolones have been an interesting struc-
tural class of compounds, which have been found to have many
uses in the field of medicinal and synthetic chemistry. In particular,
2H-isoquinolin-3-ones 1-alkyl-4-substituted derivatives were
investigated in connection with their cardiotonic and renal vasod-
ilating effects1,2 and antiplasmodial falcipain-2 inhibitors.3
COCl
CN
RMgX/CuI
PCl5
O
COOH
CN
R
CN
ArH (2) / AlCl3
(1)
(3)
A large number of methods exists in the literature for the syn-
thesis of these compounds.4,5 However, most of these multi-step
procedures have significant drawbacks such as long reaction times,
harsh reaction conditions, difficult work-up, and the use of expen-
sive and toxic reagents. For these reasons new methods for the
facile production of isoquinolinones continue to be of interest.
In a previous work, we have prepared 2H-isoquinolin-3-ones 4
with excellent yields by intramolecular cyclization of 2-acylphe-
nylacetonitriles 3 under strongly acidic conditions using sulfuric
and methanesulfonic acids as homogeneous catalysts and ion
exchange resins Amberlyst 15 as heterogeneous catalysts.6 The
2-acylphenylacetonitriles 3 used were previously obtained by
reaction of 2-cyanomethylbenzoyl chloride and Grignard reagents
in the presence of cuprous iodide (R = alkyl, aryl)7 (Scheme 1).
Another method to prepare 2-acylphenylacetonitriles 3 for
R = aryl is via Friedel–Crafts acylation of aromatic compounds with
2-methylbenzoic acid using AlCl3, followed by bromination–
cyanuration of 2-methylbenzophenone or, more directly, through
Friedel–Crafts acylation of aromatic compounds with 2-cyanometh-
ylbenzoic acid 1, but this method possesses low performance with a
large amount of toxic waste generated. Another disadvantage for the
ArH (2) / H+
H+
OH
O
NH
N
(4)
R
R
Scheme 1. Synthetic method for the preparation of 2H-isoquinolin-3-ones 4.
mentioned methods is long reaction periods (e.g., 7–10 days) to
carry out all the synthetics steps (Scheme 1).
As continuation of our work on the development of useful
synthetic methodologies, we investigated the possibility of
combining the Friedel–Crafts reactions of 2-cyanomethylbenzoic
acid 1 and intramolecular cyclization of 2-acylphenylacetonitriles
3 formed in a one-pot method for the synthesis of 1-aryl-substi-
tuted 2H-isoquinolin-3-ones
4 using heterogeneous catalysts
(Scheme 1).
The reaction between 2-cyanomethylbenzoic acid 1 (1 mmol)
and benzene was selected as a model to optimize the experimental
conditions testing various catalysts in different amounts using ben-
zene as solvent at refluxing temperature. The results, summarized
⇑
Corresponding author.
E-mail address: ascanepa@quimica.unlp.edu.ar (A.S. Cánepa).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.128

L. J. Méndez et al. / Tetrahedron Letters 53 (2012) 688–690
689
Table 1
Comparative study of catalysts for one pot synthesis of 1-phenyl-2H-isoquinolin-3-one 4a
Entry
Catalyst
Temp./time (°C/h)
Acid 1 recovered (%)
Intermediate 3a yield (%)
Product 4a yield (%)
1
2
3
Amberlyst 15
P2O5/SiO2
SO42À=ZrO2
ZrO2
80/24
80/12
80/5
90
60
16
—
35
—
—
—
70a
4
5
80/8
80/24
50
60
—
—
34a
10
ZnO
a
Extension of the reaction time (24 h) did not improve the yield.
Table 2
Synthesis de 2H-isoquinolin-3-ones 4 using sulfated zirconiaa
Entry
1
Substrate 2
C6H6
Solvent
C6H6
Time (h)
5
Temperature (°C)
Product yield (%)
Mp (°C) Found/Lit.6
Reflux
4a
4b
70
78
205–206
204–205
203–204
205–206
200–200.5
235–237
236–237
245–246
229–230
190–191 (d)
2
MeC6H5
MeC6H5
5
Reflux
3
4
EtC6H5
ClC6H5
1,2-C2H4Cl2
1,2-C2H4Cl2
5
6
Reflux
Reflux
4c
4d
75
52
5
6
7
3-Br-C6H4CH3
MeOC6H5
1,3-(MeO)2C6H4
1,2-C2H4Cl2
1,2-C2H4Cl2
1,2-C2H4Cl2
5
4
6
Reflux
Reflux
Reflux
4e
4f
4g
10
<5
30
a
Commercial SO42À=ZrO2 from Mel Chemical Co was dried at 110 °C for 2 h in air atmosphere and was subsequently calcined for 5 h in air atmosphere at 550 °C.15
in Table 1, clearly indicate that among the various catalysts studied,
sulfated zirconia was found to be the most efficient for the process.
We found that the reaction proceeded with the best yields
when performed using SO42À=ZrO2 (100 wt %). Other catalysts used
have not been effective in the generation of isoquinolinone 4a in
this one pot sequence, with the formation in some cases of 2-cya-
nomethybenzophenone 3a (Table 1, entry 2).
On the other hand, sulfated zirconia has attracted much atten-
tion in the recent years because of its good catalytic activity,
super-acidity, non-toxicity, and offer several advantages such as
short reaction times, high selectivity and the easiness of work-up
procedure.8–10 Some of these interesting methodologies studied in-
clude Friedel–Crafts acylation,11 stereo controlled glycosidation,12
synthesis of coumarins by Pechmann reaction,13 1,5-benzodiaze-
pines,14 3,2-benzothiazepine 3,3-dioxides, and 2,3-benzothiazine
2,2-dioxides15 among others.
data with those of the reported ones. Physical properties of 1H
NMR and 13C NMR spectral data and elemental analysis of new
compounds 4c, 4e, 4f, and 4g are reported in the experimental
section.16
In conclusion, a series of 2H-isoquinolin-3-ones 1-aryl-substi-
tuted were synthesized in good yields via the sequential Friedel–
Crafts acylation of 2-cyanometylbenzoic acid 1 and benzene deriv-
atives 2 followed by intramolecular cyclization of ketones formed
3, catalyzed by sulfated zirconia. The current route is a practical
and convenient method for the synthesis of 2H-isoquinolin-3-ones
4 derivatives in a one-pot reaction. Short reaction times, simplicity
of operation, and easy work-up are some advantages of this meth-
od. It is important to take into account that the waste disposal of
the process was greatly diminished compared with the alternative
methods.
With the selected catalyst, we expanded the scope of the reac-
tion to various substituted benzenes. The solvent reaction was the
benzene derivative 2 or 1,2-dichloroethane according to the prop-
erties of aromatic derivative used for the acylation, especially hav-
ing in mind a boiling temperature and availability.16 The results of
the reaction are summarized in Table 2.
Acknowledgments
The authors thank UNLP, CONICET, CICBA for the financial sup-
port and Dr. Ruben Rimada for NMR measurements. L.J.M is a
holder of a CICBA fellowship.
As seen in Table 2, the reactions proceeded smoothly with var-
ious aromatic substrates 2 in moderate to good yields. However,
1,3-(MeO)2C6H4, 3-Br-C6H4CH3, and MeOC6H5 were not good sub-
strates. As shown in entries 5, 6, and 7 we have observed the for-
mation of the products 4 in low to very low yield, with a
complex mixture of compounds formed by using different reac-
tions conditions such as temperature, catalyst ratio, and reactive
relations. Intermediates ketones 3 could be detected in low yield
in the reaction mixtures. Different results about the acylation of
methoxybenzene using sulfated zirconia have been found in the
literature.13,14
Moreover, it is noteworthy that the acylation reaction occurred
with high regioselectivity in para position to aromatic substrate,
with the exception of 3-Br-C6H4CH3 (entry 5), where the substitu-
tion occurs in ortho position at methyl group possibly due to a ste-
ric effect on the bromine substituent.
References and notes
1. Kanojia, R.M.; Lever, W.; Press J.B. U.S. Patent No. 4880817.
2. Micale, N.; Ettari, R.; Schirmeister, T.; Evers, A.; Gelhaus, C.; Leippe, M.; Zappalà,
M.; Grasso, S. Bioorg. Med. Chem. 2009, 17, 6505–6511.
3. Mokorosz, M. J.; Duszynska, B.; Wesolowska, A.; Borycs, J.; Chojnacka-Wójcik,
E.; Karolaz-Wojciechowska J. Med. Chem. Res. 2000, 10, 58–68.
4. Hazai, L. Adv. Heterocycl. Chem. 1990, 52, 155–185.
5. Suzuki, H.; Abe, H. J Org. Chem. 1994, 59, 6116–6118.
6. Cánepa, A. S.; Bravo, R. D. J. Heterocycl. Chem. 2004, 41, 979–982.
7. Cánepa, A. S.; Bravo, R. D. Synth. Commun. 2004, 34, 579–588.
8. Reddy, B. M.; Sreekanth, P. M.; Lakhsmanan, P. J. Mol. Catal. A: Chem. 2005, 237,
93–100.
9. Reddy, B. M.; Patil, M. K. Chem. Rev. 2009, 109, 2185–2208.
10. Sartori, G.; Maggi, R. Chem. Rev 2011, 111, 181–214.
11. Deutsch, J.; Prescott, H. A.; Muller, D.; Kemnitz, E.; Lieske, H. J. Catal. 2005, 231,
269–278.
12. Toshima, K.; Nagai, H.; Kasumi, K.; Kawahara, K.; Matsumura, S. Tetrahedron
2004, 60, 5331–5539.
13. Beena, T.; Mishra, K. M.; Jasra, R. V. J. Mol. Catal. A 2007, 276, 47–56.
14. Reddy, B. M.; Sreekanth, P. M. Tetrahedron Lett. 2003, 44, 4447–4449.
15. Sasiambarrena, L. D.; Mendez, L. J.; Ocsachoque, M.; Cánepa, A. S.; Bravo, R. D.;
González, M. G. Catal Lett. 2010, 138, 180–186.
The products 4a, 4b, and 4d are known compounds and were
characterized by comparison of their physical and spectroscopic

690
L. J. Méndez et al. / Tetrahedron Letters 53 (2012) 688–690
16. General procedure for the preparation of 2H-isoquinolin-3-one 4:
A
flask
(s, 3H, CH3), 6.67 (s, 1H, H-4), 7.22–7.30 (m, 2H), 7.37 (td, J = 7.6, 1.4 Hz, 2H),
7.45–7.57 (m, 3H) 8.11 (dd, J = 7.81, 1.0 Hz, 1H) 13C NMR (62.9 MHz): d = 41.23,
100.51, 122.52, 127.70, 129.14, 131.05, 131.99, 132.56, 133.23, 134.31, 134.78,
136.90, 138.24, 140.87, 143.87, 163.66. Anal. Calcd for C16H12BrNO: C, 61.17; H
3.85; Br, 15.43, N, 4.46. Found: C, 61.22; H, 3.79; N, 4.38.
Characterization data of 1-(4-methoxyphenyl)-2H-isoquinolin-3-one (4f): Yellows
needles (ethanol), mp: 229–230 °C. 1H NMR (200 MHz, CDCl3): d = 3.87 (s, 3H,
OCH3), 6.55 (s, 1H, H-4), 7.15 (m, 2H), 7.21–7.32 (m, 3H), 7.36–7.53 (m, 2H),
7.58 (d, J = 7.1 Hz, 1H), 7.98 (d, J = 7.9 Hz, 1H). 13C NMR (62.9 MHz): d = 54.66,
101.39, 114.89, 120.40, 121.0, 123.3, 127.45, 128.04, 131.5, 132.13, 133.06,
143.51, 158.46, 162.57. Anal. Calcd for C16H13NO2: C, 76.48; H, 5.21; N, 5.57.
Found: C, 76.36 H, 5.20 N, 5.45.
equipped with a reflux condenser and magnetic bar was charged with a
solution of 2-cyanomethylbenzoic acid 1 (1.0 mmol), benzenes derivatives 2
(2–2.5 mol), and the catalyst in 4 mL of dried solvent. The mixture was stirred
at reflux for the specified time. The reaction was monitored by TLC. After
cooling, the catalyst was filtered off, washed with fresh solvent, and the
organic solution was concentrated under reduced pressure to give the crude
products. They were purified by crystallization or by flash chromatography on
silica gel 60 (70–230 mesh, Merck) with CH2Cl2/MeOH (9:1) as eluent in most
cases. 1H NMR and 13C NMR spectra were recorded on a Varian Mercury 200
spectrometer using TMS as the internal standard.
Characterization data of 1-(4-ethylphenyl)-2H-isoquinolin-3-one (4c): Oranges
prisms (ethanol), mp: 200–200.5 °C.1H NMR (200 MHz, DMSO): d = 1.15 (t,
J = 7.01 Hz, 3H, CH2-CH3), 4.03 (q, J = 7.01 Hz, 2H, CH2–CH3), 6.57 (s, 1H, H-4),
7.28–7.41 (m, 4H), 7.61–7.79 (m, 2H), 7.68 (d, J = 7.52 Hz, 1H, H-5), 8.00–8.22
(m, 2H) 13C NMR (62.9 MHz): d = 14.81, 55.58, 100.41, 122.77, 126.05, 127.44,
127.55, 127.90, 128.82, 131.38, 132.51, 133.05, 136.61, 143.07, 162.95. Anal.
Calcd for C17H15NO: C, 81.90; H 6.06; N, 5.62. Found: C, 81.78; H, 6,15; N, 5.22.
Characterization data of 1-(4-bromo-2-methylphenyl)-2H-isoquinolin-3-one (4e):
Yellows needles (ethanol), mp: 244–246 °C. 1H NMR (200 MHz, CDCl3): d = 3.99
Characterization data of 1-(2,4-dimethoxyphenyl)-2H-isoquinolin-3-one (4g):
Yellows prisms (ethanol), mp: 190–191 °C (d). 1H NMR (200 MHz, DMSO):
d = 3.75 (s, 6H, –OCH3), 6.29 (s, 1H, H-4), 6.48–6.58 (m, 2H), 6.82 (s, 1H, NH),
7.18 (t, J = 7.8 Hz, 1H, H-7), 7.44–7.52 (m, 1H, H-6), 7.59 (d, J = 8.4 Hz, 1H, H-5),
7.63 (d, J = 7.8 Hz, 1H, H-8), 7.67 (d, J = 8.5 Hz, 1H, H-6) 13C NMR (62.9 MHz):
´
d = 55.74, 55.48, 100.19, 102.03, 105.47, 108. 48, 118.43, 122.85, 123.77,
126.11, 128.47, 130.65, 132.60, 140.95, 157.06, 159.97, 161.63. Anal. Calcd for
C
17H15NO3: C, 72.58; H, 5.37; N, 4.98. Found: C, 72.35 H, 5.21 N, 4.87.