Efficient synthesis of some 3-arylisoquinolin-1(2H)-ones

Article abstract of DOI:10.1007/s10593-008-0140-3

A number of 3-arylisoquinolin-1(2H)-ones were efficiently prepared from the corresponding 3-aryl-isocoumarins by refluxing with methanamide.

Full text of DOI:10.1007/s10593-008-0140-3

Chemistry of Heterocyclic Compounds, Vol. 44, No. 8, 2008
EFFICIENT SYNTHESIS OF SOME
3-ARYLISOQUINOLIN-1(2H)-ONES
Aamer Saeed1,Zaman Ashraf2
A number of 3-arylisoquinolin-1(2H)-ones were efficiently prepared from the corresponding 3-aryl-
isocoumarins by refluxing with methanamide.
Keywords: isocoumarin, isoquinolin-1(2H)-one, methanamide.
Isoquinolin-1(2H)-ones (isocarbostyrils) are the nitrogen analogues of isocoumarins (1H-2-benzopyran-
1-ones). Various isoquinolin-1(2H)-one derivatives are found in several bioactive natural products such as
thalifoline, doryphorine [1], ruprechstyril [2], narciclasine [3], pancretistatin, lycoricidine [4], alkaloids
coryaldine [5], dorianine [6, 7], hydroxyhydrastinine, and thalflavine [8]. The isoquinolone nucleus is also an
integral part of complex isoquinoline alkaloids and is a useful building block in organic synthesis.
The isoquinolone skeleton, biogenetically derived from the amino acid phenyl- alanine, exhibits
biomimetic characteristics [9]. Substituted isoquinolones are orally effective antagonists of 5-HT3 receptors,
which have shown a high efficacy in the control of cancer models [10], thymidylate synthase (TS) inhibitors
[11], human tumor necrosis factor (TNF) inhibitors, and tachykinin receptors [12]. Substituted isocarbostyrils
exhibiting antidepressant [13], anti-inflammatory [14], analgesic [15], hypolipidemic [16], and analeptic [17]
activities have also been reported.
In view of the great therapeutic value of such motifs in various bioactive molecules, a number of
synthetic routes have been developed. These include the Gabriel–Coleman synthesis [18], ring enlargement of
phthalimides [19], condensation of amines with homophthalic anhydrides [20], reaction of 2-methoxy-
carbonylstyrene oxide with ammonia or methylamine [21], and reaction of coumarin and isocoumarin
derivatives [22] with ammonia and amines. The latter method has been used in the synthesis of (±)-licoricidine
[23], narciclasine [24], (+)-deoxypancretistatin [25], and the benzophenanthridine alkaloid nitidine [26]. In
addition, the [4+2] cycloaddition of the ketenes to cyano ketones [27], treatment of indanones with sodium azide
[28], recently reported solid-phase synthesis of isoquinolinones using Bischler–Napieralski cyclization [29],
palladium-mediated synthesis of isoquinolinones [30], and syntheses via Curtius arrangement of cinnamic acids
or via an isoquinolone N-oxide have been reported [31].
The substitution of the oxygen by nitrogen atom is still one of the most important methods. A number of
reagents have been used including ammonia, ammonium acetate, or amines, but the results are never satisfactory
[32–34] except for a recently reported method [35].
__________________________________________________________________________________________
1Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan; e-mail:
aamersaeed@yahoo.com. 2Riphah Institute of Pharmaceutical Sciences, Islamabad, Pakistan; e-mail:
mzchem@yahoo.com. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1203-1208, August,
2008. Original article submitted
2008. Received September 25, 2007.
0009-3122/08/4408-0967©2008 Springer Science+Business Media, Inc.
967

The majority of the natural isocoumarins that are of polyketide origin possess a C-3 alkyl/aryl
substituent; consequently, a variety of methodologies are available for rapid access to these bioactive
heterocycles [36]. Therefore the conversion of 3-substituted isocoumarins into the analogous isoquinolin-1(2H)-
ones could prove to be a synthetically feasible procedure. In continuation of our studies on the synthesis of
naturally occurring isocoumarins [37−42] and their synthetic analogues, in this article we describe the
conversion of a number of 3-substituted isocoumarins into their nitrogen analogues.
The isocoumarins 1a-j were synthesized according to the method reported earlier [37]. An equimolar
mixture of the isocoumarin and methanamide was refluxed for 2–4 h to afford the corresponding isoquinolin-1(2H)-
ones 2a–j. The products were obtained in 76–85 % yield in high purity (Table 1). The progress of the reaction was
followed by TLC. The successful substitution was primarily indicated by the appearance of a fluorescent blue spot
under the longer wavelength of a UV lamp, having Rf values lower than those of the parent isocoumarin. The
products were further characterized by comparing their mp, IR, 1H NMR, and mass spectral data with those of the
corresponding isocoumarins. Thus, a shift of lactonic carbonyl absorption from 1710–1730 to 1630–1650 cm–1 and
1
appearance of absorption at 3220–3380 cm–1 for NH were noted in the IR spectra. In the H NMR spectra a
downfield shift of the characteristic H-4 proton of the isocoumarins at δ 6.0–6.2 to 6.6–6.9 in isoquinolinones was
observed besides the appearance of NH absorption at δ 9.4–10.8. A variety of substituents on the aryl ring are well
tolerated, and the reaction leads to completion in all the cases. The generality of the conversion was indicated by
substrates bearing an aralkyl group (2c), heterocyclic (2i), or a long aliphatic chain (2j) at position C-3.
R
R
H2N
O
O
NH
2–4 h, 76–85%
O
O
2a–j
1a–j
1, 2 a R = 3-FC6H4, b R = 4-FC6H4, c R = 2-ClC6H4CH2, d R = 2-BrC6H4, e R = 3-IC6H4,
f R = 2,4-Cl2C6H3, g R = 3-F,4-ClC6H3, h R = 4-O2NC6H4, i R = 2-ClC5H3N-6, j R = C15H31
In conclusion, one-pot conversion of a number of 3-substituted isocoumarins to the corresponding
isoquinolones has been achieved by refluxing with methanamide.
TABLE 1. Physicochemical Spectral Characteristics of Isoquinolin-
1(2H)-ones 2a–j
Com-
pound
Reflux,
time, h
1H NMR spectrum, δ, ppm
mp, °C*
Yield, %
H-4 (1)
H-4 (2)
NH (2)
2a
2b
2c
2d
2e
2f
216-218
222-224
188-190
170-172
226-228
221-222
213-214
230-232
210-212
71-73
84
82
85
82
84
78
80
84
82
76
2.5
3.0
3.5
2.0
2.5
3.0
3.5
4.0
4.0
4.0
6.10
6.40
6.24
6.2
6.83
6.80
6.66
6.63
6.8
10.25
10.54
9.53
9.4
6.34
6.21
6.35
6.26
6.3
9.8
6.66
6.65
6.94
6.84
6.89
10.89
10.05
8.79
10.2
6.62
2g
2h
2i
2j
6.24
_________
* Recrystallization solvent: ethyl acetate.
968

EXPERIMENTAL
Melting points were recorded using a digital Gallenkamp (SANYO) model MPD BM 3.5 apparatus and
1
are uncorrected. H NMR spectra were determined as CDCl3 solutions at 300 MHz on a Bruker AM-300
spectrophotometer. FT IR spectra were recorded using an FTS 3000 MX spectrophotometer; mass spectra (EI,
70 eV) on a GC-MS instrument, and elemental analyses with a LECO-183 CHNS analyzer. All compounds were
purified by thin-layer chromatography using silica gel from Merck and solvent system hexane–ethyl acetate, 4:1.
3-(3-Fluorophenyl)isocoumarin (1a). Rf 0.65. IR spectrum (KBr), n, cm–1: 2980, 1730, 1615. 1H NMR
spectrum, δ, ppm (J, Hz): 6.87 (1H, s, H-4); 8.14 (1H, s, H-2'); 7.56-7.70 (2H, m, H-4',5'); 7.4 (1H, d, J = 2.1,
H-6'); 7.3 (2H, d, J = 7.8, H-5,8); 7.22 (1H, dd, J = 1.8, J = 2.1, H-6); 7.15 (1H, dd, J = 2.5, J = 2.7, H-7). Mass
spectrum, m/z (I, %): 240 (43), 160 (100), 118 (93).
1
3-(4-Fluorophenyl)isocoumarin (1b). Rf 0.55. IR spectrum (KBr), ν, cm–1: 3020, 1725,1590. H NMR
spectrum, δ, ppm (J, Hz): 6.95 (1H, s, H-4); 8.70 (2H, d, J = 7.8, H-3',5'); 7.77 (2H, d, J = 3, H-2',6'); 7.72 (1H,
d, J = 1.2, H-5); 7.51 (3H, m, H-6,7,8). Mass spectrum, m/z (I, %): 240 (43), 160 (100), 118 (93).
3-(2-Chlorobenzyl)isocoumarin (1c). IR spectrum (KBr), ν, cm–1: 2860 (C–H), 1738 (C=O), 1558
1
(C=C). H NMR spectrum, δ, ppm (J, Hz): 2.0 (2H, s, CH2); 6.52 (1H, s, H-4); 7.48-7.51 (2H, m, H-6,7); 7.58
(1H, d, J = 1.6, H-5); 7.65 (1H, d, J = 1.5, H-8); 7.81 (1H, dd, J = 1.5, J = 1.5, H-5'); 7.85 (1H, d, J = 1.5, H-6'); 8.1
(1H, dd, J = 1.5, J = 1.8, H-4'); 8.9 (1H, d, J = 8.1, H-3'). Mass spectrum, m/z (I, %): 272, 270 (43), 160 (100),
118 (93).
1
3-(2-Bromophenyl)isocoumarin (1d). IR spectrum (KBr), ν, cm–1: 3025, 1710, 1590. H NMR
spectrum, δ, ppm (J, Hz): 6.75 (1H, s, H-4); 7.81 (1H, d, J = 2.4, H-3'); 7.55–7.65 (3H, m, H-4'−6'); 7.2-7.3 (4H,
m, H-5−8). Mass spectrum, m/z (I, %): 300 [M]+ (100), 226 (40) 109 (37), 145 (60).
1
3-(3-Iodophenyl)isocoumarin (1e). IR spectrum (KBr), ν, cm–1: 3010, 1725, 1580. H NMR spectrum, δ, ppm
(J, Hz): 6.96 (1H, s, H-4); 8.15 (1H, s, H-2'); 7.96 (1H, d, J = 9, H-4'); 7.67 (1H, d, J = 8.1, H-6'); 7.61 (1H, dd,
J = 4.8, J = 3.3, H-5'); 7.55 (4H, m, H-5–8). Mass spectrum, m/z (I, %): 348.9 (16.4), 347.9 (100.0).
1
3-(2,4-Dichlorophenyl)isocoumarin (1f). IR spectrum (KBr), ν, cm–1: 2970, 1705, 1620. H NMR
spectrum, δ, ppm (J, Hz): 6.95 (1H, s, H-4); 7.6 (1H, d, J = 0.9, H-3'); 7.5 (1H, d, J = 13.2, H-5'); 7.4 (1H, d,
J = 8.5, H-6'); 7.1–7.35 (4H, m, H-5−8). Mass spectrum, m/z (I, %): 291.9 (64.3), 290.9 (16.3).
1
3-(2-Chloro-4-fluorophenyl)isocoumarin (1g). IR spectrum (KBr), ν, cm–1: 2990, 1705, 1595. H
NMR spectrum, δ, ppm (J, Hz): 6.77 (1H, s, H-4); 7.80 (1H, s, H-3'); 7.78 (1H, d, J = 2.7, H-5'); 7.19 (1H, d,
J = 2.4, H-6'); 7.15 (4H, m, H-5–8). Mass spectrum, m/z (I, %): 276.02 (32.4), 274.02 [M]+ (100.0).
3-(3-Nitrophenyl)isocoumarin (1h). IR spectrum (KBr), ν, cm–1: 2893 (C–H), 1734 (C=O), 1512
1
(C=C). H NMR spectrum, δ, ppm (J, Hz): 7.1 (1H, s, H-4); 7.2–7.4 (4H, m, H-5−8); 7.7–7.5 (2H, m, H-5',6');
8.2 (1H, d, J = 8.2, H-4'); 8.4 (1H, s, H-2'). Mass spectrum, m/z (I, %): 267 [M]+ (97.7), 160 (100).
3-(2-Chloro-6-pyridyl)isocoumarin (1i). IR spectrum (KBr), ν, cm–1: 2882 (C–H), 1743 (C=O), 1543
(C=C). 1H NMR spectrum, δ, ppm (J, Hz): 6.95 (1H, s, H-4); 7.2–7.5 (3H, m, H-5–7); 7.6 (1H, d, J = 1.5, H-8);
8.0 (1H, dd, J = 2.2, J = 2.4, H-4'); 8.5 (1H, d, J = 2.1, H-5'); 8.7 (1H, d, J = 1.6, H-3'). Mass spectrum, m/z (I,
%): 336 (34.2), 314 (63.7), 259, 257 [M]+ (97.7), 160 (100), 118 (97.7).
3-Pentadecylisocoumarin (1j). IR spectrum (film), ν, cm–1: 2918, 2849, 1728, 1712, 1656, 1604, 1160,
642. H NMR spectrum, δ, ppm (J, Hz): 0.87 (3H, t, J = 6.3, H-15'); 1.28 (24H, br. s, H-3'–14'); 1.70 (2H, qu,
1
J = 8.4, H-2'); 2.52 (2H, t, J = 7.1, H-1'); 6.24 (1H, s, H-4); 7.34 (1H, d, J = 8.2, H-5); 7.49 (1H, td, J = 0.9,
J = 7.3, H-7); 7.65 (1H, m, H-6); 8.25 (1H, d, J = 8.2, H-8). Mass spectrum, m/z (I, %): 356 [M]+ (97.7), 336
(34.2), 314 (63.7), 160 (100), 118 (97.7).
Conversion of isocoumarins into isoquinolin-1(2H)-ones (General procedure). A mixture of
apropriate isocoumarin 1a–j (10 mmol) and methanamide (10 mmol) was refluxed for 2–4 h (Table 1). On
completion of the reaction, followed by TLC, the solution was poured into water (300 ml). The resulting
precipitates were filtered off and recrystallized from ethyl acetate to afford isoquinolin-1(2H)-ones 2a–j.
969

3-(3-Fluorophenyl)isoquinolin-1(2H)-one (2a). IR spectrum (KBr), ν, cm–1: 3332 (NH), 2825 (C–H),
1
1656 (C=O), 1517 (C=C). H NMR spectrum, δ, ppm (J, Hz): 6.83 (1H, s, H-4); 7.1–7.2 (3H, m, H-5-7); 7.23
(1H, d, J = 2.4, H-8); 7.54 (1H, dd, J = 1.8, J = 1.6, H-5'); 7.70 (1H, d, J = 1.5, H-6'); 7.72 (1H, d, J = 0.9, H-2');
8.4 (1H, d, J = 1.2, H-4'); 10.3 (1H, s, NH). Mass spectrum, m/z (I, %): 240, 239 [M]+ (82.3), 144 (53), 117
(97.7). Found, %: C 75.30; H 4.26; N 5.78. C15H10FNO. Calculated, %: C 75.30; H 4.21; N 5.85.
3-(4-Fluorophenyl)isoquinolin-1(2H)-one (2b). IR spectrum (KBr), ν, cm–1: 3320 (NH), 2870 (C–H),
1630 (C=O), 1527 (C=C). 1H NMR spectrum, δ, ppm (J, Hz): 6.8 (1H, s, H-4);7.4 (1H, dd, J = 1.2, J = 1.1, H-5);
7.5–7.6 (2H, m, H-6,7); 7.63 (1H, d, J = 1.2, H-8); 7.7 (2H, d, J = 1.8, H-2',6'); 8.4 (2H, d, J = 8.4, H-3',5'); 10.54
(1H, s, NH). EI mass spectrum, m/z (I, %): 240, 239 [M]+ (61.3), 144 (53), 117 (98.1). Found, %: C 70.29; H
4.03; N 5.52. C15H10ClNO. Calculated, %: C 70.46; H 3.94; N 5.48.
3-(2-Chlorobenzyl)isoquinolin-1(2H)-one (2c). IR spectrum (KBr), ν, cm–1: 3348 (NH), 2860 (C–H),
1
1638 (C=O), 1558 (C=C). H NMR spectrum, δ, ppm (J, Hz): 2.19 (2H, s, CH2); 6.66 (1H, s, H-4); 7.5-7.55
(2H, m, H-6,7); 7.6 (1H, d, J = 1.5, H-5); 7.7 (1H, d, J = 1.5, H-8); 7.85 (1H, dd, J = 1.5, J = 1.5, H-5'); 7.89
(1H, d, J = 1.5, H-6'); 8.3 (1H, dd, J = 1.5, J = 1.8, H-4'); 9.1 (1H, d, J = 8.1, H-3'); 9.53 (1H, s, NH). Mass
spectrum, m/z (I, %): 271, 269 [M]+ (43.7), 144 (53.5), 117 (59.2). Found, %: C 71.29; H 4.33; N 5.23.
C16H12ClNO. Calculated, %: C 71.25; H 4.48; N 5.19.
3-(2-Bromophenyl)isoquinolin-1(2H)-one (2d). IR spectrum (KBr), ν, cm–1: 3341 (NH), 2864 (C–H),
1635 (C=O), 1535 (C=C). 1H NMR spectrum, δ, ppm (J, Hz): 6.64 (1H, s, H-4); 7.34 (1H, d, J = 1.8, H-5); 7.45–
7.55 (2H, m, H-6,7); 7.63 (1H, d, J = 2.7, H-8); 7.66–7.75 (2H, m, H-4',5'); 8.38 (1H, d, J = 1.5, H-6'); 9.12 (1H,
d, J = 8.4, H-3'); 9.4 (1H, s, NH). Mass spectrum, m/z (I, %): 301, 299 [M]+ (71.3), 144 (62), 117 (87.4). Found,
%: C 60.02; H 3.36; N 4.67. C15H10BrNO. Calculated, %: C 60.02; H 3.36; N 4.67.
3-(3-Iodophenyl)isoquinolin-1(2H)-one (2e). IR spectrum (KBr), ν, cm–1: 3353 (NH), 2892 (C–H),
1643 (C=O), 1533 (C=C). 1H NMR spectrum, δ, ppm (J, Hz): 6.8 (1H, s, H-4); 7.5-7.54 (2H, m, H-6,7); 7.5 (1H,
d, J = 1.2, H-5); 7.6 (1H, d, J = 1.2, H-8); 7.74 (1H, d, J = 1.2, H-6'); 8.1 (1H, t, J = 1.8, H-5'); 8.2 (1H, d,
J = 13.8, H-4'); 8.45 (1H, s, H-2'); 10.6 (1H, s, NH). Mass spectrum, m/z (I, %): 348, 347 [M]+ (16.5), 144 (51),
117 (59.6). Found, %: C 52.10; H 2.97; N 4.08 %. C15H10INO. Calculated, %: C 51.90; H 2.90; N 4.03.
3-(2,4-Dichlorophenyl)isoquinolin-1(2H)-one (2f). IR spectrum (KBr), ν, cm–1: 3330 (NH), 2862 (C–H),
1
1650 (C=O), 1550 (C=C). H NMR spectrum, δ, ppm (J, Hz): 6.63 (1H, s, H-4); 7.5 (1H, d, J = 5.7, H-5);
7.61-7.67 (2H, m, H-6,7); 7.71 (1H, d, J = 6.9, H-8); 7.88 (1H, s, H-3'); 8.46 (1H, d, J = 7.8, H-6'); 9.06 (1H, d,
J = 8.1, H-5'); 10.89 (1H, s, NH). Mass spectrum, m/z (I, %): 291, 289 [M]+ (5.7), 144 (53), 117 (97.7). Found, %:
C 62.17; H 3. 24; N 4.79. C15H9Cl2NO. Calculated, %: C 62.09; H 3.13; N 4.83.
3-(2-Chloro-4-fluorophenyl)isoquinolin-1(2H)-one (2g). IR spectrum (KBr), ν, cm–1: 3381 (NH),
1
2876 (C–H), 1655 (C=O), 1550 (benzene ring). H NMR spectrum, δ, ppm (J, Hz): 6.65 (1H, s, H-4); 7.5-7.6
(2H, m, H-6,7); 7.7 (1H, d, J = 1.2, H-5); 7.8 (1H, d, J = 1.2, H-8); 7.9 (1H, d, J = 1.2, H-6); 8.2 (1H, s, H-3'); 8.4
(1H, d, J = 8.1, H-5'); 10.0 (1H, s, NH, H-3'). Mass spectrum, m/z (I, %): 275, 273 [M]+(72.8), 145 (53), 117
(84.4).. Found, %: C 65.91; H 3.32; N 5.06. C15H9ClFNO. Calculated, %: C 65.83; H 3.31; N 5.12
3-(3-Nitrophenyl)isoquinolin-1(2H)-one (2h). IR spectrum (KBr), ν, cm–1: 3339 (NH), 2821 (C–H),
1
1634 (C=O), 1512 (C=C). H NMR spectrum, δ, ppm (J, Hz): 6.9 (1H, s, H-4); 7.4-7.6 (4H, m, H-5–8); 7.7-7.2
(2H, m, H-5',6'); 8.4 (1H, d, J = 8.4, H-4'); 8.6 (1H, s, H-2'); 8.75 (1H, s, NH). Mass spectrum, m/z (I, %): 266
[M]+ (82.3), 145 (12), 117 (43.0). Found, %: C 67.70; H 3.41; N 10.42. C15H10N2O3. Calculated, %: C 67.67; H
3.79; N 10.52.
3-(2-Chloro-6-pyridyl)isoquinolin-1(2H)-one (2i). IR spectrum (KBr), ν, cm–1: 3353 (NH), 2882 (C–H),
1663 (C=O), 1543 (C=C). 1H NMR spectrum, δ, ppm (J, Hz): 6.84 (1H, s, H-4), 7.5-7.7 (3H, m, H-5,6,7); 7.8 (1H,
d, J = 1.5, H-8); 8.1 (1H, dd, J = 2.4, J = 2.3, H-4'); 8.7 (1H, d, J = 2.2, H-5'); 8.8 (1H, d, J = 1.8, H-3'); 10.2 (1H,
s, NH). Mass spectrum, m/z (I, %): 258, 256 [M]+ (6.9), 145 (32), 118 (63.8). Found, %: C 65.49; H 3.50; N 10.97.
C14H19ClN2O. Calculated, %: C 65.51; H 3.53; N 10.91.
970

3-Pentadecylisoquinolin-1(2H)-one (2j). IR spectrum (KBr), ν, cm–1: 3323 (NH), 2876 (C–H), 1652
1
(C=O), 1513 (C=C). H NMR spectrum, δ, ppm (J, Hz): 0.9 (3H, t, J = 5.1, H-15'); 1.5-1.7 (26H, m, H-2'–14');
2.3 (2H, t, J = 7.5, H-1'); 6.89 (1H, s, H-4); 7.6 (1H, d, J = 1.2, H-5); 7.7-7.74 (2H, m, H-6,7); 8.2 (1H, d,
J = 13.5, H-8); 6.62 (1H, s, NH). Mass spectrum, m/z (I, %): 355 [M]+ (82.3), 145 (43.6), 118 (43.3). Found, %:
C 81.12; H 10.41; N 3.98. C24H37NO. Calculated, %: C 81.07; H 10.49; N 3.94.
The authors are grateful to the Pakistan Science Foundation for a research grant under Project No.
PSF/Res/C-QU/Chem(395).
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