3-(Hetarylamino)- and 3-[(hetarylmethyl)amino]-isoquinolin-1(2H)-ones

Article abstract of DOI:10.1007/s10593-010-0531-0

The reaction of 2-(cyanomethyl)benzoic acid with amines RNH₂ (R = Ar, Het, CH₂Ar, CH₂Het) leads to the formation of the corresponding 3-NHR-isoquinolin-1(2H)-ones. When R = CH₂Ar and CH₂Het, there is a side reaction involving hydrolysis of the hydrolytically-unstable intermediates, derivatives of 2-(2-amino-2-iminoethyl) benzoic acid, leading to 2-R-isoquinoline-1,3(2H,4H)-diones.

Full text of DOI:10.1007/s10593-010-0531-0

Chemistry of Heterocyclic Compounds, Vol. 46, No. 4, 2010
3-(HETARYLAMINO)- AND 3-[(HETARYLMETHYL)AMINO]-
ISOQUINOLIN-1(2H)-ONES
L. M. Potikha1*, R. M. Gutsul1, V. A. Kovtunenko1, and A. A. Tolmachev1
The reaction of 2-(cyanomethyl)benzoic acid with amines RNH2 (R = Ar, Het, CH2Ar, CH2Het) leads to
the formation of the corresponding 3-NHR-isoquinolin-1(2H)-ones. When R = CH2Ar and CH2Het,
there is a side reaction involving hydrolysis of the hydrolytically-unstable intermediates, derivatives of
2-(2-amino-2-iminoethyl)benzoic acid, leading to 2-R-isoquinoline-1,3(2H,4H)-diones.
Keywords: amidines, 3-aminoisocarbostyryl, 2-(arylmethyl)- and 2-(hetarylmethyl)isoquinoline-
1,3(2H,4H)-diones, 3-hetarylaminoisoquinolin-1(2H)-ones, 3-(hetarylmethyl)aminoisoquinolin-1(2H)-ones,
homo-phthalimide, 2-(cyanomethyl)benzoic acid.
Interest in the chemistry of derivatives of 3-aminoisoquinolin-1(2H)-one (3-aminoisocarbostyryl) has
increased in recent years with the discovery that some of these compounds have valuable biological activity
[1-4]. The introduction of an additional heterocyclic fragment into the molecule may considerably expand the
spectrum of biological action of these compounds. A convenient method for the synthesis of noncondensed
3-aminoisocarbostyryls based on the reaction of 2-(cyanomethyl)benzoic acid (1) with amines, has previously
been used for the preparation of 3-benzylamino- [5], dialkylamino- [6], and arylaminoisocarbostyryls [6-8]. In
the present work, this approach has been expanded to hetaryl- and (hetarylmethyl)amines.
Heating mixtures of 2-(cyanomethyl)benzoic acid (1) with hetarylamines in high-boiling solvents such
as 1,2-dichlorobenzene, 1:1 DMF-1,2-dichlorobenzene, and DMF for 3-8 h leads to the formation of
3-(hetarylamino)isoquinolin-1(2H)-ones 2a-m (Scheme 1). The reaction product yield depends on the solvent.
The choice of the solvent is a function of the solubility of the starting amine in it. The highest yields of
isoquinolones 2a-m (50-70%) are achieved using chlorobenzene. The effect of the hetaryl substituent on the
reaction result is less pronounced. However, a trend is noted toward increasing yields of product 2 with
increasing basicity of the amine. For example, the yields of 3-pyridylamino derivatives 2d,e were 63-68%, while
the yields for diazinamino derivatives 2a,b,f were only 35-51%. The structure of 3-amino-isocarbostyryls 2a-m
was supported by IR and 1H NMR spectroscopy (Tables 1 and 2).
1
A characteristic feature of the H NMR spectra of isoquinolones 2 is the finding of singlets for H(2),
H(3), and 3-NH group (Table 2). The signal for 3-NH observed in a broad range from 6.7 to 11.5 ppm is the
most sensitive to the nature of the hetaryl substituent. This signal is shifted downfield with increasing
electron-withdrawing properties of the Het substituent. The Het substituent has the same but less pronounced
effect on the signals for H(2) (10.5-13.0 ppm) and H(4) protons (5.2-6.4 ppm).
_______
* To whom correspondence should be addressed, e-mail: potikha-l@mail.ru.
1Taras Shevchenko Kiev National University, Kiev 01033, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 575-590, April, 2010. Original
article submitted February 28, 2008, submitted after revision September 28, 2009.
0009-3122/10/4604-0457©2010 Springer Science+Business Media, Inc.
457

Scheme 1
O
O
O
CO2H
HetCH2NH2
HetNH2
NH
NH
NH
NH
Het
N
Het
+
O
Het
2a–m
1
CN
HN
3a–i
4a–e
O
Me
N
N
N
N
N
N
, e
, d
,
f
a
, c
, b
,
2 Het:
N
N
Me
Me
Me
Me
Me
N O
N
N
N
S
, k
,
, j
,
, i
g
h
NH
N
Me
N
N
Me
Me
, b
Me
N
N
, c
l
,
m
a
3, 4 Het:
;
NH
NH
Ph
N
N
S
S
S
N N
N
d
N
, i
, e
f
, g
, h
,
N
N
N
O
N
Me
Me
The reaction of acid 1 with (hetarylmethyl)amines under the same conditions with 1,2-dichlorobenzene or
1:3 DMF-1,2-dichlorobenzene as solvent has a more complex course. Thus, the reaction with aminomethyl
derivatives of thiophene, 1,3-thiazole, pyrazole, and 1,3,4-triazole in all cases yielded a mixture of two reaction
products in almost equal amounts (~1.15:1.00). The major component was a 3-[(hetarylmethyl)amino]isoquinolin-
1(2H)-one 3a-e, while the minor component was a 2-(hetarylmethyl)isoquinoline-1,3(2H,4H)-dione 4a-e
(Scheme 1). The use of (pyridylmethyl)amines and (2-furylmethyl)amine gave only isoquinolones 3f-i in good yield
(53-69%). All these products 3 and 4 were isolated from the reaction mixtures as pure compounds by
recrystallization with the exception of dione 4e, whose formation was established using 1H NMR spectroscopy and
LC/MS (m/z 256 [M+1]+ (100%)]. The spectral properties of the 3-NHHet (2) and 3-NHCH2Het isoquinolone
1
derivatives 2 are generally similar (Tables 1 and 2). The difference of the H NMR spectra of the 3-NHCH2Het
derivatives 3 is seen in the upfield position of the signal for proton of 3-NH group (5.4-6.3 ppm) in comparison with
the analogous proton in 3-NHHet derivatives 2 (6.7-11.4 ppm) and the formation of an A2X spin system formed by
3-NH with the CH2 protons with coupling constant 5.5-6.0 Hz. The nature of the Het substituent has no significant
1
effect on the position of the signals for H(2) (10.5-10.8 ppm) and H(4) (5.3-5.6 ppm). The H NMR spectra of
homophthalimide derivatives 4a-e (Table 2) have two singlets for the NCH2 protons at 5.1-5.2 ppm and for the
C(4)H2 protons at 4.2 ppm, while their IR spectra have carbonyl group stretching bands at 1709-1723 and
1664-1667 cm-1. The IR spectra of products 2 and 3 show one C=O band at 1650-1675 cm-1 and, furthermore,

NH bands at 3165-3406 cm-1, which are lacking in the spectra of homophthalimides 4.
Thus, the result of the reaction of acid 1 with (hetarylmethyl)amines (Scheme 1) depends on the
nature of the Het substituent. Arylamines, similar to hetarylamines studied in our laboratory, react with
acid 1 to give exclusively 3-(arylamino)isocarbostyryls of type 2 [5-8]. Of the (arylmethyl)amines, only
benzylamine has been used in this reaction. In this case, 3-benzylaminoisocarbostyryl of type 3 was obtained
in 70% yield [5]. Thus, it was of interest to study the reaction of acid 1 with other (arylmethyl)amines, of which (1,3-
benzodioxol-5-ylmethyl)amine and (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amine were selected. In both cases, a
mixture of three products was obtained (Scheme 2). The major components were the corresponding
3-(arylmethylamino)isoquinolin-1(2H)-ones 5a,b obtained in 42-47% yield and 2-(arylmethyl)isoquinoline-
458

Scheme 2
+
O
O
O
N
Ar
NH2
N
Ar
NH
NH
+
1 + ArCH2NH2
O
6a,b
5a,b
7a,b
Ar
O
O
5–7 a Ar =
Ar =
, b
O
O
1,3(2H,4H)-diones 6a,b obtained in 32-34% yield. The composition and structure of products 5 and 6 were in
good accord with the spectral and elemental analysis data. 3-Amino-2-(arylmethyl)isoquinolin-1(2H)-ones 7a,b
were also obtained in these reactions in small amounts (up to 11% yield). The formation of products such as 7
was not previously noted in the reactions of acid 1 with amines. Isoquinolone 7b was isolated from the product
mixture by recrystallization. The composition and structure of this product was established by elemental analysis
1
as well as IR and H NMR spectroscopy. The IR spectrum of isoquinolone 7b shows stretching bands for the
primary amino group at 3412 and 3333 cm-1. The 1H NMR singlet at 5.91 ppm, which exchanges with D2O, was
assigned to this group protons. The broadening of the N(2)CH2 group signal is probably the result of steric
hindrance to rotation about the N(2)–C and C–C(6') single bonds in isoquinolone 7b. The presence of
isoquinolone 7a as the third product of the reaction of (1,3-benzodioxol-5-ylmethyl)amine with acid 1 is
suggested by us on the basis of the thin-layer chromatographic and LC/MS data for this reaction mixture.
Thus, under similar conditions (9:1, benzene–EtOH) relative chromatographic mobility of the mixture
components 5a, 6a, 7a and 5b, 6b, 7b is similar: The Rf values of compounds 5a and 6a (0.71 and 0.70,
respectively), and compounds 5b and 6b (0.91 and 0.90, respectively) insignificantly. But in the case of compounds
7a and 7b, they are much lower (0.58 and 0.69). A LC/MS analysis of the product mixture obtained from
(1,3-benzodioxol- 5-ylmethyl)amine and acid 1 showed three fractions: 1) a product with m/z 296 [M+1]+
corresponding to dione 6a (35% of the mixture), 2) a product with m/z 295 [M+1]+ corresponding to isoquinolone 5a
(51% of the mixture), and 3) a product with m/z 295 [M+1]+ corresponding to the supposed product 7a (10% of the
mixture).
The formation of 2-substituted homophthalimides 4 and 6 from acid 1 eliminated during the formation
and (hetarylmethyl)amines and (arylmethyl)amines (Schemes 1 and 2) is probably a consequence of hydrolysis
of isoquinolones 3 and 5.with the participation of water Thus, when the reaction of acid 1 with (1-methyl-1H-
pyrazol-5-yl-methyl)amine and (2-furylmethyl)amine proceeds under conditions providing for the removal of
water from the reaction medium, the yields of products 3e and 3i were markedly increased (from 49 to 72% for
3e and from 67 to 78% for 3i).
Methods have been reported for the preparation of homophthalimide derivatives based on the reaction of
homophthalic acid (8) or its anhydride with amines [9, 10]. There has been only one report on the preparation of
a 2-alkylhomophthalimide from cyanoacid 1 [11] but this reaction was carried out in a sulfuric acid solution, i.e.,
under conditions facilitating hydrolysis of the cyano group. The resistance of acid 1 to hydrolysis in neutral
media upon heating in aqueous 1,2-dichlorobenzene or aqueous DMF and the independence of the yield of
homophthalimide derivatives on the nature of the amine indicate that diones 4 and 6 are formed not from acid 8
(through pathway I) but from the product of the reaction of acid 1 with the amine (through pathway II) as shown
in Scheme 3, which summarizes our results and literature data on the reaction of acid 1 with various amines (the
numbering of the compounds in the present work is shown in Scheme).
The formation of intermediate amine 9 with possible tautomeric forms A and B was shown by us in the
reaction of acid 1 with (pyridine-2-ylmethyl)amine and (5-methyl-1H-pyrazol-3-yl)amine. Thus, acids 9a and 9b,
respectively were isolated only 10-15 min after the onset of heating of mixtures of these reagents. The composition
1
and structure of acids 9 were shown by elemental analysis as well as IR and H NMR spectroscopy.
459

1
The H NMR spectrum of 9a has signals for the amidine fragment protons at 11.09 and 8.61 ppm, which
exchange with D2O, in addition to the OH group proton signal at 12.15 ppm. The methylene group proton signal
at 4.52 ppm is seen as a doublet with J = 4.0 Hz, which indicates the formation of amidine 9a in form B. The
spectrum of acid 9b has only one signal for the amidine fragment protons at 10.53 ppm, which is strongly
broadened due to rapid exchange of these protons between the two nitrogen atoms in tautomeric forms A and B
(the existence of such forms is characteristic for asymmetrical amidines [12, 13]). Thus, the formation of a
mixture of isomeric products 5 and 7 using (dialkoxybenzyl)amines described above may be attributed to the
cyclization of tautomeric forms A and B of intermediate amidines 9.
Scheme 3
O
CO2H
CO2H
R
O
H2O
RNH2
N
I
4, 6
8
1
II
CO2H
CO2H
CO2H
RNH2
9B, H2O
(R: Alk, CH2Ar,
CH2Het, Ar, Het)
(R: Alk,
CH2Ar,
CH2Het)
H2N
N
R
HN
NH
R
O
NH
R
B
A
10
9a,b
-H2O
9A,B
O
O
R
NH
N
+
NH
R
NH2
2, 3, 5
7
9 a R = pyrid-2-ylmethyl, b R = 3-methyl-1Н-pyrazol-5-yl
Examples are found in the literature for an effect of the nature of the substituent at the nitrogen atom
in acyclic amidines on their resistance to hydrolysis [13]. Our results indicate that amidines 9 with
R = CH2Ar and CH2Het undergo hydrolysis more readily than amidines with R = Ar and Het. These
compounds hydrolyze upon heating with water and are converted to amides of homophthalic acid 10, which
may cyclize to give homophthalimide derivatives 4 and 6 (pathway II) [11, 14, 15]. Thus, we find a definite
dependence of the resistance to hydrolysis of amidines 9 on the inductive effect of substituent R. The
resistance to hydrolysis of amidines 9 increases with increasing electron-withdrawing capacity of R. This
hypothesis is supported by the finding that when R = CH2Het (Het = 2-pyridyl, 3-pyridyl, 4-pyridyl, or 2-
furyl), the corresponding homophthalimide derivatives 4f-i are not formed in detectable amounts.
The inductive effect of the substituent and its bulk affect the major direction for the conversion of
amidines 9, namely, cyclization, as indicated both by our findings and literature data The direction of the
reaction of electrophilic reagents with amidines, to which we may assign amidine cyclization, depends on the
nature of the substituents at the nitrogen atoms and less regioselectivity is found for alkylamidines than for
460

arylamidines [12, 13, 16]. When R = Ar, Het [7, 8], CH2Ph [5], CH2Ar, and CH2Het, the major product of the
reaction of acid 1 with amines RNH2 is 3-NHR-isocarbostyryls 2, 3, and 5. The cyclization of intermediate
amidines 9 clearly proceeds at the more basic and less shielded unsubstituted nitrogen atom. If R is an alkyl
group, which is a stronger electron donor and less bulky substituent, amidines cyclize at the nitrogen atom
bound to this alkyl group to give exclusively 2-alkyl-3-aminoisocarbostyryl 7 [17]. A similar 2-methyl-
substituted product was also obtained in the reaction of the methyl ester of acid 1 with methylamine [18, 19]. In
the case of (arylmethyl)amines studied in this work, the large bulk of the aryl substituent is the factor
determining the low yields of 2-(arylmethyl) derivatives 7a,b and the predominant formation of 3-(arylmethyl)-
TABLE 1. IR Spectra of Compounds 2-7
Com-
pound
, cm–1
2a
2b
3171 (NH), 3047, 1667 (C=O), 1645, 1583, 1443, 1407, 783
3220 (NH), 3126 (NH), 1673 (C=O), 1633, 1614, 1552, 1505, 1340, 1147, 1007,
800, 716
2с
3216 (NH), 3053, 1653 (C=О), 1608, 1552, 1348, 1150, 1010, 783, 755, 680
2d
3200 (NH), 3109 (NH), 3053, 1661 (C=O), 1608, 1580, 1547, 1488, 1438, 1334,
1147, 766
2e
2f
3250 (NH), 3165 (NH), 2997, 1653 (C=O), 1642, 1606, 1583, 1550, 1421, 1284,
803, 750
3227 (NH), 3160 (NH), 3059, 1650 (C=O), 1614, 1550, 1494, 1435, 1365, 1343,
1155, 819, 783
2g
3232 (NH), 3130 (NH), 2980, 1659 (C=O), 1614, 1519, 1471, 1345, 1172, 1152,
1127, 803, 691
2h
2i
3243 (NH), 3145 (NH), 3070, 1664 (C=O), 1620, 1522, 789, 708
3333 (NH), 3305 (NH), 2840, 1661 (C=O), 1633, 1552, 1477, 1426, 1323, 1150, 792
3378 (NH), 3064, 1667 (C=O), 1647, 1566, 1555, 1474, 1424, 1261, 1010, 814, 750
3221 (NH), 1656 (C=O), 1614, 1555, 1510, 1180, 1147, 1015, 828, 769
2j
2k
2l
3300 (NH), 3244 (NH), 3171 (NH), 3092, 1662 (C=O), 1606, 1544, 1508, 1477,
1351, 1178, 1138, 1015, 817, 763
2m
3220 (NH), 3194 (NH), 3120 (NH), 2897, 1666 (C=O), 1607, 1553, 1501, 1470,
1347, 1288, 1148, 971, 777, 743, 706
3а
3b
3c
3274 (NH), 3222 (NH), 3097, 1658 (C=O), 1635, 1607, 1564, 792, 775, 709
3344 (NH), 3109, 1673 (C=O), 1642, 1580, 1519, 1152, 1004, 761, 685
3354 (NH), 3177 (NH), 3057, 1661 (C=O), 1650, 1635, 1610, 1590, 1555, 1475, 1421,
1316, 1190, 1151, 775
3d
3250 (NH), 3210 (NH), 3036, 1659 (C=O), 1639, 1606, 1586, 1541, 1480, 1435, 1323,
1220, 1186, 1152, 764
3e
3f
3356 (NH), 3187, 1670 (C=O), 1634, 1608, 1569, 1485, 1354, 1326, 1200, 1155, 783
3328 (NH), 3064, 1670 (C=O), 1639, 1611, 1592, 1555, 1424, 1189, 772
3406 (NH), 2846, 1675 (C=O), 1634, 1606, 1555, 1491, 1427, 774, 713
3395 (NH), 3277 (NH), 3170, 3008, 1659 (C=O), 1631, 1608, 1555, 1482, 1424, 775
3395 (NH), 3053, 1681 (C=O), 1664, 1631, 1295, 778, 741
3g
3h
3i
4a
2930, 1709 (C=O), 1664 (C=O), 1462, 1427, 1382, 1337, 1323, 1253, 1214, 1130,
741, 721
4b
3098, 2891, 1712 (C=O), 1667 (C=O), 1463, 1382, 1362, 1343, 1253, 1228, 1161, 1004,
971, 769, 741, 694
4c
4d
5a
5b
6a
3098, 1712 (C=O), 1667 (C=O), 1463, 1373, 1329, 1248, 1228, 741
3131, 1723 (C=O), 1664 (C=O), 1415, 1385, 1351, 1329, 1236, 1172, 979, 850, 789, 744
3378 (NH), 3350 (NH), 1667 (C=O), 1645, 1502, 1435, 1250 (C–O), 1189, 1035, 929, 780
3328 (NH), 3216 (NH), 1659 (C=O), 1631, 1508, 1309, 1287 (C–O), 1069, 775
2913, 1714 (C=O), 1667 (C=O), 1491, 1443, 1385, 1365, 1343, 1253 (C–O), 1029,
970, 750
6b
7b
2974, 1709 (C=O), 1659 (C=O), 1588, 1510, 1379, 1331, 1309, 1289 (C–O), 1071,
962, 750
3412 (NH2), 3333 (NH2), 2930, 1659 (C=O), 1625, 1575, 1510, 1315, 1071 (C–O), 803
461

462

463

aminoisocarbostyryls 5a,b. Since the reaction of acid 1 with benzylamine leads exclusively to product 5 [5], the
presence of electron-donor substituents in the aromatic fragment of the (arylmethyl)amines increases the
likelihood of formation isocarbostyryls 7.
TABLE 3. Physicochemical Properties and Elemental Analysis Data of
Compounds Synthesized
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °C*
7
Yield, %
C
3
H
4
N
5
S
6
1
2a
2b
2d
2e
2f
2
8
С13H10N4O
С13H10N4O
С14H11N3O
С14H11N3O
С15H14N4O
С12H9N3OS
С13H11N3O2
С15H16N4O
С14H14N4O
С13H12N4O
С12H10N4O
С11H9N5O
65.33
65.54
65.50
65.54
70.79
70.87
70.81
70.87
67.58
67.65
59.18
59.24
64.66
64.72
67.10
67.15
66.08
66.13
64.92
64.99
63.65
63.71
58.09
58.14
65.54
65.60
68.39
68.45
66.60
66.64
61.11
61.16
66.08
66.13
71.65
71.70
71.66
71.70
71.69
71.70
69.91
69.99
65.28
65.35
68.15
68.24
66.37
66.40
60.85
60.93
69.30
69.38
70.08
70.12
69.10
69.15
4.18
4.23
23.54
23.52
—
—
—
—
—
232-233
38
51
68
63
35
71
49
68
58
47
57
38
46
47
39
45
49
53
69
64
67
40
41
35
42
47
42
32
4.17
4.23
23.51
23.52
297-298
> 280 (dec)
202-203
281-282
272-273
245-246
243-244
218-219
262-263 (dec)
227-228
308-310 (dec)
177-178
244-245
175-175.5
283-284
208-209
196-197
166-167
197-198
141-142 (dec)
137-138
142-143
152-153
227-228
244-245
186-187
163-164
4.61
4.67
17.73
17.71
4.60
4.67
17.71
17.71
5.25
5.30
21.05
21.04
2g
2h
2i
3.68
3.73
17.28
17.27
13.20
13.18
4.56
4.60
17.44
17.42
—
—
—
—
—
—
5.95
6.01
20.87
20.88
2j
5.50
5.55
22.05
22.03
2k
2l
4.98
5.03
23.31
23.32
4.40
4.46
24.78
24.77
2m
3a
3b
3c
3d
3e
3f
3.93
3.99
30.82
30.82
С14H12N2OS
С19H15N3OS
С15H14N2OS
С13H13N5O
С14H14N4O
С15H13N3O
С15H13N3O
С15H13N3O
С14H12N2O2
С14H11NO2S
С19H14N2O2S
С15H13NO2S
С13H12N4O2
С17H14N2O3
С18H16N2O3
С17H13NO4
4.68
4.72
10.95
10.93
12.53
12.51
9.60
9.62
11.87
11.86
—
—
—
—
—
—
4.48
4.53
12.61
12.60
5.18
5.22
10.38
10.36
5.07
5.13
27.44
27.43
5.48
5.55
22.05
22.03
5.17
5.21
16.73
16.72
3g
3h
3i
5.15
5.21
16.74
16.72
5.16
5.21
16.72
16.72
4.97
5.03
11.65
11.66
4a
4b
4c
4d
5a
5b
6a
4.28
4.31
5.44
5.44
12.45
12.46
9.61
9.59
11.85
11.82
—
—
—
—
4.16
4.22
8.39
8.38
4.75
4.83
5.18
5.16
4.67
4.72
21.88
21.86
4.75
4.79
9.54
9.52
5.18
5.23
9.11
9.09
4.38
4.44
4.73
4.74
464

TABLE 3 (continued)
1
2
3
4
5
6
7
8
6b
С18H15NO4
С18H16N2O3
С15H15N3O2
С13H14N4O2
69.82
69.89
70.06
70.12
66.85
66.90
60.38
60.45
4.83
4.89
5.08
5.23
5.58
5.61
5.41
5.46
4.55
4.53
9.10
9.09
15.61
15.60
21.71
21.69
—
—
—
—
153-154
34
11
34
62
7b
9a
9b
208-209
229-230
231-232 (dec)
_______
* Crystallization solvents: 2-propanol for 2a,i-l, 3d, 4d, and 7b, DMF for
2b,d-h, and 9a, acetic acid for 2m, ethanol for 3a-c,e-i, 4a-c, 5a,b, 6a,b,
and 9b.
The heterocycle in 3-aminoisocarbostyryl isoquinolines undergoes opening upon heating with base or
under acid hydrolysis conditions [17, 20, 21]. We have found that products 2, 3, and 5 are stable upon heating in
2 N ethanolic NaOH, while heating these products in 2 N hydrochloric acid gives a mixture of homophthalic
acid 8 and the hydrochloride of the corresponding alkylamine or hetarylamine as shown by elemental analysis
and NMR spectroscopy.
EXPERIMENTAL
The IR spectra were taken on a Perkin-Elmer Spectrum BX spectrometer for KBr pellets. The 1H NMR
spectra were taken on a Varian Mercury-400 spectrometer at 400 MHz for 2-7 and a Bruker Avance DRX 500
spectrometer at 500 MHz for 9. In all cases, DMSO-d6 was the solvent and TMS was the internal standard. The
melting points were determined on a Boetius block and not corrected. The purity of the products was checked by
thin-layer chromatography on Silufol UV-254 plates and by LC/MS on an Agilent 1100 Series instrument with
an Agilent LC/MSD SL detector (the sample was introduced in a TFA matrix). Electron impact mass
spectrometry was employed. The Rf values were determined on Silufol UV-254 plates with 9:1 benzene–ethanol
as the eluent. Column chromatography was carried out using Silica Gel 4600 and 7:3 chloroform–ethanol as the
eluent. The physicochemical and elemental analysis data are given for compounds 2-7 and 9 in Table 3.
A sample of 2-(cyanomethyl)benzoic acid 1 was obtained according to a standard procedure [22], while
3-aminoisoquinolin-1(2H)-one was obtained according to Goya et al. [18]. Commercial samples of all the
hetaryl-, (hetaryl)methyl-, and (arylmethyl)amines were obtained from Enamine.
3-(Hetarylamino)isoquinolin-1(2H)-ones 2a,b,f,k-m (General Method). A suspension of acid 1
(1.61 g, 10.0 mmol) and hetarylamine (10.5 mmol) (hereafter in the syntheses of all 2-7 and 9, the indicated
molar amounts of the reagents were used) was prepared in 1:1 mixture 1,2-dichlorobenzene–DMF (10 ml) and
heated at reflux for 3-4 h. The solvent was evaporated in vacuum. The solid residue was recrystallized from
2-propanol or DMF to give 2a,b,f,k-m.
3-[(1-Oxo-1,2-dihydroisoquinolin-3-yl)amino]isoquinolin-1(2H)-one (2c). A suspension of acid 1 and
3-aminoisoquinolin-1(2H)-one in DMF (10 ml) was heated at reflux for 5 h and then cooled. The precipitate
formed was filtered off, washed with DMF, and recrystallized from DMF. The yield of product 2c was 1.03 g
(34%), mp >310°C (DMF) (mp >300°C (dec.) [23]).
3-(Hetarylamino)isoquinolin-1(2H)-ones 2d,e,g-j (General Method). A suspension of acid 1 and the
corresponding hetarylamine in 1,2-dichlorobenzene (10 ml) was heated at reflux for 7-8 h and then cooled. The
precipitate formed was filtered off, washed with ethanol, and recrystallized from 2-propanol or DMF to give
products 3d,e,g-j.
465

3-[(2-Thiophen-2-ylmethyl)amino]isoquinolin-1(2H)-one (3a), 3-[(3-Methylthiophen-2-ylmethyl)-
amino]isoquinolin-1(2H)-one (3c), 2-(Thiopen-2-ylmethyl)isoquinoline-1,3(2H,4H)-dione (4a), and 2-(3-
Methylthiophen-2-ylmethyl)isoquinoline-1,3(2H,4H)-dione (4c). A suspension of acid 1 and (thiophen-
2-ylmethyl)amine or (3-methylthiophen-2-ylmethyl)amine in 1,2-dichlorobenzene (10 ml) was heated at reflux
for 5 h and then cooled. The precipitate formed was filtered off and washed with ethanol to give a mixture of
products 3a and 4a or of products 3c and 4c, respectively. These mixtures were separated by column
chromatography.
3-[(2-Phenyl-1,3-thiazol-5-ylmethyl)amino]isoquinolin-1(2H)-one (3b) and 2-(2-Phenyl-1,3-thiazol- 5-
ylmethyl)isoquinoline-1,3-(2H,4H)-dione (4b). A suspension of acid 1 and (2-phenyl-1,3-thiazol-5-yl-
methyl)amine in 1,2-dichlorobenzene-DMF (3:1, 10 ml) was heated at reflux for 7 h and then cooled. The
precipitate formed was filtered off, washed with ethanol, and separated into 3b and 4b by column chromatography.
3-[(4-Methyl-4H-1,2,4-triazol-3-ylmethyl)amino]isoquinolin-1(2H)-one (3d) and 2-(4-Methyl-
4H-1,2,4-triazol-3-ylmethyl)isoquinoline-1,3(2H,4H)-dione (4d). The procedure for the preparation of 3b and
4b was used for the reaction of acid 1 and (4-methyl-4H-1,2,4-triazol-3-ylmethyl)amine. Cooling of the reaction
mixture gave a precipitate, which was recrystallized twice from 2-propanol to give product 4d. The filtrate was
evaporated and the residue was recrystallized from 2-propanol to give product 3d.
3-[(1-Methyl-1H-pyrazol-5-ylmethyl)amino]isoquinolin-1(2H)-one (3e). A. The method for the
synthesis of 3b was used for the reaction of acid 1 and (1-methyl-1H-pyrazol-5-ylmethyl)amine to give a
mixture, which, upon cooling, gave an oily precipitate. LC/MS analysis indicated that 70% of the precipitate
consisted of a 5:1 mixture of 3e and 4e. The solution was decanted and evaporated. The residue was
recrystallized from ethanol to give product 3e.
B. A suspension analogous to that described in procedure A was heated at reflux for 7 h in a flask
equipped with a Dean-Stark trap and then cooled. The precipitate formed was filtered off and washed with
ethanol to give 1.83 g (72%) product 3e.
3-[(Pyridylmethyl)amino]isoquinolin-1(2H)-ones 3f-h (General Method). A suspension of acid 1 and
the corresponding pyridylmethylamine in 10 ml 3:1 1,2-dichlorobenzene–DMF was heated at reflux for 7-8 h
and then cooled. The precipitate formed was filtered off, washed with ethanol, and recrystallized twice from
ethanol to give product 3f-h.
3-[(2-Furylmethyl)amino]isoquinolin-1(2H)-one (3i). A. A suspension of acid 1 and 2-furylmethyl-
amine in 10 ml 1,2-dichlorobenzene was heated at reflux for 5 h and then cooled. The precipitate of product 3i
formed was filtered off, washed with ethanol, and recrystallized twice from ethanol.
B. A suspension analogous to that in procedure A was heated at reflux for 5 h in a flask equipped with a
Dean-Stark trap and then cooled. The precipitate formed was filtered off and washed with ethanol to give 1.87 g
(78%) product 3i.
3-[(1,3-Benzodioxol-5-ylmethyl)amino]isoquinolin-1(2H)-one (5a) and 2-(1,3-Benzodioxol-5-yl-
methyl)isoquinoline-1,3(2H,4H)-dione (6a). A suspension of acid 1 and (1,3-bezodioxol-5-ylmethyl)amine in
10 ml 1,2-dichlorobenzene was heated at reflux for 5 h and then cooled. The precipitate formed was filtered off,
washed with ethanol, and subjected to column chromatography to give 5a (Rf 0.71) and 6a (Rf 0.70).
3-[(2,3-Dihydro-1,4-benzodioxin-6-ylmethyl)amino]isoquinolin-1(2H)-one (5b), 2-(2,3-Dihydro-
1,4-benzodioxin-6-ylmethyl)isoquinoline-1,3(2H,4H)-dione (6b), and 3-Amino-2-(2,3-dihydro-1,4-benzo-
dioxin-6-ylmethyl)isoquinolin-1(2H)-one (7b). Products 5b-7b were obtained according to the procedure for
the synthesis of 5a and 6a using (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amine. The precipitate was
recrystallized twice from ethanol to give product 6b (Rf 0.91). The filtrate was evaporated and the residue was
recrystallized from ethanol to give product 5b (Rf 0.90). The filtrate after recrystallization of 5b was evaporated
and 10 ml diethyl ether was added to the residue. The precipitate formed was recrystallized from a small amount
of 2-propanol to give product 7b (Rf 0.69).
466

2-[2-Imino-2-(pyridin-2-ylmethyl)amino]ethylbenzoic Acid (9a). A suspension of acid 1 and
(pyridine-2-ylmethyl)amine in 1,2-dichlorobenzene–DMF (3:1, 5 ml) was heated at reflux for 10 min. After
cooling, the precipitate formed was filtered off, washed with ethanol, and recrystallized twice from DMF to give
acid 9a. IR spectrum, , cm-1: 3200 (br., OH, NH). 3002, 1678 (C=O), 1653 (C=N), 1592, 1538, 1435, 1382,
761. 1H NMR spectrum, , ppm (J, Hz): 12.15 (1H, br. s, OH); 11.09 (1H, br. s, =NH); 8.61 (1H, br. s, CH2NH);
8.53 (1H, d, 3J = 5.0, H-6'); 7.75 (1H, t, 3J = 7.5, H-4'); 7.62 (1H, d, 3J = 8.0, H-6); 7.33-7.17 (5H, m, H-3, H-4,
H-5, H-3', H-5'); 4.52 (2H, d, 3J = 4.0, CH2NH); 3.92 (2H, s, CH2Ar).
2-[2-Imino-2-(3-methyl-1H-pyrazol-5-yl)amino]ethylbenzoic acid (9b). Acid 9b was obtained
according to the procedure for the synthesis of acid 9a using (3-methyl-1H-pyrazol-5-yl)amine. IR spectrum, ,
cm-1: 3240 (br., OH, NH), 2960, 1669 (br., C=O), 1581, 1553, 1384, 1020, 809, 758, 726. 1H NMR spectrum, ,
ppm (J, Hz): 12.60 (1H, s, OH); 10.53 (2H, br. s, NH2); 9.20 (1H, s, NH pyrazole); 7.63 (1H, d, 3J = 8.0, H-6);
7.36-7.25 (3H, m, H-3, H-4, H-5); 5.79 (1H, s, H-4'); 3.96 (2H, s, CH2Ar); 2.22 (3H, s, CH3).
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