Alkylation of 3-aminoisocarbostyryl derivatives

Article abstract of DOI:10.1007/s10593-011-0758-4

The alkylation of derivatives of 3-aminoisoquinolin-1(2H)-one in the presence of NaH may proceed in three directions: 1) at the carbonyl group oxygen atom, 2) at the nitrogen atom N-2, and 3) at the 3-amino group. The reaction of equivalent amounts of the reagents gives predominantly products of substitution at the 3-amino group. Repeated alkylation proceeds at the lactam fragment to give a mixture of O-alkyl and N-alkyl derivatives. Acylation of 3-dialkylamino- and 3-alkylanilinoisoquinolin- 1(2H)-ones in the presence of NaH gave derivatives of 3-amino-1-isoquinolinyl 4-ethoxybenzoate.

Full text of DOI:10.1007/s10593-011-0758-4

Chemistry of Heterocyclic Compounds, Vol. 47, No. 3, June, 2011 (Russian Original Vol. 47, No. 3, March, 2011)
ALKYLATION OF 3-AMINOISOCARBOSTYRYL DERIVATIVES
L. M. Potikha1*, R. M Gutsul 2, V. A. Kovtunenko1, and A. V. Turov1
The alkylation of derivatives of 3-aminoisoquinolin-1(2H)-one in the presence of NaH may proceed in
three directions: 1) at the carbonyl group oxygen atom, 2) at the nitrogen atom N-2, and 3) at the
3-amino group. The reaction of equivalent amounts of the reagents gives predominantly products of
substitution at the 3-amino group. Repeated alkylation proceeds at the lactam fragment to give a
mixture of O-alkyl and N-alkyl derivatives. Acylation of 3-dialkylamino- and 3-alkylanilinoisoquinolin-
1(2H)-ones in the presence of NaH gave derivatives of 3-amino-1-isoquinolinyl 4-ethoxybenzoate.
Keywords: 3-aminoisocarbostyryl, 3-amino-1-isoquinolinol, enamine, isoquinoline, alkylation.
In this work, we continued our study of the chemical properties of uncondensed derivatives of
3-aminoisoquinolin-1(2H)-one (3-aminoisocarbostyryl) [1, 2] and examined the reaction of alkyl halides with
isocarbostyryls substituted at the 3-amino group. The alkylation of 3-aminoisocarbostyryls has been studied
previously predominantly for condensed systems (reactions with alkyl halides [3-6] and dimethyl sulfate [7]).
Only the 1,4-conjugate addition of olefins to 3-aminoisoquinolin-1(2H)-one has been described for uncondensed
derivatives [8].
Electrophilic substitution in 3-aminocarbostyryls, which are ambident nucleophiles, leads to different
products depending both on the structure of the reagents and reaction conditions [3-7]. Thus, heating solutions
of 3-(arylamino)isoquinolin-1(2H)-ones 1a-c and 3-(alkylamino)isoquinolin-1(2H)-ones 1d and 1e in
acetonitrile with phenacyl bromide or alkyl halides (MeI, EtI, benzyl chloride) leads to a complex mixture of
reaction products, which failed to be separated. The same result was obtained in an attempt to carry out the
reaction by fusion of a mixture of reagents (with phenacyl bromide and benzyl chloride) or heating of the
mixture in the presence of i-OPrNa in 2-propanol (according to mass-spectrometric and 1H NMR spectral data).
We have found that compounds 1a,b,d,e react with alkyl halides (MeI, EtI, and benzyl chloride) in
DMF solution at room temperature in the presence of NaH and are converted into 3-(alkylanilino)isoquinolin-
1(2H)-ones 2a and 2b and 3-(dialkylamino)isoquinolin-1(2H)-ones 2c-e.
Isoquinolinones 2a-e were isolated from the reaction product mixtures as pure compounds and their
1
structures were established using H NMR spectroscopy (Tables 1-3). The major criterion for structure
assignment was the presence or absence of signals for the protons H-2, H-4, and 3-NH, which are observed in
_______
* To whom correspondence should be addressed, e-mail: potikha_l@mail.ru.
1Taras Shevchenko National University, 64 Volodyimirska St., 01033 Kyiv, Ukraine
2UkrOrgSynthesis, 29 Shchorsa St., 01133 Kyiv, Ukraine, e-mail: rm80@mail.ru.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 379-386, March, 2010. Original
article submitted February 21, 2010.
0009-3122/11/4703-0309©2011 Springer Science+Business Media, Inc.
309

the starting 3-aminoisocarbostyryls in different chemical shift ranges and differ in their multiplicity (for 1d,e) [1,
2, 9]: 10.5-10.7 (s, H-2), 5.4-5.9 (s, H-4), 7.6-7.9 (s, 3-NH, 1a-c) and 5.4-5.9 ppm (t, 3-NH, 1d,e). The signal for
3-NH proton is lacking in the spectra of the alkylation products, indicating the formation of compounds with
structure 2.
O
OMe
N
Me
F
N
(1 : 2)
+
Et
N
N
3a
4a
Et
MeI
O
N
F
O
O
O
R1Hal
4-EtOC6H4COCl
NH
NH
OEt
R
R
R
N
H
N
N
R1
R1
1a–e
2a–e
5a,b
2 equiv. EtI
OEt
O
OMe
Et
N
OMe
N
N
N
Et
Et
3c
4c
O
1,2 a R = 4-FC6H4, b R = 4-MeC6H4; 1c R = 4-MeOC6H4; 1d, 2c,d R =
1e, 2e R =
,
O
2 a,d R1 = Et, b R1 = CH2Ph, c,e R1 = Me;
;
O
O
, R1 = Me
5 a R = 4-MeC6H4, R1 = CH2Ph;
b R =
O
Another reaction product, namely, 1-ethoxy-N-ethyl-N-(4-methoxyphenyl)-3-isoquinolinamine (3c) was
isolated in low yield (25%) in the case of 3-(4-methoxyanilinoisoquinolin-1(2H)-one 1c under the same
conditions in DMF using NaH and EtI. The formation of a dialkyl derivative was indicated by mass
1
1
spectrometry and the H NMR spectrum. Signals for two ethyl groups are present in the H NMR spectrum of
3c, while the lack of both NH signals indicates formation of a disubstitution product at the heteroatoms of the
3-aminoisocarbostyryl system with structure 3c or 4c. The final conclusion concerning the structure of this
13
diethyl derivative was made using the data from the C NMR spectrum and two-dimensional HMQC, HMBC,
and NOESY correlation spectroscopy. Figure 1 shows the assignment of the signals in the NMR spectra from an
analysis of the observed correlations. The value of the chemical shift for the atom C-1 (159.5 ppm) observed in a
region uncharacteristic for carbonyl group carbon atoms but normal for O-alkyl or O-acyl derivatives of
3-aminoisocarbostyryls [1, 10] was the primary data enabling us to opt for the structure 3c.
310

TABLE 1. Physicochemical Data for Isoquinoline Derivatives 2a-e, 3a,
5a,b
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, оС *
Yield, %
C
H
N
С17H15FN2O
С23H20N2O
С18H16N2O3
С19H18N2O3
С15H14N2O2
С20H22N2O2
С32H28N2O3
С27H24N2O5
72.26
72.32
81.10
81.15
70.07
70.12
70.72
70.79
70.80
70.85
74.46
74.51
78.62
78.67
70.99
71.04
5.32
5.36
5.88
5.92
5.20
5.23
5.59
5.63
5.48
5.55
6.85
6.88
5.73
5.78
5.28
5.30
9.95
9.92
8.24
8.23
9.11
9.09
8.70
8.69
11.01
11.02
8.71
8.69
5.75
5.73
6.15
6.14
166-167
175-176
190-191
118-119
174-175
97-98
48
65
53
46
38
25
34
42
2a
2b
2с
2d
2e
3a
5a
5b
131-132
141-142
_______
*Solvents: acetic acid for 2a, ethanol for 2b, 3a, 2-propanol for 2c-e, 5a,b.
TABLE 2. IR Spectra for Isoquinoline Derivatives 2a-e, 3a, 5a, and 5b
Com-
, cm1
pound
3160 (NH), 3064, 2964, 1639 (C=O), 1622, 1552, 1510, 1214, 1152, 1121, 842, 750
2a
2b
3148 (NH), 3036, 2918, 2857, 1636 (br. s, C=O), 1603, 1552, 1513, 1371, 1175, 1152,
962, 844, 811, 750, 719, 697
3260 (NH), 3170, 2992, 1650 (C=O), 1616, 1602, 1555, 1505, 1303, 1287, 1256 (C–O),
1071, 816, 769
2с
3170 (NH), 2975, 1642 (C=O), 1617, 1555, 1508, 1432, 1351, 1309, 1287 (C–O), 1071,
772
2d
3182 (NH), 3103, 1628 ( br., C=O), 1600, 1555, 1371, 1267, 1147, 1001, 914, 775
2e
3a
2974, 2932, 1626 (C=O), 1582, 1572, 1512, 1473, 1413, 1369, 1325, 1295, 1246 (C–O),
1098, 844, 800, 747, 671
3025, 2986, 1731 (C=O), 1631, 1605, 1589, 1513, 1460, 1248 (уш., C–O), 1169, 1150,
1080 (C–O), 825, 761, 722
5a
5b
2937, 1732 (C=O), 1637, 1593, 1508, 1253 (br., C–O), 1172, 1071 (br., C–O), 821, 761
The formation of a disubstitution product led us to a more detailed study of repeated substitution in
3-aminoisocarbostyryls. Thus, we found that under the conditions described above in DMF using NaH and MeI,
compound 2a is converted into a mixture of dialkylation products. The GC/MS data indicated that this mixture
consists of two components with the same molecular mass (m/z 297.2 [M+1]+) but with different retention times.
Attempts to separate the mixture by chromatography or recrystallization led only to mixtures with up to 70-85%
content of one of the mixture components.
The 1H NMR spectrum of the mixture showed the presence of two sets of proton signals in 1:2 ratio. The
signal for the amide fragment H-2 with  > 10.0 ppm is lacking but one-proton singlets at 6.63 and 6.11 ppm are
found in the resonance region for H-4. These data suggest the formation of a mixture of products of O- and
N-alkylation. Comparing the spectrum of the mixture with the spectrum of diethyl derivative 3c, we concluded
that a 1:2 mixture of compounds 3a and 4a is formed in the reaction of compound 2a with MeI. The marked
downfield shift of the signal for H-4 proton in the spectrum of 3-[ethyl(4-fluorophenyl)amino]-
2-methylisoquinolin-1(2H)-one 4a in comparison with the N-ethyl-N-(4-fluorophenyl)-1-methoxy-
311

312

3-isoquinolinamine 3a ( ~ 0.5 ppm), in our opinion, should be attributed to the spatial position of the phenyl
substituent in the 3-amino group. The introduction of a methyl group at N(2) leads to inhibition of free rotation
about the C(3)-NEt(4-FC6H4) single bond and fixation of the bulky benzene ring in the trans position relative to
the 2-NMe fragment. In this conformation, proton H-4 falls in the deshielding zone of the 4-fluorophenyl
substituent.
4.50
61.7
NOE
1.48
O
CH3
7.90
124.3
15.2
159.5
55.7
O
7.02
7.31
N
3.81
CH3
157.9
115.4
6.95
113.0
141.2
138.3
1'
153.7
NOE
N
91.9
129.7
7.17
124.7
7.21
45.4
5.87
14.2
CH3
3.96
1.21
NOE
NOE
Fig. 1. Structurally-significant NOESY and HMBC correlations for compound 3c.
We then studied the acylation of N,N-disubstituted derivatives of 3-aminoisocarbostyryls 2. The
reaction of 2b and 2c with 4-ethoxybenzoyl chloride in the presence of NaH leads to the formation of
O-acylation products, namely, 3-[benzyl(4-methylphenyl)amino]isoquinolin-1-yl 4-ethoxybenzoate (5a) and
3-[(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(methyl)amino]isoquinolin-1-yl 4-ethoxybenzoate (5b), respecti-
vely. This result is primarily indicated by the IR spectra of the reaction products. The NH group stretching bands
are lacking, while the strong band at 1731-1732 cm-1 corresponds to carbonyl group stretching vibrations in the
region characteristic for esters of carboxylic acids (Table 2). The 1H NMR spectra of these products correspond
to the spectra of O-acyl derivatives of 3-aminoisocarbostyryls observed in our previous work [1].
Thus, the 3-amino group nitrogen atom is the preferred site for alkylation of 3-aminoisocarbostyryls by
alkyl halides in the presence of a strong base (NaH). Repeated alkylation under these conditions proceeds at the
lactam fragment to give a mixture of O-alkyl and N-alkyl derivatives, in which the product of substitution at the
nitrogen atom predominates. The carbonyl group oxygen atom is the predominant site for acylation in
N,N-disubstituted derivatives of 3-aminoisocarbostyryls.
EXPERIMENTAL
1
The IR spectra were taken on a Perkin-Elmer Spectrum BX spectrometer for KBr pellets. The H and
13C NMR spectra of the products and the HMQC and HMBC heteronuclear correlation experiments were carried
out on a Varian Mercury-400 spectrometer at 400 and 100 MHz, respectively, in DMSO-d6 with TMS as the
internal standard. The melting points were determined on a Boetius heating block and were uncorrected. The
purity of the products was monitored by HPLC/MS using an Agilent 1100 Series instrument with an Agilent
LC/MSD SL selective detector. The sample was introduced in a thermoplastic polyurethane (TPU) matrix with
electron impact ionization. The physicochemical data and elemental analysis results for the products are given in
Tables 1-3.
313

3-(Arylamino)isoquinolin-1(2H)-ones 1a and 1c were obtained according to our previous procedure [1],
3-(4-methylanilino)isoquinolin-1(2H)-one (1b) according to procedure in [2] and 3-alkylaminoisoquinolin-
1(2H)-ones 1d and 1e according to procedure in [9].
3-(Alkylanilino)isoquinolin-1(2H)-ones 2a and 2b and 3-(dialkylamino)isoquinolin-1(2H)-ones 2c-e
(General Method). NaH (2.4 g, 100 mmol) was added to a solution of 3-aminoisocarbostyryl 1a,b or 1d¸e (5
mmol) in DMF (20 ml) and, after 20 min, methyl iodide, ethyl iodide, or benzyl chloride (5.5 mmol) was added.
The mixture was stirred at room temperature for 20 h. The solvent was evaporated in vacuum. Then, water (50
ml) was added and the oily precipitate was separated by decanting the aqueous solution. The oil was dissolved in
hot 2-propanol. After cooling, the precipitate formed was filtered off.
1-Ethoxy-N-ethyl-N-(4-methoxyphenyl)-3-isoquinolinamine (3c) was obtained by the procedure for
the synthesis of isoquinolinones 2 using ethyl iodide (0.88 ml, 11 mmol). 13C NMR spectrum, δ, ppm: 159.5 (C-
1); 157.9 (C-4'); 153.7 (C-3); 141.2 (C-4a); 138.3 (C-1'); 130.5 (C-6); 129.7 (C-2', C-6'); 124.7 (C-5); 124.3 (C-
8); 121.6 (C-7); 115.4 (C-3', C-5'); 113.0 (C-8a); 91.9 (C-4); 61.7 (OCH2); 55.7 (OCH3); 45.4 (NCH2); 15.2
(OCH2CH3); 14.2 (NCH2CH3).
Methylation of 3-(N-ethyl-4-fluoroanilino)isoquinolin-1(2H)-one (2a) was carried out by the
procedure for the preparation of 2 using 2a (1.41 g, 5.0 mmol) and methyl iodide(0.37 ml, 6.0 mmol). The solid
product was a 1:2 mixture of N-ethyl-N-(4-fluorophenyl-1-methoxy)-3-isoquinolinamine (3a) and 3-[N-
1
ethyl(4-fluorophenyl)amino]-2-methylisoquinolin-1(2H)-one (4a). H NMR spectrum, δ, ppm (J, Hz): 8.23
(1H, d, 3J = 8.0, H-8 (4a)); 7.92 (1H, d, 3J = 8.0, H-8 (3a)); 7.69 (1H, t, 3J = 8.0, H-6 (4a)); 7.64 (1H, d, 3J = 8.0,
H-5 (4a)); 7.48 (1H, t, 3J = 8.0, H-7 (4a)); 7.42 (2H, m, H-5, H-6 (3a)); 7.35 (2H, m, H-2', H-6' (3a)); 7.28 (2H,
m, H-3', H-5' (3a)); 7.15 (1H, m, H-7 (3a)); 7.06 (2H, m, H-3', H-5' (4a)); 6.74 (2H, m, H-2', H-6' (4a)); 6.63
3
(1H, s, H-4 (4a));, 6.11 (1H, s, H-4 (3a)); 3.98 (5H, m, OCH3, NCH2 (3a)); 3.68 (2H, q, J = 7.0, NCH2 (4a));
3.37 (3H, s, NCH3 (4a)); 1.21 (6H, m, NCH2CH3 (3a+4a)).
3-[Benzyl(4-methylphenyl)amino]isoquinolin-1-yl 4-Ethoxybenzoate (5a) and 3-[(2,3-Dihydro-
1,4-benzodioxin-6-ylmethyl)(methyl)amino]isoquinolin-1-yl 4-Ethoxybenzoate (5b) (General Method).
NaH (2.4 g) was added to a solution of 3-aminoisocarbostyryl 2a or 2c (5 mmol) in DMF (20 ml). After 20 min,
4-ethoxybenzoyl chloride (1.38 g, 7.5 mmol) was added and stirred at room temperature for 10 h. The solvent
was evaporated in vacuum and water (50 ml) was added to the residue. The solid was filtered off.
Ethoxybenzoate 5a. 13C NMR spectrum, δ, ppm: 192.3 (4-C=O); 162.8 (C-1); 161.6 (C-4"); 152.0
(C-3); 151.3 (C-2'); 143.1 (C-5'); 139.3 (C-4a); 134.6 (C-1"); 131.6 (C-6); 131.3 (C-2", C-6"); 127.4 (C-8);
126.3 (C-5); 122.5 (C-7);, 120.3 (C-8a); 114.3 (C-3", C-5"); 110.9 (C-4'); 108.1 (C-3'); 96.3 (C-4); 63.8 (OCH2);
39.3 (NCH2);, 15.2 (CH2CH3).
REFERENCES
1.
L. M. Potikha, R. M. Gutsul, V. A. Kovtunenko, and A. V. Turov, Khim. Geterotsikl. Soedin., 718
(2010). [Chem. Heterocycl. Comp., 46, 569 (2010)].
2.
3.
4.
5.
T. T. Kucherenko, R. Gutsul, V. M. Kisel, and V. A. Kovtunenko, Tetrahedron, 60, 211 (2004).
J. P. Paolini, F. P. Palopoli, and L. J. Lendvay, J. Heterocycl. Chem., 24, 549 (1987).
W. A. Bolhofer and E. J. Cragoe, Jr, US Patent 4,133,885; Chem. Abstr., 90, 137793 (1979).
L. M. Potikha, N. V. Danileiko, V. M. Kisel, and V. A. Kovtunenko, Khim. Geterotsikl. Soedin., 1214
(2004) [Chem. Heterocycl. Comp., 40, 1052 (2004)].
6.
K. Nagarajan, V. Ranga Rao, R. K. Shah, S. J. Shenoy, H. Fritz, W. J. Richter, and D. Muller, Helv.
Chim. Acta, 71, 77 (1988).
314

7.
8.
S. Goya, A. Takadate, T. Tanaka, and H. Nagayama, Yakugaku Zasshi, 95, 340 (1975); Chem. Abstr.,
83, 58764 (1975).
S. Ohta, S. Kimoto, and M. Okamoto, Yakugaku Zasshi, 92, 1473 (1972); Chem. Abstr., 78, 97517
(1973).
9.
L. M. Potikha, R. M. Gutsul, V. A. Kovtunenko, and A. A. Tolmachev, Khim. Geterotsikl. Soedin., 575
(2010) [Chem. Heterocycl. Comp., 46, 457 (2010)].
10.
G. Winters, N. Di Molla, M. Berti, V. Arioli, Farmaco, 34, 507 (1979).
315