On the Synthesis and Basicity of 1,3-Diaminoisoquinolines

Article abstract of DOI:10.1007/s00706-002-0543-2

A series of 6- and 7-substituted derivatives of 1,3-diaminoisoquinoline were synthesized by the reaction of N,N-diethylarylacetamides with POCl ₃ and then with N,N-dimethylcyanamide. The products were identified by means of spectroscopic methods and their pK_a dissociation constants were determined.

Full text of DOI:10.1007/s00706-002-0543-2

Monatshefte f€ur Chemie 134, 403–409 (2003)
DOI 10.1007/s00706-002-0543-2
On the Synthesis and Basicity
of 1,3-Diaminoisoquinolines
ꢀ
´
Wojciech Zielinski and Agnieszka Kudelko
Institute of Organic Chemistry and Technology, Silesian University of Technology,
PL-44101 Gliwice, Poland
Received July 7, 2002; accepted July 22, 2002
Published online December 19, 2002 # Springer-Verlag 2002
Summary. A series of 6- and 7-substituted derivatives of 1,3-diaminoisoquinoline were synthesized by
the reaction of N,N-diethylarylacetamides with POCl3 and then with N,N-dimethylcyanamide. The
products were identified by means of spectroscopic methods and their pKa dissociation constants were
determined.
Keywords. 1,3-Diaminoisoquinolines; UV=Vis spectroscopy; pKa values.
Introduction
Compounds containing a fused isoquinoline ring represent a broad class of com-
pounds which has received considerable attention over the past years due to their
wide range of biological activities [1]. One of the subgroups are aminoisoquino-
lines. They are interesting due to the central-nervous-system activity shown by
some members of this group [2]. Methods for the construction of 1-amino- or 3-
aminoisoquinolines are rather limited. The most popular one is the nucleophilic
displacement of the appropriate chloro derivatives of isoquinoline with amines [3].
The others involve the reaction of amines with 2-cyanobenzyl cyanide precursors,
which are rather hard to obtain [4]. Earlier studies on the reactions of 2-aryl-1-
alkylvinyl compounds with different nitriles have proved a possibility to synthesize
a wide range of isoquinoline compounds. Such a method is very useful because it
starts from easily accessible alkyl-aryl ketones and organic cyanides which allow
to introduce different substituents in position 1. A few 3-methylisoquinolines sub-
stituted with electron donating or withdrawing groups have been obtained in this
way [5–7].
ꢀ
Corresponding author. E-mail: kudelkoa@zeus.polsl.gliwice.pl

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W. Zielinski and A. Kudelko
404
Results and Discussion
It was interesting to examine the use of N,N-diethylphenylacetamide derivatives
instead of alkyl-aryl ketones as the intermediates in the synthesis of 1,3-diamino-
isoquinolines. Tertiary amides had been applied earlier to the synthesis of 3-ami-
noisoquinolines [8], thus we thought that this method should be reasonable.
The N,N-diethylphenylacetamide derivatives 3a–3g (Scheme 1) were prepared
from the appropriate 3- or 4-substituted phenylacetic acids 1a–1g in two steps.
Phenylacetic acids 1 were reacted with PCl5 in the first step forming arylacetic
chlorides 2. These products were then transformed into the corresponding N,N-
diethylamides by the reaction with diethylamine under mild conditions. The new
N,N-diethylphenylacetamides 3a–3g were obtained in this way with good yields.
The N,N-diethylphenylacetamides 3 were heated with POCl3 in anhydrous
toluene to form diethylimmonium salts 4 (Scheme 2) [9]. These crude products
were reacted with N,N-dimethylcyanamide in toluene producing formamidinium
Scheme 1
Scheme 2

On the Synthesis and Basicity
405
salts [10] which after alkaline hydrolysis probably gave an acyclic product 5, a
derivative of 6-aryl-2-methyl-5-(N,N-diethylamino)-2,4-diaza-3,5-hexadiene [11].
This intermediate 5 underwent cyclization when heated for a few hours in toluene
at elevated temperature. According to this, novel 6- and 7-substituted 1-(N,N-
dimethylamino)-3-(N,N-diethylamino)-isoquinolines were synthesized (6a–6e,
method A) with good yields (66–82%). Our investigation showed that an intramo-
lecular cyclization of the 6-aryl-2-methyl-5-(N,N-diethylamino)-2,4-diaza-3,5-hexa-
diene derivative 5 took place only in the case of the activated compounds
(R ¼OCH3, H, Cl). The intermediates 5 with an electron-withdrawing group
(R ¼ NO2) in position 3 or 4 did not react under these conditions. We also tried
the activation of the formamidinium salts by the use of the Lewis acid catalyst TiCl4
(method B) but the yields of 6a–6e were only little higher (74–89%) in comparison
to method A.
Considering the fact that a biological activity of compounds is also greatly
dependent on their ability to acid–base interactions, the pKa values of 6a–6e were
determined. The determination of the pKa dissociation constants was performed
according to the spectrophotometric method of Albert and Serjeant in 50% aqueous
methanol solution (10À 5 M, room temperature) [12]. The results show that elec-
tron-donating groups in positions 6 or 7 of the isoquinoline ring cause an increase
compared with the pKa of the parent compound 6a (R ¼ H); the opposite holds for
electron-withdrawing groups.
Generally, 1-(N,N-dimethylamino)-isoquinolines are weaker bases than the cor-
responding 1-aminoisoquinolines [7]. It is quite complicated to interpret an inter-
action of substituents in ortho position since the equilibrium depends on field,
induction, resonance, and steric effects [13]. The derivatives with dimethylamino
substituents behave quite unexpectedly because of a considerable secondary steric
effect, which is related to the interaction of bulky substituents in position 1 of
isoquinoline with hydrogen in position 8. This interaction leads to a twist of the
dimethylamino group in 1-position from the ring plane (6a, 7a, Scheme 3), and
consequently to a limitation of electron coupling. It is not observed for small
substituents (8a) which are left untwisted in the ring plane. As a result,
3-methyl-1-(N,N-dimethylamino)-isoquinoline (7a) and 3-(N,N-diethylamino)-1-
(N,N-dimethylamino)-isoquinoline (6a) are weaker bases than 1-amino-3-methy-
isoquinoline (8a) in spite of the fact that the N(CH3)2 group is a better electron
donor than NH2.
Scheme 3

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W. Zielinski and A. Kudelko
406
Table 1. Dissociation constants pKa of isoquinoline bases [14]
Entry
Isoquinoline
pKa
1
2
3
4
5
isoquinolinea
5.42
1-aminoisoquinolinea
7.60
3-aminoisoquinolinea
3-methylisoquinolinea
3-amino-1-(N,N-dimethylamino)isoquinolineb
5.23
5.64
5.88 (6.29c–0.22d–0.19e)
a
b
The measurements were made in 50% methanol–water solution at room temperature; the pre-
c
dicted value according to [16]; dissociation constant pKa for 7a; the introduction of CH3 in 3-
e
position {(4)–(1)}; the introduction of NH2 in 3-position {(3)–(1)}
d
Scheme 4
The replacement of the methyl group in position 3 of the isoquinoline with
strongly electron-donating diethylamino group leads to unexpected changes in the
basicity. It is known that two ortho isomers of aminoisoquinoline behave quite
differently: 3-aminoisoquinoline is a considerably weaker base than 1-aminoiso-
quinoline (Table 1) [14]. This decrease in the base strength has been attributed to
the lower contribution of the resonance structure 9 in the resonance hybride [15].
If such foundation holds the induction effect of the substituent in position 3
should be mainly responsible for the basicity. According to this 6a should be less
basic than 7a because N(C2H5)2 and CH3 groups have opposite induction effects.
Brown and Kanner have estimated the dissociation constants for 2,6-disubstituted
pyridines on the basis of simple additivity [16]. The predicted and observed values
are indeed similar for small substituents. If such a procedure is followed, the
predicted pKa value for 3-amino-1-(N,N-dimethylamino)-isoquinoline would be
5.88 (Table 1). The observed pKa values for isoquinolines 6a–6e (6a, pKa ¼ 6.70)
indicate that the strongly electron-donating substituent in position 3 of isoquinoline
behaves quite differently. The mesomeric effect ( þ M) of the dimethylamino group
leads probably to a higher contribution of the structure 6a–a in the resonance
hybride and 6a is a considerably stronger base than expected.
Experimental
UV spectra were recorded with a Shimadzu UV-2102 spectrophotometer; basic medium: 0.05 M
NaOH in 50% aqueous methanol solution, acidic medium: 0.05M HCl in 50% aqueous methanol
solution. Absorption maxima of the isoquinoline ions (B band) were selected as analytical wave
lengths. Elemental analyses were carried out using a Perkin Elmer 240c analyzer; they were in
1
satisfactory agreement with the calculated values. H-NMR spectra were recorded on a Varian Inova
300 spectrometer in CDCl3 solution. MS were recorded on a Shimadzu QP-200 mass spectrometer.

On the Synthesis and Basicity
407
Thin layer chromatography was carried out on silica gel 60 F254 (Merck) thin layer chromatography
plates using a benzene–ethyl acetate–diethylamine mixture (6:2:1 v=v=v) as the mobile phase. Molec-
ular geometries were optimized and twist angles Y were calculated according to the MNDO method
[17] by means of the WinMopac V2.0 program.
N,N-Diethylphenylacetamide Derivatives 3a–3g – General Procedure
The substituted phenylacetic acid 1 (0.05 mol) was dissolved in 70cm3 anhydrous CHCl3 and cooled
down to 0ꢁC. Then 10.5 g PCl5 (0.05 mol) was gradually added followed by agitation. The mixture was
refluxed for 10–16h until the disappearance of the acid (TLC) was completed. CHCl3 was removed
using a rotary evaporator and the oily residue was distilled under vacuum. The arylacetic chloride 2
obtained in this way was dissolved in 50cm3 diethyl ether and this solution was added dropwise under
agitation to a mixture of 10.4cm3 diethylamine (0.10 mol) and 50cm3 diethyl ether. After the dropping
of arylacetic chloride was completed, agitation was continued for about 15min. Then the precipitate
was filtered off (diethylamine hydrochloride) and the solvent was evaporated. The crude yellowish oily
3 was distilled under vacuum.
N,N-Diethylphenylacetamide (3a, C12H17NO)
1
Yield 93.9%; bp 152–156ꢁC=8 Torr; Rf ¼ 0.38; H NMR: ꢀ ¼ 1.06 (t, J ¼ 7.2 Hz, CH2CH3), 1.11 (t,
J ¼ 7.2 Hz, CH2CH3), 3.27 (q, J ¼ 7.2 Hz, CH2CH3), 3.37 (q, J ¼ 7.2 Hz, CH2CH3), 3.68 (s, CH2-Ph),
7.20–7.26 (m, 5Har) ppm; UV (MeOH): ꢁmax (" ꢂ 10À 3) ¼ 215 (5.99) nm; MS: m=z (%) ¼ 191 (Mþ , 16).
3-Methoxy-N,N-diethylphenylacetamide (3b, C13H19NO2)
Yield 82.7%; bp 206–208ꢁC=23 Torr; Rf ¼ 0.32; 1H NMR: ꢀ ¼ 1.09 (t, J ¼ 7.2 Hz, CH2CH3), 1.12 (t,
J ¼ 7.2 Hz, CH2CH3), 3.29 (q, J ¼ 7.2 Hz, CH2CH3), 3.39 (q, J ¼ 7.2 Hz, CH2CH3), 3.67 (s, CH2-Ph),
3.79 (s, OCH3), 6.68–7.11 (m, 4Har) ppm; MS: m=z (%) ¼ 221 (Mþ , 24).
4-Methoxy-N,N-diethylphenylacetamide (3c, C13H19NO2)
1
Yield 76.5%; bp 194–196ꢁC=9 Torr; Rf ¼ 0.16; H NMR: ꢀ ¼ 1.09 (t, J ¼ 7.2 Hz, CH2CH3), 1.11 (t,
J ¼ 7.2 Hz, CH2CH3), 3.29 (q, J ¼ 7.2 Hz, CH2CH3), 3.37 (q, J ¼ 7.2 Hz, CH2CH3), 3.56 (s, CH2-Ph),
3.73 (s, OCH3), 6.86–7.10 (m, 4Har) ppm; MS: m=z (%) ¼ 221 (Mþ , 26).
3-Chloro-N,N-diethylphenylacetamide (3d, C12H16NOCl)
Yield 86.1%; bp 196–198ꢁC=20 Torr; Rf ¼ 0.34; 1H NMR: ꢀ ¼ 1.06 (t, J ¼ 7.2 Hz, CH2CH3), 1.12 (t,
J ¼ 7.2 Hz, CH2CH3), 3.35 (q, J ¼ 7.2 Hz, 2CH2CH3), 3.62 (s, CH2-Ph), 7.10–7.22 (m, 4Har) ppm;
MS: m=z (%) ¼ 225 (Mþ , 17).
4-Chloro-N,N-diethylphenylacetamide (3e, C12H16NOCl)
Yield 78.4%; bp 202–204ꢁC=15 Torr; Rf ¼ 0.27; 1H NMR: ꢀ ¼ 1.05 (t, J ¼ 7.2 Hz, CH2CH3), 1.13 (t,
J ¼ 7.2 Hz, CH2CH3), 3.28 (q, J ¼ 7.2 Hz, CH2CH3), 3.39 (q, J ¼ 7.2 Hz, CH2CH3), 3.46 (s, CH2-Ph),
7.19–7.29 (m, 4Har) ppm; MS: m=z (%) ¼ 225 (Mþ , 15).
3-Nitro-N,N-diethylphenylacetamide (3f, C12H16N2O3)
Yield 74.5%; bp 194–198ꢁC=27 Torr; Rf ¼ 0.27; 1H NMR: ꢀ ¼ 1.15 (t, J ¼ 7.2 Hz, CH2CH3), 1.20 (t,
J ¼ 7.2 Hz, CH2CH3), 3.36 (q, J ¼ 7.2 Hz, CH2CH3), 3.44 (q, J ¼ 7.2 Hz, CH2CH3), 3.75 (s, CH2-Ph),
7.38–8.14 (m, 4Har) ppm; MS: m=z (%) ¼ 236 (Mþ , 28).

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W. Zielinski and A. Kudelko
408
4-Nitro-N,N-diethylphenylacetamide (3g, C12H16N2O3)
Yield 72.8%; bp 204–206ꢁC=27 Torr; Rf ¼ 0.30; 1H NMR: ꢀ ¼ 1.14 (t, J ¼ 7.2 Hz, CH2CH3), 1.18 (t,
J ¼ 7.2 Hz, CH2CH3), 3.35 (q, J ¼ 7.2 Hz, CH2CH3), 3.41 (q, J ¼ 7.2 Hz, CH2CH3), 3.70 (s, CH2-Ph),
7.32–8.18 (m, 4Har) ppm; MS: m=z (%) ¼ 236 (Mþ , 20).
3-Aryl-2-dichlorophosphoryl-1,1-diethyl-1-azapropenylium Chlorides
4a–4e – General Procedure
The appropriate N,N-diethylarylacetamide 3 (0.05 mol), 70cm3 anhydrous toluene and 10cm3 POCl3
(0.11 mol) were gently heated at about 50ꢁC until the disappearance of amide (TLC) was completed
(15–30min.). Then toluene and POCl3 were removed using a rotary evaporator. The crude product 4
was washed with 50cm3 anhydrous diethyl ether. The oily products 4 were chromatographically pure.
2-Dichlorophosphoryl-1,1-diethyl-3-phenyl 1-azapropenylium Chloride (4a, C12H17NO2PCl3)
1
Yield 96.0%; Rf ¼ 0.05; H NMR: ꢀ ¼ 0.77 (t, J ¼ 7.2 Hz, CH2CH3), 0.98 (t, J ¼ 7.2 Hz, CH2CH3),
1.14 (s, CH2-Ph), 3.19 (q, J ¼ 7.2 Hz, CH2CH3), 3.47 (q, J ¼ 7.2 Hz, CH2CH3), 7.28–7.58 (m, 5Har)
ppm; UV (MeOH): ꢁmax (" ꢂ 10À 3) ¼ 206 (17.50), 298 (12.22) nm.
3-(N,N-Diethylamino)-1-(N,N-dimethylamino)-(6,7)-R-substituted Isoquinolines
6a–6e – General Procedure
The appropriate compound 4 was dissolved in 70cm3 anhydrous toluene and 3.5g N,N-dimethyl-
cyanamide (0.05 mol) in 5 cm3 anhydrous diethyl ether was added and left for 1–2 h.
Method A: The crude formamidinium salt 5 prepared from the diethylimmonium salt 4 and N,N-
dimethylcyanamidewas heated under reflux in 70cm3 toluene for about 4–5 h. The formation of 6 can be
monitored by TLC. After cooling it was alkalyzed with 20% aqueous NaOH and extracted with CHCl3.
The combined extracts were concentrated and chromatographed on silica (benzene:ethyl acetate¼ 3:1).
Method B: A solution of 5 cm3 TiCl4 (0.05 mol) in 10cm3 anhydrous toluene was gradually added to
the crude formamidinium salt 5. The agitation was continued at 50ꢁC for about 3 h. Toluene was
decanted from the resulting gluey solid (salts of 1,3-diaminoisoquinolines) and alkalyzed with 20%
aqueous NaOH. After a rapid decomposition the mixture was extracted with CHCl3. The combined
extracts were concentrated and the crude products 6 were chromatographed as in the method A.
3-(N,N-Diethylamino)-1-(N,N-dimethylamino)-isoquinoline (6a, C15H21N3)
1
Yield 66.0 (A), 76.5 (B) %; Rf ¼ 0.64; H NMR: ꢀ ¼ 1.21 (t, J ¼ 7.2 Hz, 2CH2CH3), 3.01 (s, 2CH3),
3.57 (q, J ¼ 7.2 Hz, 2CH2CH3), 6.11 (s, H-4), 7.01 (dd, J ¼ 7.2, 7.8 Hz, H-7), 7.31 (dd, J ¼ 7.2, 7.8Hz,
H-6), 7.42 (d, J ¼ 7.8 Hz, H-5), 7.85 (d, J ¼ 7.8 Hz, H-8) ppm; UV (MeOH-H2O): ꢁmax
(" ꢂ 10À 3) ¼ 201.2 (27.57), 248.2 (13.40), 312.6 (6.23) nm (acidic), 215.2 (16.85), 243.4 (10.93),
301.4 (6.58) nm (basic); MS: m=z (%) ¼ 243 (Mþ , 100); pKa ¼ 6.70 ꢃ 0.21.
6-Methoxy-3-(N,N-diethylamino)-1-(N,N-dimethylamino)-isoquinoline (6b, C16H23N3O)
1
Yield 82.0 (A), 89.0 (B) %; mp 180–183ꢁC; Rf ¼ 0.63; H NMR: ꢀ ¼ 1.20 (t, J ¼ 7.2 Hz, 2CH2CH3),
3.02 (s, 2CH3), 3.55 (q, J ¼ 7.2 Hz, 2CH2CH3), 3.85 (s, OCH3), 6.05 (s, H-4), 6.65 (d, J ¼ 7.2 Hz, H-7),
6.73 (s, H-5), 7.77 (d, J ¼ 7.2 Hz, H-8) ppm; UV (MeOH-H2O): ꢁmax (" ꢂ 10À 3) ¼ 200.2 (17.26), 289.6
(9.14), 319.0 (7.14) nm (acidic), 216.0 (16.57), 264.0 (17.90), 315.8 (5.44) nm (basic); MS: m=z
(%) ¼ 273 (Mþ , 34); pKa ¼ 7.15 ꢃ 0.12.

On the Synthesis and Basicity
409
7-Methoxy-3-(N,N-diethylamino)-1-(N,N-dimethylamino)-isoquinoline (6c, C16H23N3O)
1
Yield 69.0 (A), 74.0 (B) %; mp 168–170ꢁC; Rf ¼ 0.65; H NMR: ꢀ ¼ 1.19 (t, J ¼ 7.2 Hz, 2CH2CH3),
3.01 (s, 2CH3), 3.55 (q, J ¼ 7.2 Hz, 2CH2CH3), 3.87 (s, OCH3), 6.15 (s, H-4), 7.07 (d, J ¼ 7.8 Hz, H-6),
7.22 (d, J ¼ 7.8 Hz, H-5), 7.38 (s, H-8) ppm; UV (MeOH-H2O): ꢁmax (" ꢂ 10À 3) ¼ 227.4 (23.07), 301.6
(6.24), 348.2 (3.32) nm (acidic), 216.0 (25.48), 303.0 (6.30), 397.0 (2.00) nm (basic); MS: m=z
(%) ¼ 273 (Mþ , 32); pKa ¼ 6.61 ꢃ 0.14.
6-Chloro-3-(N,N-diethylamino)-1-(N,N-dimethylamino)-isoquinoline (6d, C15H20N3Cl)
1
Yield 68.0 (A), 76.0 (B) %; Rf ¼ 0.48; H NMR: ꢀ ¼ 1.23 (t, J ¼ 7.2 Hz, 2CH2CH3), 3.04 (s, 2CH3),
3.54 (q, J ¼ 7.2 Hz, 2CH2CH3), 6.01 (s, H-4), 6.91 (d, J ¼ 7.8Hz, H-7), 7.38 (s, H-5), 7.88 (d,
J ¼ 7.8 Hz, H-6) ppm; UV (MeOH-H2O): ꢁmax (" ꢂ 10À 3) ¼ 200.4 (23.59), 292.8 (3.97) nm (acidic),
214.6 (10.96), 250.0 (5.15), 301.2 (2.10) nm (basic); MS: m=z (%) ¼ 277 (Mþ , 98); pKa ¼
6.45 ꢃ 0.04.
7-Chloro-3-(N,N-diethylamino)-1-(N,N-dimethylamino)-isoquinoline (6e, C15H20N3Cl)
1
Yield 72.0 (A), 80.0 (B) %; mp 170–172ꢁC; Rf ¼ 0.51; H NMR: ꢀ ¼ 1.20 (t, J ¼ 7.2 Hz, 2CH2CH3),
3.04 (s, 2CH3), 3.56 (q, J ¼ 7.2 Hz, 2CH2CH3), 6.08 (s, H-4), 7.09–7.18 (m, H-5,6), 7.85 (s, H-8) ppm;
UV (MeOH-H2O): ꢁmax (" ꢂ 10À 3) ¼ 221.8 (16.30), 322.1 (2.20) nm (acidic), 214.0 (10.41), 260.6
(5.60), 335.8 (3.52) nm (basic); MS: m=z (%) ¼ 277 (Mþ , 100); pKa ¼ 6.14 ꢃ 0.08.
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