Synthesis of 2,2-dimethyl-1,2-dihydrobenzo[f]-isoquinolines displaying antifungal activity

Article abstract of DOI:10.1007/s10593-011-0694-3

The reaction of 2,2-dimethyl-1,2-dihydrobenzo[f]isoquinoline with malonic acid gave (2,2-dimethyl-1,2,3,4-tetrahydrobenzo[f]isoquinolin-4-yl)acetic acid, the acid chloride of which readily forms esters with alcohols and phenols. Reaction of the same azomethine with thioglycolic acid leads to (2,2-di-methyl-1,2,3,4-tetrahydro-benzo[f]isoquinolin-4-yl)thioacetic acid. Activation of the initial azomethine by iodomethylation enables reaction with 1,3-indanedione to be carried out. The obtained substances display antifungal action.

Full text of DOI:10.1007/s10593-011-0694-3

Chemistry of Heterocyclic Compounds, Vol. 46, No. 12, March, 2011 (Russian Original Vol. 46, No. 12, December, 2010)
SYNTHESIS OF 2,2-DIMETHYL-1,2-DIHYDROBENZO[f]-
ISOQUINOLINES DISPLAYING ANTIFUNGAL ACTIVITY
O. V. Surikova1, A. V. Zachinyaeva2,
A. G. Mikhailovskii1*, and Ya. V. Zachinyaev3
The reaction of 2,2-dimethyl-1,2-dihydrobenzo[f]isoquinoline with malonic acid gave (2,2-dimethyl-
1,2,3,4-tetrahydrobenzo[f]isoquinolin-4-yl)acetic acid, the acid chloride of which readily forms esters
with alcohols and phenols. Reaction of the same azomethine with thioglycolic acid leads to (2,2-di-
methyl-1,2,3,4-tetrahydro-benzo[f]isoquinolin-4-yl)thioacetic acid. Activation of the initial azomethine
by iodomethylation enables reaction with 1,3-indanedione to be carried out. The obtained substances
display antifungal action.
Keywords: 2,2-dimethyl-1,2-dihydrobenzo[f]isoquinoline, (2,2-dimethyl-1,2,3,4-tetrahydrobenzo[f]iso-
quinolin-4-yl)-2-thioacetic acid, (2,2-dimethyl-1,2,3,4-tetrahydrobenzo[f]isoquinolin-4-yl)acetic acid and its
esters, malonic acid, thioglycolic acid, activation of azomethine by iodomethylation, reaction with
1,3-indanedione, antifungal action.
Condensed isoquinolines are an important group of natural and biologically active compounds [1].
Biologically active 2,2-dimethyl-1,2-dihydrobenzo[f]isoquinolines have been obtained previously [2, 3].
Antimicrobial and antifungal preparations are widely known among condensed six-membered heterocycles [4].
The search for new medicinal substances possessing these forms of action is urgent, since strains of pathogenic
microorganisms resistant towards agents used for a long time are readily formed.
The aim of the present work was the investigation of the reactions of a cyclic azomethine derived from
benzo[f]isoquinoline. The derivatives of condensed isoquinolines thus obtained are of interest as substances
displaying activity in relation to pathogenic fungi.
The initial cyclic azomethine 1 was obtained by the cyclocondensation of the appropriate carbinol with
HCN [5-7]. On reaction with 2,2-dimethyl-1,2-dihydrobenzo[f]isoquinoline (1), malonic acid [8] is added at the
imino group and the process is accompanied by decarboxylation leading to acid 2. The acid chloride 3 of this acid
reacts with methanol, 2-propanol, 2-isopropyl-5-methylcyclohexanol (menthol), and 2-isopropyl-5-methyl-
phenol (thymol) with the formation of the corresponding esters 4a-d. Addition of thioglycolic acid to
azomethine 1 is also effected fairly readily. Acid 5 is formed in this way.
_______
* To whom correspondence should be addressed, e-mail: perm@pfa.ru.
1Perm State Pharmaceutical Academy, Perm 614990, Russia.
2S. M. Kirov Military Medical Academy, Saint Petersburg 194044, Russia; e-mail: anvz@rambler.ru.
3St Petersburg State Transport University, Saint Petersburg 190031, Russia; e-mail: yavz@rambler.ru.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1821-1826, December, 2010.
Original article submitted February 15, 2010.
0009-3122/11/4612-1471©2011 Springer Science+Business Media, Inc.
1471

2
Me
Me
Me
N
Me
Me
+
Me
N3
H
1
–
O
Cl
10
7
SOCl2
NH2
O
4
CH2(CO2H)2
–CO2
ROH
9
8
OH
H
Cl
5
H
6
2
3
1
Me
Me
Me
+
NH2
H
Me
HSCH2CO2H
–
N
Cl
O
1
OH
S
OR
H
O
H
5
Me
4a–d
4 a R = Me, b R = i-Pr, c R = menthyl, d R =
i-Pr
The reaction of 2,2-dimethyl-1,2-dihydrobenzo[f]isoquinoline (1) with such CH acid as 1,3-indane-
dione leads to diketone 7, however the process requires activation of the substrate, which is effected by
quaternization of the nitrogen atom (formation of iodomethylate 6). Salt 8 is formed on reaction with iodoacetic
acid ethyl ester, and is a potential dipole in dipolar [3+2] cycloaddition reactions.
Me
Me
Me
+
N
Me
+
Me
MeI
OEt
N
ICH2CO2Et
1
–
I
O
–
I
6
8
O
Me
Me
N
Me
O
O
O
MeONa
7
All the compounds obtained were yellow or white crystalline substances. Iodides 6 and 8 were poorly
soluble in water.
1
In the H NMR spectra of compounds 2, 4a-d (Table 2), unlike the spectrum of the initial imine 1 [7],
the singlet of the azomethine proton was missing from the region ~8.00, a doublet was displayed for the protons
of the methylene group in the 3.07-3.64 region, and also a triplet for the CH group in position 4 in the 4.41-5.12
ppm region. The signal for the protons of the 1-CH2 group in the spectra of compounds 6, 8 was displayed in the
form of a singlet which distinguishes the structure of a 3,4-dihydroisoquinoline from the corresponding 1,2,3,4-
tetrahydro derivatives. The spectrum of base 7 contains two doublets for the CH groups (4.90 and 5.00 ppm)
which points in favor of the diketone form. The spectra of acids 2 and 5 have broadened singlets for the two
+
NH2 protons, which proves the structure of the bipolar ion. All the spectra also contain the proton signals of the
substituents.
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TABLE 1. Characteristics of the Synthesized Compounds
Found, %
Calculated, %
Н
——————
Com-
pound
Empirical
formula
mp, °C
Yield, %
С
N
Cl
—
2
С17Н19NО2
75.9
75.8
67.7
67.6
69.1
69.0
73.1
73.0
74.0
74.0
67.8
67.7
54.8
54.7
81.5
81.3
7.2
7.1
6.8
6.9
7.6
7.5
8.7
8.6
7.5
7.4
6.4
6.3
5.1
5.2
6.3
6.2
5.3
5.2
4.4
4.4
4.1
4.0
3.2
3.2
3.3
3.2
4.7
4.6
4.0
3.9
3.8
3.7
248-250
200-202
224-226
210-212
186-188
72-73
80
76
65
47
52
63
92
54
90
4а
4b
4с
4d
5*
6
С18Н21NO2·НCl
С20Н25NO2·НCl
С27Н37NO2·НCl
С27Н31NO2·НCl
С17Н19NO2S
C16H18IN
11.1
11.0
10.1
10.2
7.8
7.9
8.1
8.0
—
—
—
—
188-190
135-136
180-182
7
C25H23NO2
8
C19H22INO2
53.8
53.9
5.1
5.3
3.4
3.3
_______
*Found, S: 10.5%; calculated, S: 10.6%.
The IR spectra of amino acids 2 and 5 contain bands for the stretching vibrations of the COOH (1650-
1660) and NH+ groups (3050-3100 cm-1). The ester group of compounds 4a-d, 8 is displayed in the region of
1730-1740 cm-1. In the spectrum of diketone 7 bands were observed for the stretching vibrations of two carbonyl
groups in the 1700-1720 cm-1 region. In the mass spectrum of acid 2 there were peaks for the molecular ion 269
[M]+ (5), and also peaks for ions of m/z 254 [M-CH3]+ (8) and 210 [M-CH2COOH]+ (75).
A disc-diffusion method, enabling a primary selection of substances possessing fungicidal activity, was
used to determine the sensitivity of fungi (Candida glabrata, Aspergillus niger, Trichoderma viride,
Saccharomyces cerevisiae, Alternaria alternata) to the antiseptic. Muller-Hinton medium with added Methylene
Blue and glucose was used for the investigation. The screening results showed that 7 out of 9 of the compounds
synthesized displayed activity in relation to the test-cultures used (exceptions were compounds 2 and 4d). The
range of growth inhibition of the fungus was from 12 to 30 mm.
EXPERIMENTAL
1
The IR spectra were obtained on a Specord-80 spectrometer in nujol. The H NMR spectra were
recorded on a Bruker-300 (300 MHz) instrument in CDCl3, internal standard was HMDS (0.05 ppm from TMS).
The mass spectrum of compound 2 was recorded on a Finnigan MAT Incos 50 spectrometer (70 eV, EI). A
check on the purity of the obtained substances was effected by TLC on Silufol UV-254 plates in the system
acetone–ethanol–chloroform, 1:3:6.
Compound 2 was recrystallized from a methanol–water, 1:1, mixture, the remainder from isopropyl
alcohol.
(2,2-Dimethyl-1,2,3,4-tetrahydrobenzo[f]isoquinolin-4-yl)acetic Acid (2). A mixture of azomethine 1
(2.09 g, 10 mmol) and malonic acid (1.04 g, 10 mmol) was heated for ~30 min at 120oC with constant stirring
until the end of carbon dioxide evolution. After cooling to room temperature, methanol (50 ml) was added. The
resulting solid was filtered off, dried, and recrystallized.
1473

1474

Hydrochlorides of the Methyl (4a), Isopropyl (4b), Menthyl (4c), and Thymyl (4d) Esters of (2,2-
Dimethyl-1,2,3,4-tetrahydrobenzo[f]isoquinolin-4-yl)acetic Acid. Thionyl chloride (15 ml) was added to acid
2 (2.68 g, 10 mmol), and the mixture was boiled for 40 min until the solution was black. The excess of thionyl
chloride was distilled off on a water bath. Methanol (1.2 ml, 30 mmol) (for compound 4a), 2-propanol (2.3 ml,
30 mmol) (compound 4b), menthol (2.3 g, 15 mmol) (compound 4c), or thymol (2.2 g, 15 mmol) (compound
4d) was added to the obtained residue of acid chloride 3. The reaction mixture formed was heated for 30 min
(compounds 4c,d) or 15 min (compounds 4a,b). On using thymol (ester 4d) the reaction was carried out in
benzene (30 ml). After cooling to 20oC the mixture was treated with ether (100 ml). The solid formed after 15-
20 min was filtered off, dried, and recrystallized.
(2,2-Dimethyl-1,2,3,4-tetrahydrobenzo[f]isoquinolin-4-yl)thioglycolic Acid (5). Thioglycolic acid
(1 ml, 15 mmol) was added to azomethine 1 (2.09 g, 10 mmol) in benzene (20 ml) and the mixture boiled for 15
min. After cooling to 20oC the mixture was treated with hexane (50 ml). The precipitated solid was filtered off,
dried, and recrystallized.
2,2,3-Trimethyl-1,2-dihydrobenzo[f]isoquinolinium Iodide (6) and 2,2-Dimethyl-3-(ethoxycarbonyl-
methyl)-1,2-dihydrobenzo[f]isoquinolinium Iodide (8). A mixture of azomethine 1 (2.09 g, 10 mmol) in
2-propanol (20 ml) and MeI (0.8 ml, 13 mmol) or ethyl iodoacetate (2.5 g, 12 mmol) was boiled for 2 h, cooled
to 20oC, the precipitated solid was filtered off, dried, and recrystallized.
2-(2,2,3-Trimethyl-1,2,3,4-tetrahydrobenzo[f]isoquinolin-4-yl)-1,3-indanedione (7). 1,3-Indanedione
(1.46 g, 10 mmol) was added to a solution of sodium (1.0 g, 25 mmol) in methanol (50 ml). The obtained
mixture was added to a solution of iodomethylate 6 (3.51 g, 10 mmol) in methanol (20 ml). The mixture was
boiled for 1 h 30 min on a water bath, the solvent distilled, the resulting solid was filtered off, thoroughly
washed with water, dried, and recrystallized.
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