Properties of 3,3-dialkyl-3,4-dihydro-isoquinoline cyclic azomethines

Article abstract of DOI:10.1007/s10593-010-0453-x

The reactions of 3,3-dialkyl-3,4-dihydroisoquinoline cyclic azomethines with the methyl ester and p-toluidide of iodoacetic acid gave stable quaternary ammonium salts which were suitable dipoles for [3+2] cycloaddition reactions. Azomethines activated by

Full text of DOI:10.1007/s10593-010-0453-x

Chemistry of Heterocyclic Compounds, Vol. 45, No. 12, 2009
PROPERTIES OF 3,3-DIALKYL-3,4-DIHYDRO-
ISOQUINOLINE CYCLIC AZOMETHINES
O. V. Surikova1*, A. G. Mikhailovskii1, and M. I. Vakhrin1
The reactions of 3,3-dialkyl-3,4-dihydroisoquinoline cyclic azomethines with the methyl ester and
p-toluidide of iodoacetic acid gave stable quaternary ammonium salts which were suitable dipoles for
[3+2] cycloaddition reactions. Azomethines activated by iodomethylation react with potassium cyanide
and malonodinitrile.
Keywords: 3,3-dialkyl-3,4-dihydroisoquinolines, methyl ester and p-toluidide of iodoacetic acid,
quaternary ammonium salts, dipolar [3+2] cycloaddition, reaction with potassium cyanide and
malonodinitrile.
Amongst cyclic azomethines isoquinoline derivatives [1] have greatest value in organic synthesis. We
have previously prepared 3,3-dialkyl-3,4-dihydroisoquinoline cyclic azomethines [2, 3]. The chemical properties
of these compounds have been little studied up to this time. The aim of our work was to study their reaction with
nucleophiles. The goal of the work was also to clarify the use of the named cyclic imine salts as potential dipoles
in [3+2] cycloaddition reactions.
Studies have shown that compounds 1a-c react with methyl iodoacetate to form the stable iodides 2a-c.
The base 1c forms salt 2d similarly with iodoacetic acid p-toluidide. A study of the properties of compounds
1a-c has shown that bases of these cyclic azomethines do not react with C-nucleophiles like KCN or
malonodinitrile without activation. The desired result can be achieved by activation of the imino group via
iodomethylation. Hence reaction of the iodomethylate of imine 1c with potassium cyanide in alcohol gives the
tetrahydroisoquinoline 3 which was characterized as the hydroiodide. The reaction of this compound with
malonodinitrile occurs in the presence of sodium methylate in methanol to give the dinitrile 4. In the absence of
the MeONa the reaction mixture yielded only the starting material.
R1
O
–
R
R
I
+
ICH2C(O)OMe
R1
N
OMe
N
2a–c
1a–c
1,2 a,b R = H, c R = MeO; 1a,c, 2a R1 = Me; 1, 2 b R = (CH2)5, 2c R1 = Me
_______
* To whom correspondence should be addressed, e-mail: migeo@perm.raid.ru.
1Perm State Pharmaceutical Academy, Perm 614990, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1828-1833, December, 2009.
Original article submitted April 7, 2009.
0009-3122/09/4512-1473©2009 Springer Science+Business Media, Inc.
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KCN
–KI
H
N
Me
O
–
–
I
CN
I
+
+
N
C6H4Me-p
N
3
N
Me
H
2d
N
Me
.
1c MeI
CH2(CN)2 / MeONa
NC
CN
2d, 3, 4 R = MeO, R1 = Me
4
The quaternary salts 2a-d obtained were studied as potential dipole components in cycloaddition
reactions. It should be noted that most of the reactions of this type reported in the literature relate to
heteroaromatic systems. The few examples of the use of 3,4-dihydroisquinolines in this reaction are given in the
studies [4, 5]. A feature of compounds 2a-d is their stability upon storage which makes them suitable as
reagents. Pyridine in methylene chloride was used to generate the ylides. Reaction of the ylides obtained from
salt 2c with dimethylmaleate and dimethylfumarate gives the corresponding pyrrolo[2,1-a]isoquinoline
derivatives 5, 6. Similarly, the reaction of the ylide prepared from iodide 2d with dimethylmaleate gives amide
7. According to generally available data [4-6] dipolar cycloaddition reactions occur stereospecifically, i.e. in the
case of dimethylmaleate to give the cis-isomer and for dimethylfumarate the trans isomer as a mixture of exo
and endo forms [5].
Me
MeO
CO2Me
MeO2C
H
N
Me
H
N
CO2Me
CO2Me
H
H
2c
MeO
CO2Me
H
H
H
H
CO2Me
CO2Me
CO2Me
5
6
Me
MeO
MeO
CO2Me
MeO2C
Me
H
N
2d
CONH
C6H4Me-p
H
H
H
CO2Me
CO2Me
7
All of the compounds obtained are yellow, crystalline substances. The iodides 2a-d are sparingly soluble
in water. The characteristics of for the compounds synthesized for the first time are given in Table 1.
1
The H NMR spectra of the quaternary ammonium salts 2a-d (Table 2) show a singlet H-1 proton at
9.78-10.30 ppm which is shifted to low field by about 2 ppm when compared with the shift in the starting
azomethine. By contrast with the spectrum of the starting azomethine the spectrum of the compound 3 base
shows an H-1 proton singlet at 4.97 ppm. The CH group signal is absent in the spectrum of base 4 which points
to an enamine structure. The spectra of bases 5-7 were identified by agreement with the data in [4, 5]. The
condensed tricyclic structure for the materials obtained was confirmed by the presence of four CH group
doublets, two of which (2.10-2.15 ppm and 3.13-3.15 ppm) in positions 1 and 2 are complicated by the
occurrence of interaction with the protons at positions 3 and 10b. The 1H NMR spectra also show signals for the
substituent, e.g. the CH3–Ar group at 2.20 and amide group NH proton singlet at 8.73 ppm (compound 7).
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TABLE 1. Characteristics of the Compounds Synthesized
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
Yield, %
C
H
N
2a
2b
2d
3
C14H18INO2
46.7
46.8
51.0
51.1
53.3
53.4
47.5
47.6
68.6
68.7
60.7
60.6
60.7
60.6
65.8
65.9
5.0
5.1
5.5
5.6
5.4
5.5
5.1
5.2
6.4
6.4
6.8
6.7
6.8
6.7
6.6
6.7
4.0
3.9
3.6
3.5
5.8
5.7
8.4
8.5
14.2
14.1
3.3
3.2
3.1
3.2
5.6
5.5
140-141
152-154
170-171
165-166
138-140
160-162
168-170
137-138
58
53
60
62
71
73
59
57
C17H22INO2
C22H27IN2O3
C13H16IN2•HI
C17H19N3O2
C22H29NO8
C22H29NO8
C28H34N2O7
4
5
6
7
The IR spectra of esters 2a-c contain absorption stretching bands for the ester carbonyl (1730) and the
amides 2d, 7 show amide carbonyl absorption (1680) and amide N–H group bands (3250 cm-1). In the nitriles 3,
4 the absorption bands for the nitrile groups are seen at 2280-2310 cm-1. In the spectra of compounds 5-7 the
ester group absorbs at 1735-1740 cm-1. The mass spectra of esters 5, 6 were recorded for proof of their tricyclic
structure and show molecular ion peaks ([M]+ 435) with intensities 10 and 14% respectively. Their spectra are
characterized by the presence of a peak corresponding to loss of a methoxycarbonyl group (m/z 376, intensities
45 and 53%).
EXPERIMENTAL
1H NMR spectra were recorded on a Bruker-300 (300 MHz) instrument using DMSO-d6 (compounds
2b, 3, 4) or CDCl3 (compounds 2a,d, 5-7) with HMDS as internal standard. IR spectra were taken on a Specord
M-80 spectrometer using vaseline oil. Mass spectra were recorded on a Finnigan MAT INCOS 50 instrument
(70 eV, EI). Confirmation of the purity of the compounds obtained was carried out using TLC on Silufol
UV-254 plates in the system acetone–ethanol–chloroform (1:3:6) and revealed using UV light and iodine vapor.
The synthesis of the starting azomethines, compound 2c, and compound 1c iodomethylate has been reported in
[2, 3]. All of the compounds were recrystallized from alcohol.
N-Methoxycarbonylmethyl-6,7-(R)2-3,3-(R1)2-3,4-dihydroisoquinolinium Iodides 2a-c and N-(N-
p-tolylcarbamoylmethyl)-6,7-dimethoxy-3,3-dimethyl-3,4-dihydroisoquinolinium Iodide (2d). The methyl
ester or N-p-tolylamide of iodoacetic acid (12 mmol) was added to a solution of the imine 1a-c (10 mmol) in
2-propanol (5-10 ml), refluxed for 2 h, and cooled to 20ºC. The precipitate was filtered off, dried, and
recrystallized.
1-Cyano-6,7-dimethoxy-2,3,3-trimethyl-1,2,3,4-tetrahydroisoquinoline (3). A solution of KCN
(0.78 g, 12 mmol) in water (5-7 ml) was added to a suspension of the imine iodomethylate 2c (3.61 g, 10 mmol)
in ethanol (30 ml). The mixture was refluxed for 1 h, solvent was evaporated in vacuo, and the residue was
treated with aqueous ammonia. The resulting oil was extracted with ether and the ether layer was washed with
water, solvent was distilled off, and HI (48%, 1.4 ml) was added to form the hydroiodide of compound 3. The
product was filtered off, dried, and recrystallized. The base compound 3 was prepared by treating the
hydroiodide with a solution of ammonia.
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1-Dicyanomethylidene-6,7-dimethoxy-2,3,3-trimethyl-1,2,3,4-tetrahydroisoquinoline (4). Sodium
(1.0 gm 25 mmol) was dissolved in methanol (50 ml). Malonodinitrile (0.66 g, 10 mmol) was added to the
obtained solution and the mixture was then added to a solution of the iodomethylate 2c (3.61 g, 10 mmol) in
methanol (150 ml). The mixture was refluxed for 2 h, solvent was distilled off, and the residue formed was
filtered off and thoroughly washed with water, dried, and recrystallized.
Trimethyl Esters of 8,9-Dimethoxy-5,5-dimethyl-1,2,3,5,6,10b-hexahydro-1,2,3-tricarboxylic Acid
(5, 6) and 1,2-dimethyl Ester of 8,9-Dimethoxy-5,5-dimethyl-1,2,3,5,6,10b-hexahydro-1,2,3-tricarboxylic
acid 3-N-p-Tolylamide (7). The corresponding dipolarophile (10 mmol) was added to a solution of the
appropriate quaternary ammonium salt (10 mmol) in pyridine (5-7 ml) and methylene chloride (10 ml). Heating
of the solution was observed. The mixture was left for 24 h at 20ºC, methylene chloride was distilled off, and the
product was diluted with water (150 ml). The precipitate was filtered off, dried, and recrystallized.
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