Enamines of the 1,2,3,4-tetrahydroiso-quinoline series in the Chichibabin synthesis of pyrrolo[2,1-a]isoquinolines and in reaction with oxalyl chloride

Article abstract of DOI:10.1007/s10593-007-0142-6

It has been shown that the Chichibabin reaction of enamines of the 1,2,3,4-tetrahydroisoquinoline series and 1,2,3,4-tetrahydrobenzo[f]isoquinoline series with p-bromophenacyl bromide leads to pyrrolo[2,1-a]isoquinoline derivatives. The same heterocyclic

Full text of DOI:10.1007/s10593-007-0142-6

Chemistry of Heterocyclic Compounds, Vol. 43, No. 7, 2007
ENAMINES OF THE 1,2,3,4-TETRAHYDROISO-
QUINOLINE SERIES IN THE CHICHIBABIN
SYNTHESIS OF PYRROLO[2,1-a]ISOQUINOLINES
AND IN REACTION WITH OXALYL CHLORIDE
N. N. Polygalova, A. G. Mikhailovskii, E. V. Vikhareva, and M. I. Vakhrin
It has been shown that the Chichibabin reaction of enamines of the 1,2,3,4-tetrahydroisoquinoline series
and 1,2,3,4-tetrahydrobenzo[f]isoquinoline series with p-bromophenacyl bromide leads to
pyrrolo[2,1-a]isoquinoline derivatives. The same heterocyclic system is obtained on interaction of
1-alkyl-3,4-dihydroisoquinolines or their benzo[f]-analogs with oxalyl chloride. The obtained
dioxopyrrolines form derivatives of benzo[g]quinoxalino[2,3-b]indolizine on condensation with
o-phenylenediamine.
Keywords: 1-alkyl-3,4-dihydroisoquinolines, benzo[g]quinoxalino[2,3-b]indolizine derivatives, p-bromo-
phenacyl bromide, enamines of the 1,2,3,4-isoquinoline series, oxalyl chloride, pyrrolo[2,1-a]isoquinolines,
1,2,3,4-tetrahydrobenzo[f]isoquinolines, Chichibabin reaction, condensation with o-phenylenediamine.
Pyrrolo[2,1-a]isoquinolines are used widely in organic synthesis, medicine, and other areas [1]. The
classical method of design the pyrrolo[2,1-a]isoquinoline system is the interaction of 1-alkylisoquinolines with
α-halo ketones (the Chichibabin reaction) [1, 2]. It is known [3] that on cyclization with the formation of
condensed systems a determining role is played by the radicals in position 3 of the isoquinoline ring. The aim of
the present work is an investigation of the potentialities of this reaction in the presence of two methyl groups in
position 3 and also of a different structure for the enamine fragment.
The reaction of enamines of the 1,2,3,4-tetrahydroisoquinoline series with oxalyl chloride has also been
widely investigated [1, 4, 5]. In the given examples, both bases, in the molecules of which the structure of the
enamine is already fixed, and compounds in the imino form, enter into this reaction. The latter is characteristic
for derivatives of 1-alkylisoquinoline [6, 7], the alkyl residue in the structure of which, unlike carbonyl or just
withdrawing groups, does not aid stabilization of the enamine form. Consequently our aim is the study of the
conditions of carrying out and the structures of the products of the named reaction in the presence of an alkyl
residue at position 1 of the isoquinoline ring.
The investigations showed that the reaction of enamines 1a-c with p-bromophenacyl bromide proceeds
readily on boiling in alcohol in the presence of Na2CO3 and compounds 2a-c are formed. On using drotaverine
(no-spa) base as the initial enamine the reaction product is compound 2d. Enamino amides and enamino esters of
the benzo[f]isoquinoline series, analogous in structure to compounds 1a-c, form the corresponding tetracyclic
derivatives 3a-c in this reaction.
__________________________________________________________________________________________
Perm State Pharmaceutical Academy, Perm 614990, Russia; e-mail: perm@pfa.ru. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1068-1074, July, 2007. Original article submitted
September 21, 2005.
900
0009-3122/07/4307-0900©2007 Springer Science+Business Media, Inc.

Me
Me
Me
Me
R
R
R
R
N
NH
BrCH2C(O)C6H4Br-p
+
R1
O
C6H4Br-p
O
R1
2a–c
1a–c
Me
Me
EtO
3
5
4 N
6
g
N
EtO
EtO
2
7
C6H4Br-p
1
8
C6H4Br-p
R1
O
EtO
3a–c
2d
1, 2 a R = OMe, b, c R = H; 1–3 a R1 = N-pyrrolidinyl, b R1 = N-morpholinyl, с R1 = OEt
1-Alkyl-substituted isoquinolines, such as compound 4, react with oxalyl chloride with the formation of
condensed pyrroledione 5. 4-Alkyl-2,2-dimethyl-1,2-dihydrobenzo[f]isoquinolines react analogously, forming
substances 6a-d. The investigations showed that a temperature of -10 to 0°C is optimal for carrying out the
reaction. The character of residue R has no influence on the yield. The reaction occurs analogously to the already
known when R = H [8] (compound 6a).
Me
Me
MeO
MeO
Me
N
MeO
MeO
(COCl)2
O
N
Me
Et
O
CH2CH2Me
5
4
Me
Me
Me
Me
O
O
N
5
5
4 N
4 N
6
6
3
b
3
g
g
2
2
N
7
7
1
8
1
8
R
R
6a–d
7a–d
EtO
7
g
6
1
5
N
N
N
8
4
EtO
EtO
3
2
EtO
8
6, 7 a R = H, b R = Me, c R = Et, d R = Pr
901

TABLE 1. Characteristics of the Compounds Synthesized
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °C
Yield, %
C
H
Br
N
2a
2b
2с
2d
3a
3b
3c
5
C27H29 BrN2O3
C25H25 BrN2O2
C23H22 BrNO2
C32H34 BrNO4
C29H27 BrN2O
C29H27 BrN2O2
C27H24 BrNO2
C18H21NO4
C19H17NO2
C20H19NO2
C21H21NO2
C24H19N3
63.6
63.7
64.4
64.5
65.0
65.1
66.5
66.7
69.6
69.7
67.4
67.6
68.2
68.4
68.4
68.6
78.2
78.3
78.5
78.7
78.8
79.0
82.3
82.5
82.5
82.6
81.2
81.4
82.7
82.8
73.3
73.4
5.6
5.7
5.3
5.4
5.1
5.2
5.7
5.9
5.4
5.5
5.2
5.3
5.0
5.1
6.6
6.7
5.7
5.9
6.2
6.3
6.5
6.6
5.3
5.5
5.7
5.8
6.0
6.1
6.3
6.4
6.3
6.4
15.5
15.7
17.0
17.2
18.7
18.8
13.8
13.9
15.8
16.0
15.4
15.5
16.7
16.8
—
—
—
—
—
—
—
—
—
5.6
5.5
6.0
6.0
3.4
3.3
2.5
2.4
5.7
5.6
5.3
5.4
3.1
3.0
4.5
4.4
4.9
4.8
4.6
4.6
4.5
4.4
12.1
12.0
11.6
11.6
11.2
11.0
10.8
10.7
8.1
8.0
268-269
264-266
215 (dec.)
146-148
256-258
281-282
239-241
145-147
210-212
205-207
204-206
203-205
212-214
223-225
204-205
155-157
57
67
62
68
70
78
67
58
54
61
63
64
62
59
56
61
6b
6c
6d
7a
7b
7c
7d
8
C25H21N3
C26H23N3
C27H25N3
C32H33N3O4
The obtained dioxopyrrolines 6a-d on boiling with o-phenylenediamine in glacial acetic acid readily
form condensed quinoxalines 7a-d. The course of the reaction is easily followed by the change in color of the
reaction mixture. The initial dioxopyrrolines have a bright-red color, the reaction products are bright-yellow. A
derivative of drotaverine 8 was obtained analogously. A previously obtained dicarbonyl compound [9] was taken
as starting material in this case. Solutions of compounds 7a-d, 8 have a marked luminescence. The electronic
absorption and luminescence spectra of analogs of compounds 7a-d, having no benzoannelated ring in their
structure, were studied previously [10]. Benzoannelation (compounds 7a-d) and the introduction of
auxochromic ethoxy groups (compound 8) must lead to a strengthening of properties useful in practice, such as
light absorption and luminescence.
Bases 2, 3 are light-yellow substances, dioxopyrrolines bright-red, and quinoxalines 7, 8 bright-yellow.
On dissolving compounds 7, 8 in conc. H2SO4 halochromism is displayed, the solutions become dark-blue, and
on dilution with water the color changes to red (Table 1).
In the 1H NMR spectra of pyrrolo[2,1-a]isoquinolines 2 and 3 (Table 2), in contrast to the spectra of the
initial enamines, singlets for the protons of the ring NH group and the CH of the enamine fragment were not
present, but a singlet was present for the CH group of the pyrrole fragment (5.8-6.5 ppm). In the spectrum of
compound 5 a triplet (1.1) and a quadruplet (2.6 ppm) characteristic of the ethyl group were present, and there
were also signals for the corresponding alkyl groups in the spectra of compounds 6b-d and 7b-d. In the spectrum
of quinoxaline 8 there was no singlet for the methylene group of the benzyl fragment characteristic of
drotaverine base.
902

903

The IR spectra of amides 2a,b and 3a,b contain characteristic absorption bands for carbonyl groups at
1630-1640, in the spectra of compounds 2c and 3c the ester carbonyl absorbs near 1740 cm-1. The spectra of
dioxopyrrolines 5 and 6a-d contain absorption bands for lactam (1705) and ketone (1735 cm-1) carbonyls.
The mass spectra of compounds 2, 3 have peaks* of low intensity (5-25%) for the molecular ions. For
amides 2, 3 there are significant peaks corresponding to the removal initially of the tertiary amino group and
then carbonyl, for example, for morpholide 2b they are 100 (378) and 20% (350) respectively. The mass
spectrum of ester 3c contains a peak for the molecular ion (80%, M+ 474), and also peaks corresponding to
removal of carbethoxy (45%, 400) and later methyl (50%, 387) groups. In the spectra of drotaverine derivatives
2d, 8 there are peaks for the molecular ions at M+ 577 and M+ 523 respectively, both of 100%.
The phenomenon of halochromism in the condensed quinoxaline series is seen visually in the example of
drotaverine derivative 8 containing four auxochromic groups in the side chain. The absorption spectrum of this
compound was recorded in ethanol beginning from 200 nm. The aromatic fragment is displayed by the presence
of a β-band of the π→π* transition in the region of 230 nm (log ε 3.72) [11]. A K-band for general π-π
conjugation in the molecule is observed at 390 nm (log ε 4.18) [12]. The broad band at 440 nm (log ε 3.64) has a
lower intensity linked with the presence of the ethoxy groups (R-band of substituent). The dark-blue solution of
quinoxaline 8 in conc. H2SO4 changes color on dilution with water. Dilution of 1 : 1 (by volume) causes a green
coloration, on further dilution to threefold the solution acquires a raspberry color. In conc. H2SO4, in comparison
with the spectrum in alcohol, the main changes are observed in the visible region. In comparison with the
unionized form a strong bathochromic shift occurs (λmax 627 nm, log ε 4.18). In solution diluted 1 : 1, as usual
the most intense band remains at 627 nm (log ε 4.23), however a new peak appears at 415 nm (log ε 3.86),
corresponding probably to the presence of an unionized or less ionized form. After further dilution the band at
627 nm disappears (destruction of the solvate shell occurs) and two bands of approximately equal intensity are
displayed at 435 (log ε 4.34) and 505 nm (log ε 4.38). Analogous halochromism phenomena were detected
previously for compounds close in structure to substance 8 [10].
EXPERIMENTAL
1
The H NMR spectra of compounds 2d, 8 were recorded on a Bruker DRX 500 (500 MHz) instrument,
the spectra of the remaining substances were recorded on a Tesla BS 567 (100 MHz) instrument in CDCl3,
internal standard was HMDS (δ 0.05 ppm). The IR spectra were recorded on a Specord 80 spectrometer in nujol.
Mass spectra were described on a MAT 311 instrument (70 eV, EI), and UV spectra on a SF-46 instrument.
Checking for purity of the obtained substances was effected by TLC on Silufol UV-254 plates in
acetone–ethanol–chloroform, 1 : 3 : 6, visualization in UV light and with iodine vapor.
All compounds were recrystallized from isopropyl alcohol.
The starting materials for the synthesis of compounds 2, 3 are described in [6, 13, 14], and of substances
5, 6 in [15]. Drotaverine base was isolated from tablets with a suitable expiry date, mp 58-60°C, its purity was
checked by TLC.
2-(p-Bromophenyl)-1-(R2-carbonyl)-5,5-dimethyl-6,7-(R1)2-5,6-dihydropyrrolo[2,1-a]isoquinolines
2a-c, 1-(3',4'-Diethoxyphenyl)-8,9-diethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline (2d), and 2-(p-Bromo-
phenyl)-1-(R2-carbonyl)-5,5-dimethyl-5,6-dihydronaphtho[1,2-g]indolizines 3a-c (General Method). The
appropriate enamine (10 mmol) in 2-propanol (50 ml) was boiled for 1-2 h with p-bromophenacyl bromide
(2.0 g, 10 mmol) in the presence of Na2CO3 (1.5 g) (check by TLC). The solution was cooled to 20°C, diluted
with water (100 ml), the precipitated solid was filtered off, dried, and recrystallized.
_______
* Here and subsequently values of m/z are given for ion peaks.
904

1-Ethyl-8,9-dimethoxy-5,5-dimethyl-2,3-dioxo-2,3,5,6-tetrahydropyrrolo[2,1-a]isoquinoline (5) and
1-R3-5,5-Dimethyl-2,3,5,6-tetrahydronaphtho[1,2-g]indolizine-2,3-diones 6a-d (General Method).
A
mixture of the appropriate enamine and triethylamine (2.80 g, 20 mmol) in ether (150 ml) was added during 15
min to oxalyl chloride (0.86 ml, 10 mmol) in absolute ether (50 ml) at -10 to 0°C. The reaction mixture was
brought to 20°C and left at this temperature for a further 30 min. The precipitated solid was filtered off, dried,
and recrystallized.
1-R3-5,5-Dimethyl-2,3,5,6-tetrahydronaphtho[1,2-g]quinoxalino[2,3-b]indolizines 7a-d and 1-(3',4'-
Diethoxyphenyl)-2,3,5,6-tetrahydro(3",4"-diethoxybenzo)[g]quinoxalino[2,3-b]indolizine (8) (General
Method). o-Phenylenediamine (1.08 g, 10 mmol) was added to a solution of the initial dioxopyrroline
(10 mmol) in glacial acetic acid (25 ml). The mixture was boiled for 1 h, cooled, diluted with 25% ammonia
solution (100 ml), the precipitated solid was filtered off, washed with water, dried, and recrystallized.
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905