Reaction of 2,3-dioxopyrrolo[2,1-a]iso-quinolines with binucleophiles

Article abstract of DOI:10.1007/s10593-009-0396-2

The reaction of 2,3-dioxopyrrolo[2,1-a]isoquinolines with binucleophiles such as 2-amino-4-methyl-phenol, o-aminothiophenol, and caprolactam hydrazidine proceeds with opening of the dioxopyrroline ring and is accompanied by heterocyclization to give heter

Full text of DOI:10.1007/s10593-009-0396-2

Chemistry of Heterocyclic Compounds, Vol. 45, No. 9, 2009
REACTION OF 2,3-DIOXOPYRROLO[2,1-a]ISO-
QUINOLINES WITH BINUCLEOPHILES
O. V. Surikova1, A. G. Mikhailovskii1*, and M. I. Vakhrin1
The reaction of 2,3-dioxopyrrolo[2,1-a]isoquinolines with binucleophiles such as 2-amino-4-methyl-
phenol, o-aminothiophenol, and caprolactam hydrazidine proceeds with opening of the dioxopyrroline
ring and is accompanied by heterocyclization to give heteroaromatic benzoxazole, benzothiazole, and
1,2,4-triazole systems. Heterocyclization does not occur in the reaction of o-hydroxybenzylamine,
o-aminobenzyl alcohol, and the hydrazide of anthranilic acid; the corresponding linear N-benzylamide,
benzyl ester, and diacylhydrazide products are formed.
Keywords: o-aminobenzyl alcohol, 2-amino-4-methylphenol, o-aminothiophenol, N-benzylamide,
benzyl ester, anthranilic acid hydrazide, caprolactam hydrazidine, o-hydroxybenzylamine, diacyl
hydrazide, 5,5-dialkyl-2,3-dioxopyrrolo[2,1-a]isoquinolines, benzoxazole, benzothiazole, and
1,2,4-triazole derivatives.
We have already studied the reactions of 2,3-dioxopyrrolo[2,1-a]isoquinolines with several
binucleophiles such as aliphatic diamines [1], o-phenylenediamine [2-4], and o-aminophenol [5]. These
examples show that the reactions of these compounds with binucleophiles may proceed through various
pathways, namely, ordinary acylation of the amino group [1], annelation of the heterocycle [2, 4], and
heterocyclization with benzoxazole formation [5]. In the present work, we studied the dependence of the
structure of the products on the structure of both the binucleophile and the dicarbonyl reagent.
Brief heating of 2,3-dioxopyrrolo[2,1-a]isoquinolines 1a,c with 2-amino-4-methylphenol in 2-propanol at
reflux gives heterocyclic enamino ketones 2a,b, which contain the benzoxazole residue. The use of
o-aminothiophenol as the binucleophile in the reaction with dioxopyrrolines 1a-d leads to benzothiazole
derivatives 2c-f. We have recently shown that dioxopyrroline ring opening occurs in the reaction of
pyrroloisoquinoline 1a with caprolactam hydrazidine to give the bicyclic 1,2,4-triazolo[4,5-a]azepine system [6].
When amide 1d or ester 1e is used as the starting reagent, the reaction proceeds analogously to give the
corresponding amide 3a and ester 3b. In the latter case, caprolactam hydrazidine does not attack the ester group.
The retention of the ester group provides the potential for further chemical transformations. When a
spirocyclopentyl substituent is present in the starting dicarbonyl compound 1c, annelation of the triazole ring is
not observed. This failure may be attributed to the large bulk of the spirocyclopentyl substituent in comparison
with two methyl groups. On the other hand, the bulky structure of benzo[f]isoquinoline is not a hindrance to
annelation of the triazole ring in the formation of morpholide 4.
_______
* To whom correspondence should be addressed, e-mail: perm@pfa.ru.
1Perm State Pharmaceutical Academy, Perm 614990, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1412-1418, September, 2009.
Original article submitted March 14, 2008.
0009-3122/09/4509-1131©2009 Springer Science+Business Media, Inc.
1131

It is readily seen that heteroaromatic systems are formed in these examples of the preparation of
compounds 2a-f, 3a,b, and 4. On the other hand, the reactions of other binucleophiles, in which the direct
formation of an aromatic system is impossible, proceed differently. Thus, the reaction of dioxopyrroline 1 with
o-hydroxybenzylamine in 2-propanol gives enamino ketoamide 6. Thin-layer chromatography and the mixed
melting point showed that only the starting reagent was recovered in an attempt to achieve heterocyclization of
enamino ketoamide 6 by the action of TsOH or AcOH. New reaction products were not obtained from
o-aminobenzyl alcohol upon simple mixing of this reagent with isoquinoline 1a in 2-propanol or benzene. The
reaction proceeds in benzene in the presence of an equimolar amount of sodium, which is in accord with
previous work [7, 8], in which we showed that opening of the dioxopyrroline ring in compound 1a proceeds
readily by the action of alcoholates. Further heating of esters 7 in the presence of TsOH or AcOH does not lead
XH
R2
NH2
X
N
R3
R3
N
O
H
2a–f
R1
N
N
H
O
R
R
2
R1
1
R2
3
O
O
8
N
4
R2
N
7
NHNH2
N
1
5
R = Me
N
3a,b
1a–e
6
N
H
O
Me
Me
N
H
R12
O
N
= (CH2)4
N
O
NHNH
5
N
N
O
N
O
4
1 а R = R2 = Н, R1 = Me; b R = МеО, R1 = Me, R2 = H, с R = R2 = H, R1 = (СН2)4;
2
d R = Н, R1 = Me, R2 = N-morpholinocarbonyl; е R = Н, R1 = Me, R2 = СО2Et
Compound
R
R1
R2
R3
Х
2
2а
2b
2с
2d
2e
2f
Н
Ме2
H
H
H
H
H
Me
O
O
S
S
S
S
H
(СН2)4
Me2
Me
H
H
MeO
H
Me2
H
(СН2)4
Me2
H
H
H
NHC(O)
NC(O)
O
3a
H
Me2
O
3b
5
H
H
Me2
CO2Et
H
(СН2)4
1132

to change in the structure of this compound. Ring opening in the hydrazide of anthranilic acid also proceeds
readily upon heating in 2-propanol at reflux to give N-acylated enaminoketohydrazide 8. The course of this
reaction may be monitored easily according to the color of the solution: the red color of the starting
dioxopyrroline turns to yellow.
N
H
NH2
O
Me
N
OH
O
Me
O
O
NH
OH
NHNH2
NH2
OH
NH2
N
6
H
O
O
1a
N
H
O
H
N
NH2
O
N
H
O
NH2
O
O
8
7
The enamino ketones obtained are yellow-orange crystalline compounds. Characteristics of the
compounds synthesized for the first time are given in Table 1.
1
The H NMR spectra of the products given in Table 2 contain signals for protons of substituents R3-R4,
the 4-CH2 group of the tetrahydroisoquinoline ring, aromatic protons of the isoquinoline ring, and protons of the
substituents of the isoquinoline side chain. The spectra of ketones 2a-f, in contrast to the spectra of starting
reagents 1a-d, show multiplets for the aromatic protons of the benzoxazole or benzothiazole rings and singlets
TABLE 1. Characteristics of the Compounds Synthesized
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °C
Yield, %
C
H
N
S
2а
2b
2с
2d
2e
2f
3а
3b
4
C21H20N2O2
C23H22N2O2
C20H18N2OS
C22H22N2O3S
C22H20N2OS
C25H25N3O3S
C25H31N5O3
С23Н28N4O3
C29H33N5O3
C22H28N4O2
C21H22N2O3
C21H22N2O3
C21H22N4O3
75.7
75.9
76.9
77.1
71.7
71.8
66.9
67.0
73.2
73.3
67.0
67.1
66.7
66.8
67.7
67.6
69.6
69.7
69.3
69.4
71.9
72.0
71.8
72.0
6.0
6.1
6.1
6.2
5.3
5.4
5.5
5.6
5.5
5.6
5.5
5.6
6.9
7.0
7.0
6.9
6.6
6.7
7.3
7.4
6.1
6.3
6.2
6.3
8.5
8.4
7.9
7.8
8.5
8.4
7.2
7.1
7.9
7.8
9.5
9.4
15.7
15.6
13.8
13.7
14.1
14.0
14.8
14.7
8.1
8.0
8.0
8.0
202-204
208-210
78-80
70
61
75
85
80
43
62
65
67
75
45
32
45
9.4
9.6
8.0
8.1
8.8
8.9
7.1
7.2
198-200
82-84
118-120
118-120
102-104
110-112
96-98
5
6
176-178
102-104
246-248
7
8
66.5
66.6
5.8
5.9
14.9
14.8
1133

1134

for the NH groups of the isoquinoline ring at 11.5-11.6 ppm. The spectra of compounds 3a,b also have singlets
for the ring NH groups at 12.1 and 8.9 ppm, which also supports the proposed enamino ketone structure. The
spectrum of morpholide 4 is similar. The spectrum of hydrazide 5 has a broad singlet for the C(O)NHNH
hydrazide group at 4.6 ppm, corresponding in intensity to two NH group protons, and a singlet for the ring NH
group at 11.8 ppm. The spectrum of phenol 6 has a singlet for the phenol OH group at 9.5 ppm. The spectrum of
amine 7 has a singlet for the protons of the free NH2 group at 3.9 ppm and of the ring NH group at 11.3 ppm.
The spectrum of enaminoketohydrazide 8 has a broad singlet for the CONHNH hydrazide fragment at 10.5 ppm
and singlet for the ring NH group at 11.6 ppm, which also supports the indicated linear structure.
The IR spectra were taken in chloroform for solutions with c = 0.1 mol/liter. All the compounds
obtained are enamines. The presence of broad long-wavelength bands for the stretching vibrations of the ring
NH groups at 3040-3200 cm-1 and enamino ketone carbonyl at 1600-1620 cm-1, which corresponds to an
H-chelate form, is characteristic for these compounds. The carbonyl group of tertiary amines 2f, 3a, and 4 give a
band at 1640 cm-1, while the ester group in the spectrum of compound 3b gives a band at 1725 cm-1 and the
hydrazide group carbonyl of hydrazides 5 and 8 gives a band in the vicinity of 1700 cm-1. The spectra of
compounds 6-8 also have bands for the stretching vibrations of the phenol OH groups at 3320 cm-1, the NH
amide group at 3300 cm-1, the hydrazide NH group at 3340 cm-1, and the free NH2 groups at 3350-3400 cm-1.
The mass spectra of compounds 2-7 contain molecular peaks, whose intensity ranges from 12% for
compound 2 to 100% for ketones 2a,b. The spectra of all these compounds with the exception of compounds 2a,b,
3a,b, and 4 have peaks corresponding to the isoquinolinomethylidenocarbonyl fragment (200 for, 3,3-dimethyl-,
226 for 3-spirocyclopentyl-, and 260 for 3,3-dimethyl-6,7-dimethoxy-3,4-dihydroisoquinoline), whose intensity is
100%.
The mass spectrum of ester 7 contains a molecular ion peak (350 [M]+ 33%) as well as the indicated
peak at 200 (100%), corresponding to loss of the CH2C6H4NH2 group (65%). The spectrum of hydrazide 8 also
has a the peak at 200 (6%) as well as peaks for the C6H4(NH2)CONH group at 135 (5%), COC6H4NH2 group at
120 (98%), and C6H4NH2 group at 92 (28%).
EXPERIMENTAL
1
The H NMR spectra were taken on a Tesla BS-567A spectrometer at 100 MHz in DMSO-d6 for
compounds 6-8 and CDCl3 for the other compounds with HMDS as the internal standard (0.05 ppm). The IR
spectra were taken on a Specord M-80 spectrometer. The electron impact mass spectra were taken on a MAT-311
mass spectrometer at 70 eV. The purity of the compounds was checked by thin-layer chromatography on
Silufol UV-254 plates using 1:3:6 acetone–ethanol–chloroform as the eluent and development by UV light and
iodine vapor. Products 1a,b, 2d, 3b, 6, and 8 were recrystallized from acetonitrile. The other compounds were
recrystallized from hexane.
The preparations of starting reagents 1a-e and benzo[f]isoquinoline for the synthesis of compound 4
were described in our previous work [3, 9].
1-(5-Methyl-1,5-benzoxazol-2-ylcarbonylmethylidene)-3,3-(R1)2-1,2,3,4-tetrahydroisoquinolines 2a,b.
A solution of a mixture of the dioxopyrroline 1a,b (10 mmol) and 2-amino-4-methylphenol (1.64 g, 15 mmol) in
2-propanol (30 mmol) was heated at reflux for 1 h with monitoring by thin-layer chromatography. The color of
the solution turned from red to yellow. The solution was cooled to 20°C and 100 ml water was added. The
precipitate was filtered off, dried, and recrystallized.
1-(1,3-Benzothiazol-2-ylcarbonylmethylidene)-6,7-(R1)2-3,3-(R2)2-1,2,3,4-tetrahydroisoquinolines
2c-e (General Method). A solution of a mixture of the corresponding starting reagent 1a-c (10 mmol) and
2-aminothiophenol (1.85 g, 10 mmol) in glacial acetic acid (10 ml) was heated at reflux for 20 min with
monitoring by thin-layer chromatography and cooled to 20°C. Then, water (100 ml) was added. The precipitate
was filtered off, washed with ammonium hydroxide and, then, water, dried, and recrystallized.
1135

Morpholide of 4-(1,3-Benzothiazol-2-yl)-2-(3,3-dimethyl-1,2,3,4-tetrahydroisoquinolin-1-ylidene)-
3,4-dioxobutanoic Acid (2f). A solution of a mixture of dioxopyrroline 1d (3.4 g, 10 mmol) and 2-amino-
thiophenol (1.85 g, 15 mmol) in 2-propanol (30 ml) with one or two little crystals of p-TsOH was heated at
reflux for 1 h with monitoring by thin-layer chromatography. The product was separated analogously to the
procedure for 2c-e.
Morpholide (3a) and Ethyl Ester of 2-(3,3-Dimethyl-1,2,3,4-tetra-hydroisoquinolin-1-ylidene)-3-oxo-
3-(1,2,4-triazolo[4,5-a]azepan-8-yl)propanoic Acid (3b), Morpholide of 2-(2,2-Dimethyl-1,2,3,4-tetrahydro-
benzo[f]isoquinolin-4-ylidene)-3-oxo-3-(1,2,4-triazolo[4,5-a]azepan-8-yl)propanoic Acid (4), and
N-(3,4,5,6-Tetrahydro-2H-azepin-2-yl)hydrazide of 2-Oxo-3-(3,3-tetramethylene-1,2,3,4-tetrahydroiso-
quinolin-1-ylidene)propanoic Acid (5) (General Method). 2-Hydrazino-3,4,5,6-tetrahydro-2H-azepine
(caprolactam hydrazidine) (1.91 g, 15 mmol) was added to a solution of the corresponding dioxopyrroline
(10 mmol) in benzene (20 ml). Upon heating to 60-70°C, the red color of the mixture disappeared over 5 min.
The addition of hexane (50 ml) leads to formation of a yellow precipitate, which was filtered off, dried, and
recrystallized.
2-Hydroxybenzylamide of 3-(3,3-Dimethyl-1,2,3,4-tetrahydroisoquinolin-1-ylidene)-2-oxopropanoic
Acid (6) and N-(2-Aminobenzoyl)hydrazide of 3-(3,3-Dimethyl-1,2,3,4-tetrahydroisoquinolin-1-ylidene)
2-oxopropanoic Acid (8). A mixture of dioxopyrroline 1a (2.27 g, 10 mmol) and o-hydroxybenzylamine
(1.84 g, 15 mmol) or anthranilic acid hydrazide (2.20 g, 15 mmol) in 2-propanol (50 ml) was heated at reflux
for 10 min (for compound 6) or 90 min (for hydrazide 8). The solution color turned from red to yellow. At the
end of the reaction as indicated by thin-layer chromatographic monitoring, the solution was cooled to 20°C and
diluted by adding water (100 ml). The precipitate formed was filtered off, dried, and recrystallized.
2-Aminobenzyl 2-Oxo-3-(3,3-dimethyl-1,2,3,4-tetrahydroisoquinolin-1-ylidene)propanoate (7).
Metallic sodium (0.28 g, 12 mmol) was added to o-aminobenzyl alcohol (0.15 g, 12 mmol) in benzene (50 ml).
Dioxopyrroline 1a (2.27 g, 10 mmol) was added to the sodium alcoholate suspension obtained. Upon heating at
reflux for 10 min, the mixture turned yellow. The solution was cooled to 20°C and hexane (100 ml) was added.
The precipitate was filtered off, thoroughly washed with water, dried, and recrystallized.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
N. N. Polygalova and A. G. Mikhailovskii, Khim. Geterotsikl. Soedin., 1383 (2005). [Chem. Heterocycl.
Comp., 41, 1178 (2005)].
A. G. Mikhailovskii and V. S. Shklyaev, Khim. Geterotsikl. Soedin., 946 (1994). [Chem. Heterocycl.
Comp., 30, 818 (1994)].
A. G. Mikhailovskii, V. S. Shklyaev, and B. B. Aleksandrov, Khim. Geterotsikl. Soedin., 808 (1990).
[Chem. Heterocycl. Comp., 26, 674 (1990)].
N. N. Polygalova, A. G. Mikhailovskii, E. V. Vikhareva, and M. I. Vakhrin, Khim. Geterotsikl. Soedin.,
1068 (2007). [Chem. Heterocycl. Comp., 43, 900 (2007)].
O. V. Surikova, A. G. Mikhailovskii, N. N. Polygalova, P. G. Neifel'd, and M. I. Vakhrin, Zh. Org.
Khim., 43, 1416 (2007).
O. V. Surikova, A. G. Mikhailovskii, and M. I. Vakhrin, Khim. Geterotsikl. Soedin., 298 (2008). [Chem.
Heterocycl. Comp., 44, 231 (2008)].
A. G. Mikhailovskii and V. S. Shklyaev, Khim. Geterotsikl. Soedin., 1697 (1995). [Chem. Heterocycl.
Comp., 31, 1475 (1995)].
8.
9.
A. G. Mikhailovskii, Khim. Geterotsikl. Soedin., 685 (1996). [Chem. Heterocycl. Comp., 32, 590 (1996)].
V. S. Shklyaev, B. B. Aleksandrov, A. G. Mikhailovskii, and M. I. Vakhrin, Khim. Geterotsikl. Soedin.,
963 (1987). [Chem. Heterocycl. Comp., 23, 790 (1987)].
1136