Condensed isoquinolines 30.* acylation and alkylation of 5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-one

Article abstract of DOI:10.1007/s10593-008-0078-5

It was shown that 6-acyl-5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-ones are formed when 5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-one is heated with the chlorides and anhydrides of carboxylic acids in the presence of bases (pyridine, NaOAc) while

Full text of DOI:10.1007/s10593-008-0078-5

Chemistry of Heterocyclic Compounds, Vol. 44, No. 5, 2008
CONDENSED ISOQUINOLINES
30.* ACYLATION AND ALKYLATION
OF 5,13-DIHYDRO-11H-ISOQUINO-
[3,2-b]QUINAZOLIN-11-ONE
L. M. Potikha, R. M. Gutsul, V. A. Kovtunenko,
G. G. Dubinina, and A. A. Tolmachev
It was shown that 6-acyl-5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-ones are formed when 5,13-
dihydro-11H-isoquino[3,2-b]quinazolin-11-one is heated with the chlorides and anhydrides of
carboxylic acids in the presence of bases (pyridine, NaOAc) while 5-acyl-5,13-dihydro-11H-
isoquino[3,2-b]quinazolin-11-ones are formed in the presence of NaH. In the presence of NaH 6-acyl-
5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-ones form the products from acylation and alkylation
at position 5. The action of heat on 5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-one in oxalyl
chloride leads to 7H,8H-2a,7a-diazacyclopenta[fg]naphthacene-1,2,8-trione.
Keywords: 2a,7a-diazacyclopenta[fg]naphthacene, enamines, isoquino[3,2-b]quinazoline, acylation,
alkylation.
Investigations in the region of the chemistry of isocarbostyril derivatives are extremely promising from
the pharmacological standpoint. According to the MDDR database [2], the isoquinol-1-one structural fragment is
present in three medical products on the pharmaceutical market: Draquinolol, Tilisolol, and Palonosetron.
Derivatives of 3-aminoisoquinol-1-one have also been patented: A non-narcotic analgesic [3] and an inhibitor of
poly(ADP-riboso)synthetase [4].
Data on the properties of derivatives of the isoquino[3,2-b]quinazoline series first appeared in the middle
of the last century: The cyanoethylation and oxidation of 5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-one
(1) were mentioned in [5], and high antifungal and antibacterial activity was discovered in the case of 6,11-
dihydro-13H-isoquino[3,2-b]quinazolin-13-one [6]. The presence of a secondary enamine fragment in the
molecule of isoquino[3,2-b]quinazolin-11-one 1 is promising in respect of further modification of the structure,
and this makes it possible to expect that the high activity and chemical selectivity of this group will appear in
reactions with electrophilic reagents.
In the present work we studied the most characteristic reactions of enamines – acylation and alkylation.
_______
* For Communication 29 see [1].
__________________________________________________________________________________________
Taras Shevchenko Kiev National University, Kiev 01033, Ukraine; e-mail: potikha_l@mail.ru.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 741-750, May, 2008. Original article
submitted May 29, 2007.
0009-3122/08/4405-0585©2008 Springer Science+Business Media, Inc.
585

O
O
N
N
N
N
H
H
N
(COCl)2
O
O
O
6
N
N
O
3
N
H
1
RCOCl (a), Ac2O (b)
RCOCl (a–f), Ac2O/AcONa (g)
NaH
+
PyH
O
H
O
N
N
R
+
H
N
N
H
RCOCl
NaH
O
R
O
2a–g
4a,b
O
N
N
O
R
O
R
5
2 a R = 4-EtOC6H4, b R = 4- O2NC6H4, c R = 2-MeC6H4, d R = 3,5-(O2N)2C6H3,
e R = 2-furyl, f R = 2-thienyl, g R = Me; 4 a R = 4-EtOC6H4, b R = Me; 5 R = 4-EtOC6H4
The limited solubility of the quinazolinone 1 in a series of solvents (nonpolar and low-boiling polar
solvents) and also its tendency to oxidize that we had previously observed [7] predetermined the choice of
conditions for acylation to a significant degree. It was found that 6-acyl-5,13-dihydro-11H-isoquino-
[3,2-b]quinazolin-11-ones 2a-f are formed with high yields (64-83%) when compound 1 is heated with
carboxylic acid chlorides in anhydrous pyridine. The use of 4-nitro- and 3,5-dinitrobenzoyl chlorides in this
reaction leads to a mixture of products from acylation 2b,d and oxidation (the dimer 5,13,5',13'-
tetrahydro[6,6']bi[isoquino[3,2-b]quinazoline]-11,11'-dione (3) [7]); the latter is easily separated during
recrystallization of the reaction products from DMF. The boiling of isoquino[3,2-b]quinazolin-11-one (1) in
acetic anhydride in the presence of an excess of anhydrous sodium acetate leads to the formation of 6-acetyl-
5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-one (2g).
The structure of the obtained acyl-substituted isoquino[3,2-b]quinazolin-11-ones was established on the
basis of their spectral characteristics (see Table 1). The retention of the signal for the N(5)H group (νNH 3450
1
cm−1 and δNH in the region of 13.02-10.19 ppm respectively) in the IR and H NMR spectra and the absence of
1
resonance from the H-6 proton in the H NMR spectra indicate the formation of C(6)-substitution products.
Attention is drawn to the position of the signal for the H-7 proton in the 1H NMR spectra of the products 2a-g. In
the case of the 6-acetyl derivative 2g, as expected, its resonance is observed in a more downfield region (7.81
ppm) compared with the initial compound 1 (7.36 ppm) [7], while in the 6-aroyl and 6-hetaroyl
586

587

588

derivatives 2a-f it is in the more upfield region (6.66-7.20 ppm). We attribute the last effect to the relative
increase in the population of the synperiplanar conformation of the acylation products 2a-g as a consequence of
restricted rotation about the C(6)–COR bond, due to steric effects and to the formation of an intramolecular
hydrogen bond between the N(5) atom and the oxygen atom of the carbonyl group in the acyl substituent.
Earlier [8-10] we established that condensed derivatives of 3-aminoisoquinolin-1-one (which also have a
secondary amine fragment in their structure) exhibit ambident characteristics in reactions with electrophiles.
Thus, mixtures of products from C- and N-acylation, the composition of which depended on the structure of the
reagents, were obtained during the acylation of 2,3-dihydroimidazo[1,2-b]isoquinolin-5(1H)-one [8, 9] and
benzimidazo[1,2-b]isoquinolin-11(5H)-one [10] in the presence of bases (pyridine, triethylamine). However, the
formation of appreciable amounts of the isomeric acylation product was not observed (by TLC and NMR) in the
case of isoquino[3,2-b]quinazolin-11-one (1). At the same time if a stronger base (sodium hydride) was used in
DMF with heat the 5-acyl-5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-ones 4a,b were the only products.
Acylation of the anion generated from the isoquino[3,2-b]quinazolin-11-one 1 by the action of the strong base
obviously occurs in this case. The formation of the N(5)-acyl-substituted isoquino[3,2-b]quinazolin-11-ones is
indicated by the absence of signals for the N(5)H group in their 1H NMR and IR spectra and by the presence of
1
signals for the methine proton in the H NMR spectra in the region of 6.68 (4a) and 6.85 ppm (4b). The
broadening of the signal for the protons of the methylene group H-13 in the spectrum of compound 4b indicates
a decrease in the conformational mobility of the isoquino[3,2-b]quinazoline ring as a result of the familiar effect
of increase in the order of the N–CO amide bond in amides [11].
The observed changes in the chemical shifts of the aromatic protons, for the accurate assignment of
which homonuclear two-dimensional correlation spectroscopy COSY was used (for the case of 2a and 4a), agree
fully with the structure of compounds 2a-g and 4a,b. The assignment of the structure of the acylation products to
C(6)- or N(5)-acyl-substituted isoquino[3,2-b]quinazolin-11-ones was also confirmed by the data from the 13C
NMR and UV spectra (for the case of 2a,g and 4a, see Experimental).
It is known [9, 12] that N-acyl-substituted enamines are capable of rearrangement. In the case of
compounds 4a,b the formation of the isomeric 6-acylisoquino[3,2-b]quinazolin-11-ones 2a,g during prolonged
heating of their solutions in high-boiling solvents (DMF, DMSO) and pyridine was not detected (according to
the data from TLC). Compounds 2a-g and 4a,b proved unstable when heated in acetic acid and were easily
hydrolyzed with the formation of isoquino[3,2-b]quinazolin-11-one 1. In a basic medium (pyridine) the acyl
derivatives of isoquino[3,2-b]quinazolin-11-one are completely stable, and they are inert to the action of
acylating reagents. However, by heating compound 2a in DMF with p-ethoxybenzoyl chloride in the presence of
sodium hydride we were able to isolate and characterize the product from repeated acylation – 5,6-di(4-ethoxy-
benzoyl)-5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-one (5).
The transformation of isoquino[3,2-b]quinazolin-11-one 1 on heating with oxalyl chloride, leading to
7H,8H-2a,7a-diazacyclopenta[fg]naphthacene-1,2,8-trione (6), obviously takes place according to the same
scheme – C-acylation followed by N-acylation. A derivative of this heterosystem (7H,8H-2a,7a-diaza-
cyclopenta[fg]naphthacene-1,7(2H)-dione) was obtained earlier [13] under similar conditions by heating
6,11-dihydro-13H-isoquino[3,2-b]quinazolin-13-one in chloroacetyl chloride. In the case of compound 1 heating
in chloroacetyl chloride leads to a complex mixture of unidentified products. The structure of the product 6 was
confirmed by mass spectrometry and its IR and NMR spectra. Two strong absorption bands in the region of 1686
and 1628 cm−1 in the IR spectrum correspond to the stretching vibrations of the carbonyl groups of the
conjugated ketones and amides respectively. In the 13C NMR spectrum there are three signals for the carbon
atoms of the carbonyl groups at 173.15 (C-1), 161.34 (C-8), and 158.53 ppm (C-2). The signals of the aromatic
protons, observed in the downfield region, were assigned to H-12 (8.35), H-3 (8.19), and H-9 (8.16 ppm). The
descreening of the H-12 and H-3 protons is due both to increase in the electron-accepting properties of the
neighboring atoms (C-12b and N-2a) and to the anisotropic effect of the carbonyl groups C(1)=O and C(2)=O.
589

We then studied the alkylation of isoquino[3,2-b]quinazolin-11-one 1. The fusion of compound 1 with
alkyl halides or alkyl tosylates at 120-160°C leads to a complex mixture of products, the main component of
which is the product from oxidative coupling – the dimer 3. A similar result was obtained by heating a solution
of 1 in acetonitrile with bromoacetophenone. The reaction of compound 1 with alkyl halides in the presence of
bases only leads to alkylation products when the mixture of reagents is heated in DMF in the presence of sodium
hydride. Under these conditions high yields of the 5-alkyl-5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-ones
1
7a-c are obtained. As in the case of the 5-acyl-substituted 4a,b, the H NMR spectra of compounds 7a-c are
characterized by the presence of a signal for the methine proton H-6 and the absence of a signal for N(5)H (see
Table 1).
O
O
N
RCH2Hal
NaH
N
O
EtI
1
2a
NaH
N
N
CH2R
Et
7a–c
EtO
8
a R = H, b R = Me, c R = 4-ClC6H4
The obtained 5-alkyl-substituted isoquino[3,2-b]quinazolin-11-ones 7a-c are inert toward alkylating and
acylating agents. At the same time 6-acylisoquino[3,2-b]quinazolin-11-one 2a is readily converted into 6-(4-
ethoxybenzoyl)-5-ethyl-5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-one (8) when heated with ethyl iodide
in DMF in the presence of NaH. The signals in the 1H NMR spectrum of compound 8 were assigned on the basis
1
of COSY and NOESY experiments. Its H NMR spectrum has a number of special features. The presence of
bulky substituents at the peri positions (5 and 6) leads to restricted rotation about the N(5)–C and C(6)–C single
bonds and, consequently, to the realization of restricted conformations and to increase in the asymmetry of the
molecule, which shows up in the broadening of the signal for the protons of the H-13 methylene group. Another
result is the upfield shift of the signals for the protons of the N(5)–C2H5 group compared with those for
compound 7b not having an electrophilic substituent at the C-6 atom, and this is due to the anisotropic effect of
the benzoyl carbonyl group.
Analysis of the literature on the biological characteristics of 1-isoquinolone revealed an extremum in
respect of transmembrane receptors in their pharmacological activity profile. In order to assess the biological
potential of the substances described in the present work the biological activity spectrum was calculated. The
PASS program (Prediction of Activity Spectra for Substances) was used for the calculations [14-16]. The
program is based on comparison of the calculated 2D descriptors for each molecule (MNA – Multilevel
Neighbourhoods of Atoms) with the set of descriptors for selection of the compounds with high activity and
selection of the inactive compounds respectively. The final result is presented by the program as the probability
of the appearance of activity (Pa) and inactivity (Pi) in the compounds expressed as fractions.
More than 3000 types of activities for each compound were included in the calculation, and the activity
threshold was selected as Pa > 0.75; Pi < 0.2. It was found that compounds 7b and 8 have the greatest
pharmacological potential. Among the activities characteristic of most of the compounds predicted with high
probability it is necessary to single out their inhibition of various types of hydrolases and hydratases and also
their regulatory activity with respect to transmembrane receptors. They include muscarine acetylcholine (type
M1), GABA, and α1-adrenoreceptors. However, whereas antagonistic activity is predicted for the first two
receptors, these substances must exhibit mimetic characteristics toward the α1-adrenoreceptor. It has also been
suggested that they have the characteristics of adrenaline release inhibitors. Among the pharmacological effects
predicted for compounds of such type there are the correction of sleep disturbances, coronary deficiency, and
myocardial ischemia.
590

TABLE 2. The Physicochemical Characteristics and Elemental Analyses
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C *
Yield, %
C
H
N
2a
2b
2c
2d
2e
2f*2
2g
4a
4b
5
C25H20N2O3
75.65
75.74
69.42
69.52
78.60
78.67
62.37
62.45
73.61
73.68
70.32
70.37
74.33
74.47
75.68
75.74
74.36
74.47
74.85
74.98
71.47
71.52
77.78
77.84
78.18
78.24
73.97
74.09
76.33
76.39
4.98
5.08
3.74
3.80
4.88
4.95
3.13
3.19
4.04
4.12
3.89
3.94
4.80
4.86
5.00
5.08
4.79
4.86
5.10
5.18
3.27
3.33
5.30
5.38
5.73
5.84
4.55
4.60
5.65
5.70
7.10
7.07
10.60
10.57
7.67
7.65
12.67
12.66
8.21
8.18
7.83
7.82
9.69
9.65
7.11
7.07
9.66
9.65
5.15
5.14
9.26
9.27
10.70
10.68
10.14
10.14
7.54
7.51
6.61
6.60
170-172
226-227
206-208
288-289
187-188
175-176
209-211
205-207
204-206
152-154
318-320
123-124
156-158
177-179
148-149
82
85
67
83
64
78
83
78
58
53
69
58
53
46
75.5
C23H15N3O4
C24H18N2O2
C23H14N4O6
C21H14N2O3
C21H14N2O2S
C18H14N2O2
C25H20N2O3
C18H14N2O2
C34H28N2O5
C18H10N2O3
C17H14N2O
C18H16N2O
C23H17ClN2O
C27H24N2O3
6
7a
7b
7c*3
8
_______
* Solvent for crystallization: DMF (compounds 2a-f, 4a, b and 7a-c) and
1:1 DMF–2-propanol (compounds 2g, 4b, 5, and 8).
*2 Data from analysis for S: Calculated 8.95%; found 8.90%.
*3 Data from analysis for Cl: Calculated 9.51%; found 9.55%.
EXPERIMENTAL
The IR spectra of the compounds (in tablets with potassium bromide) were recorded on a Hewlett
1
Packard UR 20 instrument. The H and 13C NMR spectra of the products were obtained and the COSY
homonuclear correlation experiments were preformed on a Varian Mercury-400 spectrometer (400 and 100 MHz
respectively) in DMSO-d6 with TMS as internal standard. The UV spectra were recorded on a SHIMADZU UV-
3100 UV-vis-NIR recording spectrophotometer in methanol. The mass spectra of the compounds were obtained
by HPLC-MS on an AGILENT/100-Series instrument (CI, acetonitrile, 0.05% formic acid). The reactions and
the purity of the products were monitored by TLC on Silufol UV-254 plates.
6-Acyl-5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-ones (2a-f). Isoquinoquinazoline 1 (0.25 g,
1 mmol) was dissolved by heating in anhydrous pyridine (15 ml), and aroyl (hetaroyl) chloride (1.1 mmol) was
added. The mixture was boiled for 3-5 h and cooled, and of water (50 ml) was added. The precipitate was
filtered off and washed with 2-propanol. The product was crystallized from DMF.
591

Compound 2a. 13C NMR spectrum, δ, ppm: 193.37 (6-С=O); 162.28 (С-11); 161.37 (С-4"); 144.66
(С-5а); 137.03 (С-4а); 134.86 (С-1'); 133.26 (С-6а); 132.36 (С-8); 131.91 (С-2',6'); 129.01 (С-3); 127.83
(С-10); 126.97 (С-1); 125.25 (С-7); 123.66 (С-9); 123.32 (С-2); 120.47 (С-10а); 118.59 (С-13а); 115.57 (С-4);
114.58 (С-3',5'); 94.67 (С-6); 63.94 (ОСН2); 47.72 (С-13); 14.99 (СН3). UV spectrum, λmax (ε·10−4, l·mol-1·cm-1): 295
(2.47), 389 (1.66). Mass spectrum, m/z (I, %): 397 [М+1]+ (100).
6-Acetyl-5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-one (2g). A mixture of isoquinoquinazoline
1 (0.25 g, 1 mmol) and anhydrous sodium acetate (0.12 g, 1.5 mmol) in acetic anhydride (10 ml) was boiled for
2 h. The mixture was cooled, and water (30 ml) was added. The precipitate was filtered off and washed with
2-propanol. The product was crystallized from a 1:1 mixture of 2-propanol and DMF. 13C NMR spectrum, δ,
ppm: 197.21 (6-С=0); 161.19 (С-11); 147.11 (С-5а); 136.33 (С-4а); 133.91 (С-6a); 133.26 (С-8); 129.13 (С-3);
128.14 (С-10); 126.99 (С-1); 125.03 (С-7); 124.04 (С-2,9); 121.08 (С-10а); 118.71 (С-13а); 115.87 (С-4); 96.06
(С-6); 42.65 (С-13); 32.11 (СН3). Mass spectrum, m/z (I, %): 291 [М+1]+ (100).
5-Acyl-5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-ones 4a,b. Isoquinoquinazoline 1 (0.25 g,
1 mmol) was dissolved by heating in anhydrous DMF (25 ml). Sodium hydride (0.03 g, 1.2 mmol) was added to
the cooled solution. When the release of hydrogen had stopped p-ethoxybenzoyl chloride or acetic anhydride
(1.1 mmol) was added. The mixture was stirred at 20°C for 1.5 h, and the precipitate was filtered off. The filtrate
was evaporated under vacuum, and the residue was crystallized from DMF.
Compound 4a. 13C NMR spectrum, δ, ppm: 167.84 (5-С=0); 161.18 (С-11); 160.67 (С-4′); 138.12
(С-5а); 137.10 (С-4а); 136.32 (С-1′); 133.20 (С-6а,8); 131.44 (С-2',6'); 129.87 (С-3); 128.60 (С-10); 127.62
(С-1); 127.15 (С-7); 126.82 (С-4); 126.73 (С-2,9); 124.17 (С-13а); 122.98 (С-10а); 114.30 (С-3',5'); 101.21
(С-6); 63.78 (ОСН2); 42.58 (С-13); 14.91 (СН3). UV spectrum (EtOH), λmax, nm (ε·10-4, l/mol-1·cm-1): 276
(1.71), 335 (0.93). Mass spectrum, m/z (I, %): 397 [М+1]+ (100).
5,6-Di(4-ethoxybenzoyl)-5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-one (5). This compound
was obtained by the method described above for the synthesis of the products 4a,b, using 6-(4-ethoxy-
benzoyl)isoquinoquinazoline 2a (0.4 g, 1 mmol) instead of the isoquinoquinazoline 1. The reaction mixture was
heated for 7 h, and the product was purified by recrystallization from a 1:1 mixture of 2-propanol and DMF.
7H,8H-2a,7a-Diazacyclopenta[fg]naphthacene-1,2,8-trione (6). A mixture isoquinoquinazoline 1
(0.25 g, 1 mmol) and oxalyl chloride (10 ml) was boiled for 2 h. The excess of the oxalyl chloride was
evaporated under vacuum, and the residue was recrystallized twice from DMF. 13C NMR spectrum, δ, ppm:
173.15 (С-1); 161.34 (С-8); 158.53 (С-2); 157.98 (С-12с); 135.54 (С-11); 131.63 (С-2b); 129.35 (С-12а);
129.26 (С-4); 128.66 (С-9); 128.18 (С-6); 126.36 (С-12); 125.80 (С-10); 122.35 (С-5); 120.79 (С-8а); 117.81
(С-6a); 115.28 (С-3); 90.71 (С-12b); 42.87 (С-7). UV spectrum, λmax (ε·10−4, l·mol-1·cm-1): 246 (1.74), 279
(2.11). Mass spectrum, m/z (I, %): 303 [М+1]+ (100).
5-Alkyl-5,13-dihydro-11-isoquino[3,2-b]quinazolin-11-ones 7a-c. The compounds were obtained by
the method described above for the synthesis of the products 4a,b, using (1.2 mmol) of alkyl halide instead of
p-ethoxybenzoyl chloride. The reaction mixture was heated for 3-4 h, and the product was purified by
recrystallization from DMF.
6-(4-Ethoxybenzoyl)-5-ethyl-5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-one (8). The compound
was synthesized by the method described for the synthesis of the products 4a,b using 6-(4-ethoxy-
benzoyl)isoquinoquinazoline 2a (0.4 g, 1 mmol) instead of the isoquinoquinazoline 1 and ethyl iodide (0.16 g,
2 mmol) instead of p-ethoxybenzoyl chloride. The reaction mixture was heated for 7 h, and the product was purified
by recrystallization from a 1:1 mixture of 2-propanol and DMF. Mass spectrum, m/z (I, %): 425 [M+1]+ (100).
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