Anthranilic acid hydrazide in the synthesis of fused polycyclic compounds with quinazoline moieties

Article abstract of DOI:10.1007/s11172-008-0333-z

A modified procedure was developed for the synthesis of 5,6,7,8,13,13a-hexahydrophthalazino[1,2-b]quinazoline-5,8-dione and 6-amino-5,6,6a,11-tetrahydroisoindolo[2,1-a]quinazoline-5,11-dione from o-formylbenzoic acid and anthranilic acid hydrazide. The mechanism of the transformation is suggested, some reactions were studied, and new derivatives of these compounds were synthesized. Anthranilic acid hydrazide was used in the novel synthesis of 5-substituted phthalazino[1,2-b]quinazolin-8-one derivatives. The possible reaction mechanism is discussed. 5,6,7,8-Tetrahydrophthalazino[1, 2-b]quinazoline-5,8-dione and 5-phenylphthalazino[2,1-b]quinazolin-8-one were studied by X-ray diffraction.

Full text of DOI:10.1007/s11172-008-0333-z

Russian Chemical Bulletin, International Edition, Vol. 57, No. 11, pp. 2340—2348, November, 2008
2340
Anthranilic acid hydrazide in the synthesis
of fused polycyclic compounds with quinazoline moieties
L. Yu. Ukhin,a L. G. Kuz´mina,b T. N. Gribanova,a L. V. Belousova,a and Zh. I. Orlovaa
aInstitute of Physical and Organic Chemistry, Southern Federal University,
194/2 prosp. Stachki, 344090 RostovꢀonꢀDon, Russian Federation.
Fax: +7 (863) 243 4776. Eꢀmail: may@ipoc.rsu.ru
bN. S. Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences,
31 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (495) 953 1279. Eꢀmail: kuzmina@igic.ras.ru
A modified procedure was developed for the synthesis of 5,6,7,8,13,13aꢀhexahydroꢀ
phthalazino[1,2ꢀb]quinazolineꢀ5,8ꢀdione and 6ꢀaminoꢀ5,6,6a,11ꢀtetrahydroisoindolo[2,1ꢀa]ꢀ
quinazolineꢀ5,11ꢀdione from oꢀformylbenzoic acid and anthranilic acid hydrazide. The
mechanism of the transformation is suggested, some reactions were studied, and new
derivatives of these compounds were synthesized. Anthranilic acid hydrazide was used in the
novel synthesis of 5ꢀsubstituted phthalazino[1,2ꢀb]quinazolinꢀ8ꢀone derivatives. The possible
reaction mechanism is discussed. 5,6,7,8ꢀTetrahydrophthalazino[1,2ꢀb]quinazolineꢀ5,8ꢀdione
and 5ꢀphenylphthalazino[2,1ꢀb]quinazolinꢀ8ꢀone were studied by Xꢀray diffraction.
Key words: anthranilic acid hydrazide, oꢀformylbenzoic acid, oꢀacetylbenzoic acid,
oꢀbenzoylbenzoic acid, 5,6,7,8,13,13aꢀhexahydrophthalazino[1,2ꢀb]quinazolineꢀ5,8ꢀdione,
6ꢀaminoꢀ5,6,6a,11ꢀtetrahydroisoindolo[2,1ꢀa]quinazolineꢀ5,11ꢀdione, phthalazino[1,2ꢀb]ꢀ
quinazolinꢀ8ꢀone derivatives.
It is known1 that heating of anthranilic acid hydrazide
the reaction in butanol instead of dimethylacetamide proꢀ
ceeds analogously and gives the products in high yield,
the reaction time decreasing from 3 to 1 h (Scheme 1).
Compound 3 is insoluble in boiling butanol, as
opposed to dimethylacetamide,1 and precipitates from this
solvent in an analytically pure form. After separation of
compound 3, compound 4 crystallizes from the cooled
filtrate also in a nearly pure state. The identical results
obtained in different solvents, such as aprotic bipolar
dimethylacetamide and protic butanol, show that the
solvation does not play a significant role in the interaction
under consideration. Moreover, the reaction under
(1) with oꢀformylbenzoic acid (2) in dimethylacetamide
affords a mixture of 5,6,7,8,13,13aꢀhexahydrophthalazinoꢀ
[1,2ꢀb]quinazolineꢀ5,8ꢀdione (3) and 6ꢀaminoꢀ5,6,6a,11ꢀ
tetrahydroisoindolo[2,1ꢀa]quinazolineꢀ5,11ꢀdione (4).
Biological assays showed that phthalazinoquinazoline 3,
like many other compounds containing the —CO—N—N—
structural fragment, have analgesic properties, and some
derivatives of 3 exhibit antiinflammatory activity.2
In the present study, we report the modified proceꢀ
dure for the synthesis of compounds 3 and 4, which does
not require their additional separation. It was found that
Scheme 1
i. Δ, 1 h, BunOH.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2294—2302, November, 2008.
1066ꢀ5285/08/5711ꢀ2340 © 2008 Springer Science+Business Media, Inc.

Synthesis of polycyclic quinazolines
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008 2341
solventꢀfree conditions (in a melt) is completed within
5—10 min and gives the same compounds in a total yield
of ~80% (see the Experimental).
nitrogen atom is most suitable for this transfer. The
carbenium center that appears at the adjacent carbon atom
reacts with the oꢀamino group. In the resulting zwitterꢀ
ionic structure 6, the positive charge on the N(3) atom
increases the electrophilicity of the adjacent carbon
atom C(2) and facilitates its interaction with N(4), resultꢀ
ing finally in the ring contraction and the formation of the
exocyclic amino group. In tetrahydroquinazolinone 7,
the intramolecular dehydration can be accompanied
by the proton abstraction from either NH2 or NH to give
either compound 3 or 4, respectively (Scheme 2).
To estimate the probability of the proposed reaction
mechanism, we analyzed the characteristics of the possible
stationary points along the reaction path. Quantum chemiꢀ
cal calculations by the DFT method (B3LYP/3ꢀ21G)9,10
showed that all structures 5—7 correspond to energy
minima (λ = 0) on the potential energy surface. System 5
can exist as a series of conformational isomers, some of
which are presented in Fig. 1. According to the results of
the calculations, conformer 5d is the most stable comꢀ
pound. Conformers 5a, 5b, and 5c are less stable than 5d
by 19.9, 27.2, and 17.5 kcal mol–1, respectively (Table 1).
The structure of conformer 5d is characterized by the
virtually planar conformation (only a slight rotation about
the HN–CO single bond by approximately 6° is observed
in the system). This is indicative of the pronounced π
conjugation, which distinguishes conformer 5d from the
other conformers and ensures the highest stability. The
planar conformation is additionally stabilized by a short
(1.793 Å) hydrogen bond between the proton of the amino
group and the carbonyl oxygen atom, which is also
responsible for the fact that this conformer is thermoꢀ
dynamically more favorable. Therefore, conformer 5d is
the most probable product of the first step in the reaction
1 + 2 → 5. The transformation of the starting compounds
into 5d is exothermic (the calculated energy effect is
It is known that oꢀformylbenzoic acid is able to
undergo the tautomeric transformation 2a → 2b.3 In the
solid state and in aqueous solutions, this acid exists
predominantly in the cyclic 3ꢀhydroxyphthalide form 2b.4
At the same time, this acid is involved in reactions typical
of aldehydes. Thus, it undergoes the Cannizzaro reacꢀ
tion,5 reacts with a silver ammonia solution,6 and forms
oxime6 with hydroxylamine and hydrazone1 with anthraꢀ
nilic acid hydrazide. The dissociation constant of
oꢀformylbenzoic acid (2.76•10–5)7 has a value expected
for oꢀsubstituted benzoic acid. The proposed pathway of
the reaction of oꢀformylbenzoic acid 2 with hydrazide 1
in butanol is presented in Scheme 2. The hydrazine group
in hydrazide 1 is more active in reactions with aldehydes
compared to the amino group. For example, the reaction
with an equimolar amount of benzaldehyde affords
hydrazone.8 The reaction of hydrazide 1 with an equiꢀ
molar amount of oꢀformylbenzoic acid in dioxane at room
temperature proceeds analogously to give hydrazone 5,
which is transformed into compound 3 upon heating in
dimethylacetamide,1 i.e., hydrazone 5 is an intermediate
in the reaction giving rise to compound 3, in which
the nitrogen atom of the amino group of the starting
hydrazide 1 is bound to the carbon atom of the aldehyde
group of oꢀformylbenzoic acid 2. This bond can be formed
only if the sevenꢀmembered ring closure occurs in hydraꢀ
zone 5, which apparently takes place during heating in
dimethylacetamide1 or butanol. Presumably, the cyclizaꢀ
tion is accompanied by the proton transfer from the
carboxy group to the nitrogen atom (in the case under
consideration, of the hydrazone nitrogen atom) typical of
amino acids. The structure of conformer 5c with a hydroꢀ
gen bond between the carboxy group and the hydrazone
Scheme 2

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Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008
Ukhin et al.
Fig. 1. Geometric characteristics corresponding to the energy minima (λ = 0) on the potential energy surface of conformers 5
calculated at the B3LYP/3ꢀ21G level.

Synthesis of polycyclic quinazolines
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008 2343
Table 1. Total energies (Etotal/a.u.), relative energies (ΔE/kcal mol–1),
and minimal harmonic vibrational frequencies (ω /cm–1) of conꢀ
formers 5 corresponding to the energy minima1(λ = 0) on the
potential energy surface
in the first steps according to the proposed mechanism.
However, this mechanism is possible at high temperaꢀ
tures, as observed experimentally. The calculations showed
that the initial thermal initiation is necessary for the reacꢀ
tion to proceed toward the products. This explains the
experimental results of the present study, as well as
the results obtained earlier.1
As mentioned above, oꢀformylbenzoic acid exists
predominantly in the cyclic phthalide form both in the
solid state and in aqueous solutions. This acid reacts with
aniline upon heating in acetone with elimination of water
and retention of the phthalide structure.4 It should be
taken into account that the reaction can proceed by the
same mechanism during fusion of the components. In
this case, the first step of the reaction should give phthalide
derivative 8 (Scheme 3). However, the reaction giving
rise to compounds 3 and 4 should then proceed according
to Scheme 2 either through hydrazone 5c or directly
through benzotriazepinone 6 (Scheme 3).
It has been reported1 that compound 3 is methylated
with dimethyl sulfate in an aqueous NaOH solution at
the N(6) atom. We found that both nitrogen atoms in
compound 3 are alkylated with an excess of CH3I or
BrCH2C≡CH in the DMSO/NaOH system to form comꢀ
pounds 9a and 9b, respectively. The hydroxymethylation
of 3 with formaldehyde proceeds exclusively at the N(6)
atom, regardless of the reagent ratio and the reaction
time, to give compound 10. Compound 3 does not react
with acetic anhydride upon heating, whereas compound
4 is acylated to form monoacyl derivative 11. The reacꢀ
tion with an excess of CH3I in DMSO/NaH produces
dimethyl derivative 12 (Scheme 4).
Compound 3 was oxidized with potassium permangaꢀ
nate to 5,6,7,8ꢀtetrahydrophthalazino[1,2ꢀb]quinazolineꢀ
5,8ꢀdione 13.1 Apparently, the oxidation can proceed in
solution even under the action of atmospheric oxygen
in an attempt to prepare a specimen for Xꢀray diffraction.
The crystal, which was obtained by slow evaporation of a
Conformer
Etotal
ΔE
ω
1
5a
5b
5c
5d
–963.97897
–963.96734
–963.99272
–964.01062
19.9
27.2
17.5
0
23.7
18.2
18.1
20.7
9.2 kcal mol–1), resulting in the spontaneous formation
of conformer 5d at room temperature in the synthesis
described in the study.1
At the same time, according to the proposed mechaꢀ
nism (see Scheme 2), conformer 5c is the most probable
direct precursor of intermediate 6 providing the further
reaction steps toward the final products. The distinguishꢀ
ing feature of conformer 5c is that the amino group is
oriented with respect to the C=N bond in such a way that
the system is structurally prepared for the further transforꢀ
mation 5→7 (the proton transfer from the amino group to
the nitrogen center and the formation of a new C—N
...
bond). The calculated N C interatomic distance (3.090 Å)
is substantially smaller than the sum of the van der Waals
radii of the nitrogen and carbon atoms (3.39 Å)11 and is
indicative of the attractive character of the interaction.
There is also a strong (1.528 Å) hydrogen bond between
the hydrazone nitrogen atom and the hydrogen atom of
the carboxy group. At the same time, these secondary
interactions eliminate conjugation in the fragments bound
to the sp3ꢀhybridized nitrogen atom, which may account
for the lower stability of conformer 5c compared to
5d. The calculations showed that the further transforꢀ
mation 5c→6 is energetically favorable (the energy gain is
8.2 kcal mol–1).
Therefore, a substantial destabilization of 5c compared
to 5d excludes the possibility of the spontaneous reaction
Scheme 3
10 min

2344
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008
Ukhin et al.
Scheme 4
R = CH3 (a), CH2C≡CH (b).
azinones, we suggested that the condensation proceeds
through the formation of hydrazones 16a,b and phthalꢀ
azinones 17a,b, which then undergo cyclization with
elimination of an H2O molecule from intermediates 18a,b
to give the final products (Scheme 5).
solution of compound 3 in acetonitrile, proved to be
(Xꢀray diffraction data) its oxidation product 13 (see
Scheme 4).
We used hydrazide 1 also in the synthesis of 5ꢀmethylꢀ
(14a) and 5ꢀphenylphthalazino[1,2ꢀb]ꢀquinazolinꢀ8ꢀones
(14b). Earlier, these compounds have been synthesized
by the condensation of 1ꢀchloroꢀ4ꢀmethylꢀ and 1ꢀchloroꢀ
4ꢀphenylphthalazines with anthranilic acid;12,13 compound
14b was prepared also by the reaction of 6a,11ꢀdihydroꢀ
6aꢀphenylisoindolo[2,1ꢀa][3,1]benzoxazineꢀ5,11ꢀdione
with hydrazine.14
We found that hydrazide 1 reacts with oꢀacetylꢀ and
oꢀbenzoylbenzoic acids (15a and 15b, respectively) upon
heating in ethylene glycol to give phthalazinoquinazolinones
14a and 14b, respectively.
Based on the known fact15 that oꢀacetylbenzoic acids
readily react with hydrazines to give 2ꢀsubstituted phthalꢀ
The IR and 1H NMR spectroscopic data for the comꢀ
pounds synthesized are given in Table 2.
The crystal structures of compounds 13 and 14b were
established by Xꢀray diffraction (Figs 2 and 3; Tables 3
and 4, respectively).
Molecule 13 is an aromatic system consisting of four
fused sixꢀmembered rings. Two central heterocycles conꢀ
tain two nitrogen atoms each. As a whole, the molecule is
planar. The dihedral angles between the planes of the
adjacent rings vary in the range of 0.8—2.7°.
The C(1)—O(1) and C(9)—O(2) carbonyl bonds have
similar lengths (1.231(3) and 1.220(3) Å, respectively).
Scheme 5
Reagent and conditions: i, glycol, Δ.

Synthesis of polycyclic quinazolines
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008 2345
Table 2. Spectroscopic characteristics of the compounds synthesized
Comꢀ IR, ν/cm–1
Solvent
1H NMR,
pound (Nujol)
δ (J/Hz)
3
3287, 3185, 3100 (NH),
1680, 1675, 1660 (CO),
1607, 1575, 1515,
DMSOꢀd6
6.20 (d, 1 Н, С(13а)Н, J = 4.4); 6.62 (t, 1 H, CHarom, J = 7.5);
6.89 (d, 1 Н, СНarom, J = 8.1); 7.26 (m, 1 Н, СНarom);
7.35—7.65 (m, 4 Н, СНarom); 7.87 (br.d, 1 Н, С(9)Н);
7.94 (d, 1 Н, N(13)Н, J = 4.4); 10.67 (s, 1 H, N(6)H)
4.55 (s, 2 H, NH2); 6.19 (s, 1 Н, С(6а)Н); 7.32 (m, 1 Н, СНarom);
7.55—7.75 (m, 3 Н, СНarom); 7.97 (br.d, 1 Н, СНarom);
1487 (arom.)
4
3315, 3265, 3180 (NH),
1707, 1675, 1660 (СО),
1607, 1574, 1487 (arom.)
1687, 1657 (CO), 1607,
1595, 1570, 1500 (arom.)
CDCl3
CDCl3
CDCl3
8.05—8.25 (m, 3 Н, СНarom
)
9a
9b
3.48, 3.56 (both s, 6 Н, СН3); 6.02 (s, 1 H, C(13)H); 6.75—6.90 (m, 2 Н,
СНarom); 7.00 (m, 1 Н, СНarom); 7.35—7.50 (m, 3 Н, СНarom); 7.80 (dd,
1 Н, С(9)Н, 3J = 7.8, 4J = 1.5); 8.05 (m, 1 Н, СНarom
)
3287, 3270, 3260,
2.29, 2.47 (both t, 2 Н, ≡СН, J = 2.5); 4.24, 4.39, 4.56, 5.37 (all dd, 4 Н,
СН2, 2J = 17.6, 4J = 2.5); 6.30 (s, 1 Н, С(13а)Н), 6.97 (m, 1 Н, СНarom);
7.16 (d, 1 Н, СНarom, J = 8.2); 7.30—7.45 (m, 3 Н, СНarom); 7.51 (m, 1 Н,
СНarom); 7.84 (dd, 1 Н, С(9)Н, 3J = 7.8, 4J = 1.5); 8.03 (m, 1 Н, СНarom
4.48 (m, 1 Н, СН2); 5.66 (m, 1 Н, СН2); 6.10 (t, 1 Н, ОН, J = 7.1);
6.23 (d, 1 Н, С(13а)Н, J = 4.3); 6.63 (t, 1 Н, СНarom, J = 7.4);
6.91 (d, 1 Н, СНarom, J = 8.0); 7.05—7.75 (m, 5 Н, СНarom);
7.90 (d, 1 Н, СНarom, J = 7.4); 8.00 (d, 1 Н, N(13)Н, J = 4.3)
2.12 (s, 3 Н, СН3); 6.59 (s, 1 Н, С(6а)Н); 7.35 (m, 1 Н, СНarom);
7.50—8.40 (m, 7 Н, СНarom); 10.37 (s, 1 Н, NH)
3233 (≡СН), 1654 (СО),
1680, 1667, 1600, 1567,
1487 (arom.)
3260 (NH), 1675,
1655 (СО), 1605, 1575,
1515, 1485 (arom.)
)
10
DMSOꢀd6
11
3300 (NH), 1727, 1700,
1660 (СО), 1600, 1505,
1487 (arom.)
1680, 1660 (CO), 1615,
1600, 1580, 1560,
1500 (arom.)
DMSOꢀd6
CDCl3
12
3.48, 3.56 (both s, 6 Н, СН3); 6.02 (s, 1 Н, С(6а)Н); 6.83 (m, 2 Н,
СНarom); 7.00 (m, 1 Н, СНarom); 7.35—7.50 (m, 3 Н, СНarom);
7.80 (dd, 1 Н, С(4)Н, 3J = 7.8, 4J = 1.6); 8.05 (m, 1 Н, СНarom
)
14а
14b
1694 (CO), 1620 (пл.),
1600, 1575, 1555,
1495 (arom.)
1715 (CO), 1615, 1600,
1575, 1480 (arom.)
DMSOꢀd6
DMSOꢀd6
2.84 (s, 3 Н, СН3); 7.52 (m, 1 Н, СНarom); 7.65—8.20 (m, 5 Н, СНarom);
8.33 (d, 1 Н, СНarom, J = 7.8); 8.96 (m, 1 Н, СНarom
)
7.50—8.10 (m, 11 Н, СНarom); 8.34 (d, 1 Н, СНarom, J = 7.8);
9.03 (d, 1 Н, СНarom, J = 7.8)
The N(3)—C(1) bond is substantially longer (1.351(3) Å)
than the formally double N(1)—C(8) bond (1.293(3) Å)
but is slightly shorter than the two other formally single
N(1)—C(11) and N(2)—C(8) bonds (1.385(3) and 1.384(3) Å,
respectively). The N(3)—C(1) bond length is close to the
analogous bond lengths in 2ꢀpyridones (the Cambridge
Structural Database,16 version 5.25).
A slight difference in the lengths of the N—C single
bonds is apparently attributed to the characteristic feaꢀ
tures of the πꢀelectron density delocalization in the molꢀ
ecule. In particular, the bonds slightly alternate according
to the formal binding scheme. For example, the C(2)—C(7)
C(18)
C(19)
C(17)
H(3A)
N(3)
O(1)
O(2)
O(2)
C(20)
C(16)
N(3)
C(21)
C(9)
C(1)
C(9)
C(10)
N(2)
N(2)
C(1)
C(15)
C(14)
C(10)
C(15)
C(2)
C(2)
C(3)
C(4)
C(3)
C(8)
C(7)
C(8)
C(14)
C(13)
C(13)
C(7)
C(6)
C(11)
C(11)
N(1)
N(1)
C(4)
C(5)
C(12)
C(12)
C(6)
C(5)
Fig. 3. Molecular structure of 14b. Displacement ellipsoids are
Fig. 2. Molecular structure of 13. Displacement ellipsoids are
drawn at the 50% probability level.
drawn at the 50% probability level.

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Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008
Ukhin et al.
Table 3. Selected bond lengths (d) in molecule 13
Table 4. Selected bond lengths (d) in molecule 14b
Bond
d/Å
Bond
d/Å
Bond
d/Å
Bond
d/Å
O(1)—C(1)
O(2)—C(9)
N(1)—C(8)
N(1)—C(11)
N(2)—N(3)
N(2)—C(8)
N(2)—C(9)
N(3)—C(1)
C(1)—C(2)
C(2)—C(3)
C(2)—C(7)
C(3)—C(4)
1.231(3)
1.220(3)
1.293(3)
1.385(3)
1.395(2)
1.384(3)
1.420(3)
1.351(3)
1.498(3)
1.397(3)
1.395(3)
1.378(4)
C(4)—C(5)
C(5)—C(6)
C(6)—C(7)
C(7)—C(8)
C(9)—C(10)
C(10)—C(11)
C(11)—C(12)
C(12)—C(13)
C(13)—C(14)
C(14)—C(15)
C(15)—C(10)
1.406(4)
1.381(4)
1.393(3)
1.480(3)
1.450(3)
1.415(3)
1.422(3)
1.370(4)
1.396(4)
1.369(3)
1.405(3)
С(1)—C(16)
O(2)—C(9)
N(1)—C(8)
N(1)—C(11)
N(2)—N(3)
N(2)—C(8)
N(2)—C(9)
N(3)—C(1)
C(1)—C(2)
C(2)—C(3)
C(2)—C(7)
C(3)—C(4)
1.487(2)
1.211(2)
1.303(2)
1.380(2)
1.389(2)
1.390(2)
1.427(2)
1.298(2)
1.462(2)
1.405(3)
1.401(2)
1.383(3)
C(4)—C(5)
C(5)—C(6)
C(6)—C(7)
C(7)—C(8)
C(9)—C(10)
C(10)—C(11)
C(11)—C(12)
C(12)—C(13)
C(13)—C(14)
C(14)—C(15)
C(15)—C(10)
1.395(3)
1.379(3)
1.404(2)
1.458(2)
1.463(3)
1.399(3)
1.411(2)
1.381(3)
1.395(3)
1.377(3)
1.406(3)
bond (1.395(3) Å) in the N(2),N(3),C(1)...C(8) ring is
substantially shorter than the other two C—C bonds
(C(1)—C(2), 1.498(3) Å; C(7)—C(8), 1.480(3) Å), although
it is virtually equal in length to the conjugated bonds in
the C(2)...C(7) ring (see Table 3).
Experimental
The IR spectra were recorded on a Specord IRꢀ75 instruꢀ
ment in Nujol mulls. The 1H NMR spectra were measured on a
Varian UNITYꢀ300 spectrometer. The spectroscopic characterꢀ
istics of the compounds are given in Table 2.
The conjugated tetracyclic system of molecule 14b is
planar. The dihedral angles between the adjacent rings are
in the range of 2.3—5.6° (see Fig. 3). The phenyl group at
the C(1) atom is twisted from the plane of the correꢀ
sponding heterocycle by 50.4°.
In molecule 14, the N(3)—C(1) bond (1.298(2) Å) is
formally double. The length of this bond is comparable
with the length of the N(1)—C(8) double bond (1.304(2) Å).
The N(2)—N(3) bond length (1.389(2) Å) is equal,
within experimental error, to that in molecule 13,
although the N(3) atom in this molecule does not form a
double bond.
In molecule 14b, a slight alternation of the C—C bond
lengths is also observed in accordance with the formal
structural formula of the compound. Actually, the C(2)—C(7)
bond (1.401(2) Å) in the N(2),N(3), C(1)...C(8) ring is
substantially shorter than the bonds conjugated with this
bond in the ring and is virtually equal in length to the
adjacent C—C bonds in the C(2)...C(7) ring. In the latter
ring, a certain degree of πꢀelectron density localization at
the C(3)—C(4) and C(5)—C(6) bonds is also observed
(see Table 3).
Xꢀray diffraction study. Single crystals were coated with a
perfluorinated oil and mounted on a Bruker SMART CCD
diffractometer under a cold nitrogen stream. The experimental
Xꢀray data were collected with MoꢀK
monochromator and the ωꢀscanning technique
α
radiation using a graphite
The crystalloꢀ
.
graphic parameters and the Xꢀray diffraction data collection and
refinement statistics are given in Table 5.
Both structures were solved by direct methods and refined
by the fullꢀmatrix leastꢀsquares method based on F 2 with anisoꢀ
tropic displacement parameters for all nonhydrogen atoms. The
hydrogen atoms were located in difference Fourier maps and
refined isotropically.
The measured reflections were processed with the use of the
Bruker SAINT software.17 The structure solution and refinement
were carried out using the SHELXTLꢀPlus program package.18
A 57—63% NaH suspension in a mineral oil (Lancaster) and
a 80% toluene solution of propargyl bromide (Acros) were used
in the synthesis.
5,6,7,8,13,13aꢀHexahydrophthalazino[1,2ꢀb]quinazolineꢀ
5,8ꢀdione (3) and 6ꢀaminoꢀ5,6,6a,11ꢀtetrahydroisoindolo[2,1ꢀa]ꢀ
quinazolineꢀ5,11ꢀdione (4). A. A hot solution of oꢀformylbenzoic
acid (3 g, 0.02 mol) in BuOH (15 mL) was added to a boiling
solution of anthranilic acid hydrazide 1 (3 g, 0.02 mol) in BuOH
(15 mL). The reaction mixture was refluxed for 1 h. The hot
precipitate was filtered off, washed with hot BuOH and petroꢀ
leum ether, and dried. Compound 3 was obtained in a yield of
3.3 g (62%) as a colorless crystalline compound, m.p. 242—244
°C (cf. lit data1: m.p. 228—230 °C). The filtrate was cooled and
allowed to stand for 12 h. The precipitate was filtered off, washed
with cold PriOH and petroleum ether, and dried. Compound 4
was obtained in a yield of 1.1 g (21%) as a colorless crystalline
compound, m.p. 201 °C (cf. lit data1: m.p. 204 °C (with
decomp.)).
The carbonyl group in molecule 14b is slightly shorter
(1.211(2) Å) than that in the aboveꢀconsidered molecule,
but it falls within the typical range.
In the crystal structure of compound 13, the molꢀ
ecules are linked to each other to form centrosymmetric
...
dimers through two N(3)—H O(2) hydrogen bonds
...
...
(N(3) O(2), 2.608(2) Å; H O(2), 2.00(3) Å; the angle
at the H atom is 153(1)°).
B. Hydrazide 1 (0.5 g, 3.3 mmol) and oꢀformylbenzoic acid
2 (0.5 g, 3.3 mmol) were triturated in a mortar and fused on an
oil bath at 130 °C for 10 min. After 5 min, the melt completely
In compound 14b, the “active proton” capable of being
involved in hydrogen bonding is absent.

Synthesis of polycyclic quinazolines
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008 2347
Table 5. Crystal parameters and the Xꢀray diffraction data collection and refinement statistics for compounds 13 and 14b
Parameter
13
14b
Molecular formula
Molecular weight (kg kmol–1
C15H9N3O2
263.25
C21H13N3O
323.34
)
Crystal system
Space group
a/Å
Monoclinic
C2/c
12.2481(4)
9.4399(3)
Orthorhombic
Pbca
6.8262(8)
b/Å
17.270(2)
c/Å
19.7697(7)
90.957(2)
2285.47(13)
8
25.437(3)
β/deg
V/Å3
Z
90
2998.8(6)
8
ρ
calc/g cm–3
1.530
1.432
F(000)
1088
1344
μ(MoKα)/mm–1
Crystal dimensions/mm
Temperature/K
Radiation/Å
θꢀScanning range/deg
hkl Ranges of
reflections
0.106
0.28 × 0.24 × 0.16
123.0(2)
MoKα (0.71073)
2.06 — 26.99
–14 ≤ h ≤ 15,
–12 ≤ k ≤ 11,
–25 ≤ l ≤ 23,
8196
0.091
0.32 × 0.18 × 0.16
123.0(2)
MoKα (0.71073)
1.60 — 29.00
–9 ≤ h ≤ 8
–23 ≤ k ≤ 23,
–34 ≤ l ≤ 30
17291
Number of measured reflections
Number of independent reflections
Number of reflections with I > 2σ(I)
Number of refinement variables
R Factors based on reflections with I > 2σ(I)
based on all reflections
2474 (Rint = 0.0361)
1747
3972 (Rint = 0.0910)
2667
217
278
R1 = 0.0573, wR2 = 0.1196
R1 = 0.0879, wR2 = 0.1284
1.076
R1 = 0.0548, wR2 = 0.1300
R1 = 0.0978, wR2 = 0.1583
1.001
Goodnessꢀofꢀfit on F 2
Residual electron density, min/max, e/Å3
–0.258/0.562
–0.511/0.486
solidified. The solid product was refluxed with BuOH (5 mL)
and filtered hot. Compound 3 was obtained in a yield of 0.62 g
(70%). The filtrate was cooled, kept on ice for 2 h, and ground
with a rod. The precipitate was filtered off. Compound 4 was
obtained in a yield of 0.135 g (15%). Compounds 3 and 4 were
identified by IR spectroscopy and taking into account that the
mixtures of these compounds and the authentic samples showed
no melting point depression.
6,13ꢀDimethylꢀ5,6,7,8,13,13aꢀhexahydrophthalazino[1,2ꢀb]ꢀ
quinazolineꢀ5,8ꢀdione (9a). Sodium hydroxide (0.52 g, 13 mmol)
was triturated in DMSO (3 mL) in a conical flask. Then comꢀ
pound 3 (0.43 g, 1.6 mmol) was added, the reaction mixture was
ground for 10 min, and CH3I (0.3 mL, 4.8 mmol) was added.
The reaction mixture was triturated and allowed to stand for 12 h.
Water (10 mL) was added to the solidified mixture, the mixture
was kept on ice for 1 h, and the precipitate was filtered off,
washed with water, dried, and twice recrystallized from MeOH.
The product contained a yellow impurity. To remove the latter,
the product was refluxed with isooctane, filtered, and washed
with hot isooctane. Compound 9a was obtained in a yield of 0.1 g
(21%) as a colorless crystalline compound, m.p. 210—215 °C.
Found (%): C, 69.73; H, 4.95; N, 14.28. C17H15N3O2. Calcuꢀ
lated (%): C, 69.61; H, 5.15; N, 14.33.
The reaction mixture was ground for 10 min, and a toluene
solution of propargyl bromide (1.6 mL, 13 mmol) was added.
The reaction mixture was triturated and allowed to stand for 3 h.
Then 50% MeOH (10 mL) was added, the reaction mixture was
kept on ice for 1 h, and the precipitate was filtered off, twice
washed with 50% MeOH, and recrystallized from MeOH (20 mL).
Compound 9b was obtained in a yield of 1 g (48.5%) as paleꢀ
cream crystals, m.p. 153—155 °C (from MeOH). Found (%):
C, 74.06; H, 4.62; N, 12.17. C21H15N3O2. Calculated (%): C,
73.89; H, 4.43; N, 12.31.
6ꢀHydroxymethylꢀ5,6,7,8,13,13aꢀhexahydrophthalazinoꢀ
[1,2ꢀb]quinazolineꢀ5,8ꢀdione (10). Compound 3 (0.263 g,
1 mmol) and paraformaldehyde (80 mg, 2.6 mmol) in a mixture
of a 30% aqueous solutions of formaldehyde (2 mL) and MeOH
(10 mL) was refluxed until dissolution (~2.5 h). The solution
was filtered off from a small amount of a sediment and then
cooled. Water (5 mL) was added, and the mixture was kept on
ice for 1 h. The precipitate was filtered off, washed with 50%
MeOH, and dried. Colorless compound 10 was obtained in a
yield of 0.18 g (61%), m.p. 183—188 °C (from CH3CN). Found
(%): C, 68.52; H, 4.95; N, 14.83. C16H13N3O2. Calculated (%):
C, 68.81; H, 4.69; N, 15.04.
6ꢀAcetylaminoꢀ5,6,6a,11ꢀtetrahydroisoindolo[1,2ꢀa]ꢀ
quinazolineꢀ5,11ꢀdione (11). Compound 4 (0.25 g, 0.94 mmol)
was heated in Ac2O (1 mL) until dissolution, after which a new
precipitate rapidly formed and the reaction mixture was solidiꢀ
6,13ꢀDipropargylꢀ5,6,7,8,13,13aꢀhexahydrophthalazino[1,2ꢀb]ꢀ
quinazolineꢀ5,8ꢀdione (9b). Compound 3 (1.6 g, 6 mmol) was
added to NaOH (1 g, 25 mmol) triturated with DMSO (5 mL).

2348
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008
Ukhin et al.
fied. The mixture was cooled, PriOH (2 mL) was added, and the
precipitate was filtered off, washed with PriOH and petroleum
ether, and dried. Compound 11 was obtained in a yield of 0.19 g
(67%) as a colorless crystalline compound, m.p. 280—283 °C.
Found (%): C, 69.73; H, 4.87; N, 14.29. C17H13N3O2. Calcuꢀ
lated (%): C, 70.09; H, 4.50; N, 14.42.
6ꢀDimethylaminoꢀ5,6,6a,11ꢀtetrahydroisoindolo[1,2ꢀa]ꢀ
quinazolineꢀ5,11ꢀdione (12). Methyl iodide (0.25 mL, 100%
excess) was added to a mixture of compound 4 (0.265 g, 1 mmol)
and a NaH suspension (0.1 g, 2.5 mmol) in a mineral oil in
DMSO (2 mL). The reaction mixture was kept for 2 h. The
precipitate with the oil, which was obtained after the treatment
with water, was kept for 12 h. Then the precipitate was filtered
off, washed with water, and dried. The yield of the crude
product was 0.14 g (47.8%). A colorless crystalline compound
was isolated, m.p. 195—200 °C (from a 1 : 1 toluene—isooctane
mixture). Found (%): C, 69.40; H, 5.37; N, 14.17. C17H15N3O2.
Calculated (%): C, 69.61; H, 5.15; N, 14.33.
5ꢀMethylphthalazino[1,2ꢀb]quinazolinꢀ8ꢀone (14a). A mixꢀ
ture of hydrazide 1 (0.75 g, 5 mmol) and oꢀacetylbenzoic acid
(0.82 g, 5 mmol) in glycol (5 mL) was refluxed for 30 min and
cooled. Then MeOH (10 mL) was added, and the mixture was
cooled with ice. The precipitate was filtered off, washed with
cold MeOH and petroleum ether, and dried. Colorless
compound 14a was obtained in a yield of 0.54 g (41.5%),
m.p. 268—270 °C (cf. lit. data7: m.p. 266—268 °C).
5ꢀPhenylphthalazino[1,2ꢀb]quinazolinꢀ8ꢀone (14b). A mixꢀ
ture of hydrazide 1 (0.75 g, 5 mmol) and oꢀbenzoylbenzoic acid
(1.2 g, 5.3 mmol) in glycol (5 mL) was refluxed for 30 min and
cooled. Then MeOH (10 mL) was added. The precipitate was
filtered off, washed with cold MeOH and petroleum ether, and
dried. Colorless compound 14b was obtained in a yield of 0.75 g
(47%), m.p. 245—247 °C (cf. lit. data7: m.p. 238—240 °C).
6. S. Racine, Ann., 1887, 239, 80.
7. J. Tirouflet, Compt. Rend. Acad. Sci., 1953, 236, 1426.
8. C. Thode, J. Pract. Chem., 1904, [2], 69, 92.
9. J. B. Foresman, E. Frisch, Exploring Chemistry with Electronic
Structure Methods (2nd ed.), Gaussian Inc., Pittsburg, 1996.
10. M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, J. A. Montgomery, Jr.,
T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S.
Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi,
G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada,
M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida,
T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene,
X. Li, J. E. Knox, H. P. Hratchian, J. B. Cross, C. Adamo,
J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A.
J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala,
K. Morokuma, G. A. Voth, P. Salvador, J. J. Dannenberg,
V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C. Strain,
O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari,
J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford,
J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko,
P. Piskorz, I. Komaromi, R. L. Martin, D. J. Fox, T. Keith,
M. A. AlꢀLaham, C. Y. Peng, A. Nanayakkara, M. Challacombe,
P. M. W. Gill, B. Johnson, W. Chen, M. W. Wong,
C. Gonzalez, J. A. Pople, Gaussian 03, Revision B.03,
Pittsburgh PA: Gaussian Inc., 2003.
11. J. Emsley, The Elements, Clarendon Press, Oxford, 1991.
12. C. E. Völcker, J. Marth, H. Beyer, Chem. Ber., 1967, 100,
875.
13. M. Razvi, T. Ramalingam, P. B. Sattur, Indian J. Chem.,
1990, 29B, 399.
14. M. Lamchen, J. Chem. Soc. (c), 1966, 573.
15. Heterocyclic Compounds, 6, Ed. R. C. Elderfield, John
Wiley & Sons, Inc., New York, Chapmen & Hall, Ltd,
London.
16. F. H. Allen, Acta Crystallogr., 2002, B58, 380.
17. SAINT. Version 6.02A, Bruker AXS Inc. Madison Wisconsin,
USA, 2001
18. SHELXTLꢀPlus. Release 5.10, Bruker AXS Inc., Madison,
Wisconsin, USA, 1997.
References
1. M. Ghelardoni, V. Pestellini, Annali di Chimica, 1974, 64, 445.
2. V. Pestellini, M. Ghelardoni, G. Volterra, P. Del Soldato,
Eur. J. Med. Chem. – Chimica Therapeutica, 1978, 13, N 3,
296.
3. P. R. Jones, Chem. Rev., 1963, 63, 461.
4. D. D. Wheeler, D. C. Young, D. C. Erley, J. Org. Chem.,
1957, 22, 547.
Received December 28, 2007;
in revised form July 2, 2008
5. A. Hamburger, Monatsh. Chem., 1898, 19, 430.