Anthranilic acid hydrazide in the synthesis of fused polycyclic ...

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Russian Chemical Bulletin, International Edition, Vol. 57, No. 11, pp. 2340—2348, November, 2008

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 a

Institute of Physical and Organic Chemistry, Southern Federal University, 194/2 prosp. Stachki, 344090 RostovonDon, Russian Federation. Fax: +7 (863) 243 4776. Email: [email protected] b N. S. Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, 31 Leninsky prosp., 119991 Moscow, Russian Federation. Fax: +7 (495) 953 1279. Email: [email protected] A modified procedure was developed for the synthesis of 5,6,7,8,13,13ahexahydro phthalazino[1,2b]quinazoline5,8dione and 6amino5,6,6a,11tetrahydroisoindolo[2,1a] quinazoline5,11dione from oformylbenzoic 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 5substituted phthalazino[1,2b]quinazolin8one derivatives. The possible reaction mechanism is discussed. 5,6,7,8Tetrahydrophthalazino[1,2b]quinazoline5,8dione and 5phenylphthalazino[2,1b]quinazolin8one were studied by Xray diffraction. Key words: anthranilic acid hydrazide, oformylbenzoic acid, oacetylbenzoic acid, obenzoylbenzoic acid, 5,6,7,8,13,13ahexahydrophthalazino[1,2b]quinazoline5,8dione, 6amino5,6,6a,11tetrahydroisoindolo[2,1a]quinazoline5,11dione, phthalazino[1,2b] quinazolin8one derivatives.

It is known1 that heating of anthranilic acid hydrazide (1) with oformylbenzoic acid (2) in dimethylacetamide affords a mixture of 5,6,7,8,13,13ahexahydrophthalazino [1,2b]quinazoline5,8dione (3) and 6amino5,6,6a,11 tetrahydroisoindolo[2,1a]quinazoline5,11dione (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 proce dure for the synthesis of compounds 3 and 4, which does not require their additional separation. It was found that

the reaction in butanol instead of dimethylacetamide pro 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

Scheme 1

i. Δ, 1 h, BunOH.

Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2294—2302, November, 2008. 10665285/08/57112340 © 2008 Springer Science+Business Media, Inc.

Synthesis of polycyclic quinazolines

Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008

solventfree conditions (in a melt) is completed within 5—10 min and gives the same compounds in a total yield of ~80% (see the Experimental). It is known that oformylbenzoic 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 3hydroxyphthalide form 2b.4 At the same time, this acid is involved in reactions typical of aldehydes. Thus, it undergoes the Cannizzaro reac tion,5 reacts with a silver ammonia solution,6 and forms oxime6 with hydroxylamine and hydrazone1 with anthra nilic acid hydrazide. The dissociation constant of oformylbenzoic acid (2.76•10–5)7 has a value expected for osubstituted benzoic acid. The proposed pathway of the reaction of oformylbenzoic 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 equi molar amount of oformylbenzoic 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 oformylbenzoic acid 2. This bond can be formed only if the sevenmembered ring closure occurs in hydra zone 5, which apparently takes place during heating in dimethylacetamide1 or butanol. Presumably, the cycliza 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 hydro gen bond between the carboxy group and the hydrazone

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nitrogen atom is most suitable for this transfer. The carbenium center that appears at the adjacent carbon atom reacts with the oamino group. In the resulting zwitter 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), result 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 chemi cal calculations by the DFT method (B3LYP/321G)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 com 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 thermo 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

Scheme 2

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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/321G level.



Table 1. Total energies (Etotal/a.u.), relative energies (ΔE/kcal mol–1), and minimal harmonic vibrational frequencies (ω1/cm–1) of con formers 5 corresponding to the energy minima (λ = 0) on the potential energy surface Conformer 5a 5b 5c 5d

Etotal

ΔE

ω1

–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 mecha 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 distinguish 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 transfor 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 sp3hybridized nitrogen atom, which may account for the lower stability of conformer 5c compared to 5d. The calculations showed that the further transfor 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

in the first steps according to the proposed mechanism. However, this mechanism is possible at high tempera tures, as observed experimentally. The calculations showed that the initial thermal initiation is necessary for the reac 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, oformylbenzoic 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 com 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 reac tion with an excess of CH3I in DMSO/NaH produces dimethyl derivative 12 (Scheme 4). Compound 3 was oxidized with potassium permanga nate to 5,6,7,8tetrahydrophthalazino[1,2b]quinazoline 5,8dione 13.1 Apparently, the oxidation can proceed in solution even under the action of atmospheric oxygen in an attempt to prepare a specimen for Xray diffraction. The crystal, which was obtained by slow evaporation of a

Scheme 3

10 min

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Ukhin et al.

Scheme 4

R = CH3 (a), CH2C≡CH (b).

solution of compound 3 in acetonitrile, proved to be (Xray diffraction data) its oxidation product 13 (see Scheme 4). We used hydrazide 1 also in the synthesis of 5methyl (14a) and 5phenylphthalazino[1,2b]quinazolin8ones (14b). Earlier, these compounds have been synthesized by the condensation of 1chloro4methyl and 1chloro 4phenylphthalazines with anthranilic acid;12,13 compound 14b was prepared also by the reaction of 6a,11dihydro 6aphenylisoindolo[2,1a][3,1]benzoxazine5,11dione with hydrazine.14 We found that hydrazide 1 reacts with oacetyl and obenzoylbenzoic acids (15a and 15b, respectively) upon heating in ethylene glycol to give phthalazinoquinazolinones 14a and 14b, respectively. Based on the known fact15 that oacetylbenzoic acids readily react with hydrazines to give 2substituted phthal

azinones, we suggested that the condensation proceeds through the formation of hydrazones 16a,b and phthal azinones 17a,b, which then undergo cyclization with elimination of an H2O molecule from intermediates 18a,b to give the final products (Scheme 5). The IR and 1H NMR spectroscopic data for the com pounds synthesized are given in Table 2. The crystal structures of compounds 13 and 14b were established by Xray diffraction (Figs 2 and 3; Tables 3 and 4, respectively). Molecule 13 is an aromatic system consisting of four fused sixmembered rings. Two central heterocycles con 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.



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Table 2. Spectroscopic characteristics of the compounds synthesized Com IR, ν/cm–1 pound (Nujol) 3

4

9a

9b

10

12

14а

14b

NMR,

δ (J/Hz)

3287, 3185, 3100 (NH), 1680, 1675, 1660 (CO), 1607, 1575, 1515, 1487 (arom.) 3315, 3265, 3180 (NH), 1707, 1675, 1660 (СО), 1607, 1574, 1487 (arom.) 1687, 1657 (CO), 1607, 1595, 1570, 1500 (arom.)

DMSOd6

3287, 3270, 3260, 3233 (≡СН), 1654 (СО), 1680, 1667, 1600, 1567, 1487 (arom.) 3260 (NH), 1675, 1655 (СО), 1605, 1575, 1515, 1485 (arom.)

CDCl3

CDCl3

CDCl3

DMSOd6

3300 (NH), 1727, 1700, 1660 (СО), 1600, 1505, 1487 (arom.) 1680, 1660 (CO), 1615, 1600, 1580, 1560, 1500 (arom.) 1694 (CO), 1620 (пл.), 1600, 1575, 1555, 1495 (arom.) 1715 (CO), 1615, 1600, 1575, 1480 (arom.)

11

1H

Solvent

DMSOd6

CDCl3

DMSOd6

DMSOd6

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); 8.05—8.25 (m, 3 Н, СНarom) 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) 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) 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) 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 2pyridones (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 fea tures of the πelectron density delocalization in the mol 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)

O(2)

H(3A)

O(2)

O(1)

C(20)

C(9) C(15)

C(9)

C(1)

N(2)

C(10)

C(16)

N(3)

N(3) C(15) C(14)

C(2)

C(10)

C(21)

N(2)

C(1) C(2)

C(3) C(3) C(8)

C(14) C(11) C(13)

C(12)

N(1)

C(13)

C(7) C(4)

C(6) C(5)

Fig. 2. Molecular structure of 13. Displacement ellipsoids are drawn at the 50% probability level.

C(11)

N(1)

C(8) C(7)

C(12) C(6)

C(4) C(5)

Fig. 3. Molecular structure of 14b. Displacement ellipsoids are drawn at the 50% probability level.

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Table 3. Selected bond lengths (d) in molecule 13

Ukhin et al.

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). 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 corre 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 πelectron density localization at the C(3)—C(4) and C(5)—C(6) bonds is also observed (see Table 3). The carbonyl group in molecule 14b is slightly shorter (1.211(2) Å) than that in the aboveconsidered molecule, but it falls within the typical range. In the crystal structure of compound 13, the mol 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)°). In compound 14b, the “active proton” capable of being involved in hydrogen bonding is absent.

Experimental The IR spectra were recorded on a Specord IR75 instru ment in Nujol mulls. The 1H NMR spectra were measured on a Varian UNITY300 spectrometer. The spectroscopic character istics of the compounds are given in Table 2. Xray 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 Xray data were collected with MoKα radiation using a graphite monochromator and the ωscanning technique. The crystallo graphic parameters and the Xray diffraction data collection and refinement statistics are given in Table 5. Both structures were solved by direct methods and refined by the fullmatrix leastsquares method based on F 2 with aniso 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 SHELXTLPlus 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. 5,6,7,8,13,13aHexahydrophthalazino[1,2b]quinazoline 5,8dione (3) and 6amino5,6,6a,11tetrahydroisoindolo[2,1a] quinazoline5,11dione (4). A. A hot solution of oformylbenzoic 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 petro 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 data 1 : m.p. 204 ° C (with decomp.)). B. Hydrazide 1 (0.5 g, 3.3 mmol) and oformylbenzoic 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



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Table 5. Crystal parameters and the Xray diffraction data collection and refinement statistics for compounds 13 and 14b Parameter Molecular formula Molecular weight (kg kmol–1) Crystal system Space group a/Å b/Å c/Å β/deg V/Å3 Z ρcalc/g cm–3 F(000) μ(MoKα)/mm–1 Crystal dimensions/mm Temperature/K Radiation/Å θScanning range/deg hkl Ranges of reflections 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 Goodnessoffit on F 2 Residual electron density, min/max, e/Å3

13

14b

C15H9N3O2 263.25 Monoclinic C2/c 12.2481(4) 9.4399(3) 19.7697(7) 90.957(2) 2285.47(13) 8 1.530 1088 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 2474 (Rint = 0.0361) 1747 217 R1 = 0.0573, wR2 = 0.1196 R1 = 0.0879, wR2 = 0.1284 1.076 –0.258/0.562

C21H13N3O 323.34 Orthorhombic Pbca 6.8262(8) 17.270(2) 25.437(3) 90 2998.8(6) 8 1.432 1344 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 3972 (Rint = 0.0910) 2667 278 R1 = 0.0548, wR2 = 0.1300 R1 = 0.0978, wR2 = 0.1583 1.001 –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. 6,13Dimethyl5,6,7,8,13,13ahexahydrophthalazino[1,2b] quinazoline5,8dione (9a). Sodium hydroxide (0.52 g, 13 mmol) was triturated in DMSO (3 mL) in a conical flask. Then com 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. Calcu lated (%): C, 69.61; H, 5.15; N, 14.33. 6,13Dipropargyl5,6,7,8,13,13ahexahydrophthalazino[1,2b] quinazoline5,8dione (9b). Compound 3 (1.6 g, 6 mmol) was added to NaOH (1 g, 25 mmol) triturated with DMSO (5 mL).

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 pale 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. 6Hydroxymethyl5,6,7,8,13,13ahexahydrophthalazino [1,2b]quinazoline5,8dione (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. 6Acetylamino5,6,6a,11tetrahydroisoindolo[1,2a] quinazoline5,11dione (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 solidi

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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. Calcu lated (%): C, 70.09; H, 4.50; N, 14.42. 6Dimethylamino5,6,6a,11tetrahydroisoindolo[1,2a] quinazoline5,11dione (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. 5Methylphthalazino[1,2b]quinazolin8one (14a). A mix ture of hydrazide 1 (0.75 g, 5 mmol) and oacetylbenzoic 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). 5Phenylphthalazino[1,2b]quinazolin8one (14b). A mix ture of hydrazide 1 (0.75 g, 5 mmol) and obenzoylbenzoic 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).

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Received December 28, 2007; in revised form July 2, 2008