ISSN 1070-3632, Russian Journal of General Chemistry, 2016, Vol. 86, No. 8, pp. 1832–1837. © Pleiades Publishing, Ltd., 2016. Original Russian Text © P.P. Mukovoz, V.O. Koz’minykh, A.V. Gorbunova, E.N. Koz’minykh, P.A. Slepukhin, O.S. El’tsov, I.N. Ganebnykh, 2016, published in Zhurnal Obshchei Khimii, 2016, Vol. 86, No. 8, pp. 1293–1298.

Reactions of 3,4-Dihydroxyhexa-2,4-diene-1,6-dioic Acid Esters with Anthranilic Acid Hydrazide P. P. Mukovoza*, V. O. Koz’minykhb, A. V. Gorbunovac, E. N. Koz’minykhb, P. A. Slepukhind,e, O. S. El’tsove, and I. N. Ganebnykhd,e a

Orenburg Branch, Moscow Institute of Technology, pr. Pobedy 75, Orenburg, 460018 Russia *e-mail: [email protected] b

Perm State Humanitarian Pedagogical University, Perm, Russia c

d

Orenburg State University, Orenburg, Russia

Postovsky Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences, Yekaterinburg, Russia e

Ural Federal University, Yekaterinburg, Russia Received February 16, 2016

Abstract—Reactions of 3,4-dihydroxyhexa-2,4-diene-1,6-dioic acid esters with anthranilic acid hydrazide lead to the formation of 3,4-bis(2-aminobenzoylhydrazono)hexane-1,6-dioic acid esters. Structural features of the synthesized compounds are discussed. Keywords: 3,4-dihydroxyhexa-2,4-diene-1,6-dioic acid ester, anthranilic acid hydrazide, 3,4-bis(2-aminobenzoylhydrazono)hexane-1,6-dioic acid ester

DOI: 10.1134/S1070363216080090 1,2,4-Tricarbonyl compounds such as acylpyruvic acid are known to react with anthranilic acid hydrazide (2-aminobenzoylhydrazine) to form biologically active pyridazino[2,3-b]quinazolines [1]. Reactions of 1,3,4,6tetracarbonyl compounds [2, 3] including these with terminal ester groups [4] with anthranilic acid hydrazide have not been studied. We found that the reactions of alkyl 3,4-dihydroxyhexa-2,4-diene-1,6-dioates (ketipinates) 1a–1d

(major dienol tautomer 1A and minor dioxo tautomer 1B, Scheme 1) with anthranilic acid hydrazide afforded novel (3E,4E)-3,4-bis(2-aminobenzoylhydrazono)hexane-1,6-dioic acid esters 2a–2d. Compounds 2a–2d were pale yellow crystalline substances soluble in methanol, moderately soluble in DMSO, and insoluble in water. Structure of compounds 2a–2d was confirmed by IR and 1H NMR spectroscopy, mass spectrometry, and X-ray diffraction data.

Scheme 1.

NH2 O O

AlkO

H

O

O OAlk

O

H

O

AlkO 1а−1d

1А

O

H2N OAlk

O

O

H N

O

N NH2

+2

1B

−2H2O

NH O

AlkO OAlk

N O HN O

Alk = Me (а), Et (b), n-Pr (c), p-Bu (d).

1832

H2N

2а−2d

REACTIONS OF 3,4-DIHYDROXYHEXA-2,4-DIENE-1,6-DIOIC ACID ESTERS

1833

Fig. 1. Crystal structure of compound 2b.

The IR spectra of hydrazonoesters 2a–2d contained the absorption bands at 3407–3494 (asymmetrical stretching) and 3299–3384 cm–1 (symmetrical stretching) corresponding to the primary amino groups as well as at 3179–3313 cm–1 due to stretching of the secondary NH-groups. Absorption at 1658–1676 (amide I) and 1512–1523 cm–1 (amide II) confirmed the presence of amide units in the molecule. Absorption bands at 1705–1727 and 1236–1248 cm–1 indicated the presence of ester moieties in the molecules of compounds 2a–2d. Shift of the absorption bands of NH2 group to low-frequency range (note that non-associated primary amino groups give rise to two absorption bands at νas ≈ 3500 and νs ≈ 3400 cm–1 [5]) as well as the relatively low frequency of the ester carbonyl groups revealed the presence of hydrogen bonding in the molecules of 2a–2d. Spectral methods did not allow unambiguous structure elucidation of compounds 2a–2d in the solid phase. Therefore, crystals of 2b and 2d were grown and studied by X-ray diffraction. According to the results, in the solid state those compounds existed in the form of (3E,4E)-bisbenzoylhydrazone. Their molecules were located in a special position with respect to the inversion center of the crystal. Hydrazone units C10=N1–N2 in the molecules of compound 2b were trans-positioned relative to each other and were coplanar with the benzoyl carbonyl groups (within 0.2 Å). Aromatic substituents in the molecule of 2b were twisted with respect to the plane of bisazomethine

units by 18°, indicating the conjugation of two benzoylhydrazone fragments in a single π-system (Fig. 1). Amide CONH unit in the molecule of 2b was trans-configured; carbonyl C7=O3 groups formed a sixmembered NH···O=C chelating moiety with one of the protons H3A of the primary amino group of the aromatic ring, with conformation of the latter fixed by intramolecular hydrogen bonding (Fig. 2). The second proton H3B of the primary amino group was linked with the amide carbonyl C7=O3 group of the adjacent molecule by intermolecular hydrogen bond. The ester carbonyl C8=O1 groups in compound 2b formed intramolecular hydrogen bond with the protons H2 of =N–NH unit, giving a seven-membered fragment of non-planar –NH···O=C chelate type, its methylene C2(5)H2 group deviating from the ring plane. Crystal packing of the molecules of compound 2b was caused by intermolecular hydrogen bonding involving the amino protons and carbonyl groups of hydrazone fragments. Conformation of compound 2d differed significantly from that of 2b. The amide carbonyl C7=O1 group in the molecule of 2d was by 5° out of plane of bisazomethine unit and formed a 36.5° angle with the aromatic ring plane (Fig. 3). Amide CONH unit in the molecule of 2d had cis-configuration; carbonyl C7=O1 groups formed a non-planar (within 0.3 Å) sixmembered –NH···O=C chelate moiety with the proton H3A of the primary amino group of aromatic ring. In

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(3E,4E)-configured hydrazone units (10.85– 11.02 ppm), supporting the axial symmetry of bishydrazones 2 with respect to the C3–C4 bond. The signals of methine and NH protons of ene-hydrazine units were not registered, confirming the absence of possible ene-hydrazine tautomers of compounds 2 in the solutions of non-polar solvents. Note that the compounds formed by reacting ketipinates 1 with arylhydrazines have the structure similar to bishydrazones 3 (Scheme 2) [6–8].

Fig. 2. Hydrogen bonding in the crystal of 2b.

contrast to compound 2b, in the molecule of 2d the ester carbonyl C12=O2 group formed no intramolecular hydrogen bonds with the protons H2 of hydrazone units, due to the steric requirements (Fig. 4). Instead, hydrazone fragments of compound 2d formed dimeric intermolecular NH···O=C hydrogen bonds in the crystal; that fully compensated for the lack of intramolecular bonding with the ester carbonyl group. Similarly to the solid state case, compounds 2a–2d existed in bisbenzoylhydrazone form 2A (Scheme 2) in solutions of nonpolar solvents, as evidenced by 1H NMR data. For example, the 1H NMR spectra of compounds 2a–2d contained a characteristic singlet of four protons of two methylene C2,5H2 groups (4.08– 4.16 ppm), a singlet of four protons of two NH2 groups (5.65–5.83 ppm), and a singlet of two NH protons of

The molecular structure of compounds 2a–2d was consistent with HRMS data: the mass spectra contained the peaks of molecular ions [M + H]+, [M + Na]+, and [M + K]+ as well as the peaks of cluster ions [2M + H]+ and [2M + Na]+. Probably, the reaction of ketipinates 1 with anthranilic acid hydrazide starts with a nucleophilic attack of NH2 group of the reagent at the C3(4) carbonyl groups of the oxo form 1B, followed by formation of intermediates A–B and elimination of two water molecules to form the final compound 2 (Scheme 3). In summary, 3,4-bis(2-aminobenzoylhydrazono) hexane-1,6-dioic acid esters, obtained by reacting dialkyl ketipinates with anthranilic acid hydrazide are the planar conjugated structures existing in the (3E,4E)form in the solid state and in solutions. Amide CONH units in the molecules of bisbenzoylhydrazones have a cis- or trans-configuration, depending on steric factors. IR spectra were recorded using a Bruker Alpha FTIR spectrometer (ATR, ZnSe). 1H NMR spectra (CDCl3) were obtained using a Bruker AVANCE II

Fig. 3. Crystal structure of compound 2d. RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 8 2016

REACTIONS OF 3,4-DIHYDROXYHEXA-2,4-DIENE-1,6-DIOIC ACID ESTERS

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Scheme 2.

N

AlkO

NH2

NH2

NH2

O

O

O

NH O

N

O

H

H

O

N

O

NH

H

N

NH

OAlk

O N HN Ar

O

H2N

2А, 2а−2d

AlkO OAlk

O

O H2N

N

AlkO OAlk

AlkO OAlk

O N HN

HN

NH O

Ar NH O N

H2N 2C

2B

3

Ar = Ph, Alk = Me; Ar = 2,4-(NO2)2-Ph, Alk = Et, p-Pr, p-Bu.

Scheme 3. H N

.. H2N

δ− O O

O NH2

AlkO

+

AlkO O

O

O OH

OAlk

NH O HN

OAlk

δ+

H

H

O

O H2N

1B

δ− O O δ+

AlkO O N HN −H2O

OAlk

H N

H 2N ..

O

HN

NH2 +

AlkO

O

O N HN

H2N

O B

Fourier spectrometer (400 MHz) relative to internal TMS. Mass spectra (ESI) were recorded using a maXis impact HD quadrupole TOF mass spectrometer (Bruker Daltonik GmbH). TLC was performed using Sorbfil UV-254 plates and eluting with chloroform–

А NH2

NH2

O

O

NH O

OH H H

N OAlk −H2O

NH O

AlkO O N HN

OAlk

O

H2N

H2N C

2

methanol (20 : 1) and chloroform–hexane mixtures (10 : 1) or with chloroform. X-Ray diffraction study was carried out using an Xcalibur 3 automatic four-circle diffractometer

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Methyl (3E,4E)-3,4-bis(2-aminobenzoylhydrazono)hexane-1,6-dioate (2a). Yield 5.97 g (51%), mp 243– 245°C. IR spectrum, ν, cm–1: 3494 [νas(NH2)], 3384 [νs(NH2)], 3241 (NH), 3060, 3020 (CHAr), 2953 [νas(CH3)], 1727 (C1(6)=O), 1660 (C=O, amide I), 1618, 1586 [C=C, δas(NH2), in-plane)], 1523 (C=O, amide II), 1503, 1438 (C=C), 1248 (C–OCH3, ester), 1207, 1138, 1114, 1026, 1005 [ν(C–C)], 946, 884 [δ (CHAr), out-of-plane], 751 [δrocking(C2,5H2)], 679 [ν(C–C)]. 1H NMR spectrum, δ, ppm: 3.82 s (6H, CH3), 4.16 s [4H, C2(5)CH2], 5.83 s (4H, NH2), 6.77–7.67 m (8HAr, C6H4), 11.02 s (2H, NH). Mass spectrum: m/z 469.1830 [M + H]+ (calculated C22H25N6O6+: 469.1826). Fig. 4. Hydrogen bonding in the crystal of 2d.

equipped with a CCD-detector [ω-scanning, MoKαradiation, 295(2) K]. The absorption was empirically corrected for. Structures of the compounds obtained were solved by direct statistical methods and refined under full-matrix anisotropic approximation over F2 for all non-hydrogen atoms. Hydrogen atoms of the C–H bonds were placed into the geometrically calculated positions and refined under the isotropic approximation. Positions of NH-protons were independently refined. All calculations were performed using Olex2 software [9]. Crystals of compound 2b were monoclinic, the unit cell parameters: space group P21/n, a = 9.9420(6), b = 8.3850(4), c = 15.0922(9) Å, β = 107.539(6)°, μ = 0.101 mm–1. 5153 reflections were collected in the range of 2.82 < θ < 30.60°, 3227 of them were independent (Rint 0.0212) including 2423 reflections with I > 2σ(I). Final refinement indices: R1 = 0.0685, wR2 = 0.1650 (all reflections), R1 = 0.0481, wR2 = 0.1485 [reflections with I > 2σ(I)]. Residual electron density peaks were 0.282/–0.243 ē Å–3. Crystals of compound 2d were monoclinic, the unit cell parameters: space group P-1, a = 6.9747(4), b = 9.1150(7), c = 12.6289(10) Å, α = 71.401(7), β = 84.386(6), γ = 73.119(6)°, μ = 0.090 mm–1. 6906 reflections were collected in the range of 2.45 < θ < 30.84°, 3953 of them were independent (Rint = 0.0175) including 2846 with I > 2σ(I). Final refinement indices: R1 0.0542, wR2 0.1482 (all reflections), R1 = 0.0760, wR2 = 0.1695 [reflections with I > 2σ(I)], GooF 1.002. Residual electron density peaks were 0.29/–0.25 ē Å–3.

Ethyl (3E,4E)-3,4-bis(2-aminobenzoylhydrazono)hexane-1,6-dioate (2b). Yield 6.94 g (56%), mp 195– 197°C. IR spectrum, ν, cm–1: 468 [νas(NH2)], 3362 [νs(NH2)], 3256 (NH), 3069, 3028 (CHAr)], 2975 [νas(CH3)], 2933 [νas(CH2)], 1718 (C1(6)=O), 1668 (C=O, amide I), 1623, 1585 [C=C, δas(NH2), inplane)], 1512 (C=O, amide II), 1502, 1448 (C=C), 1239 (C–OC2H5, ester), 1167, 1133, 1027, 966 [ν(C–C)], 886, 856 [δ(CHAr), out-of-plane], 738 [δrocking(C2,5H2)], 673 [ν(C–C)]. 1H NMR spectrum, δ, ppm: 1.23 t (6H, CH2CH3, J = 7.1 Hz), 4.08 s (4H, C2(5)CH2), 4.23 q (2H, CH2CH3, J = 7.1 Hz), 5.77 s (4H, NH2), 6.63– 7.61 m (8HAr, C6H4), 10.94 s (2H, 2NH). Mass spectrum: m/z 497.2145 [M + H]+ (calculated C24H29N6O6+: 497.2143). Propyl (3E,4E)-3,4-bis(2-aminobenzoylhydrazono)hexane-1,6-dioate (2c). Yield 5.63 g (43%), mp 193– 195°C. IR spectrum, ν, cm–1: 3407 [νas(NH2)], 3299 [νs(NH2)], 3179 (NH), 3065, 3022 (CHAr), 2959 [νas(CH3)], 2937 [νas(CH2)], 2878 [νs(CH3)], 1705 [C1(6)=O], 1658 (C=O, amide I), 1620, 1583 [C=C, δas(NH2), in-plane], 1519 (C=O, amide II), 1501, 1454 (C=C), 1236 (C–OC3H7, ester), 1205, 1169, 1134, 1101, 1035, 1004 [ν(C–C)], 947, 884, 848 [δ(CHAr), out-of-plane], 736 [δrocking(C2,5H2)], 700, 674 [ν(C–C)]. 1 H NMR spectrum, δ, ppm: 0.94 t (6H, CH2CH2CH3, J = 7.5 Hz), 1.70 m (4H, CH2CH2CH3), 4.11 s [4H, C2(5)CH2], 4.15 t (2H, CH2CH2CH3, J = 7.5 Hz), 5.77 s (4H, NH2), 6.74–7.64 m (8HAr, C6H4), 10.85 s (2H, 2NH). Mass spectrum: m/z 525.2460 [M + H]+ (calculated C26H33N6O6+: 525.2456). Butyl (3E,4E)-3,4-bis(2-aminobenzoylhydrazono)hexane-1,6-dioate (2d). Yield 5.11 g (37%), mp 148– 152°C. IR spectrum, ν, cm–1: 3461 [νas(NH2)], 3370 [νs(NH2)], 3313 (NH), 3062, 3024 (CHAr), 2956 [νas(CH3)], 2929 [νas(CH2)], 2868 [νs(CH3)], 1718

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REACTIONS OF 3,4-DIHYDROXYHEXA-2,4-DIENE-1,6-DIOIC ACID ESTERS

[C1(6)=O], 1676 (C=O, amide I), 1619, 1585 [C=C, δas(NH2) in-plane], 1512 (C=O, amide II), 1502, 1452 (C=C), 1243 (C–OC4H9, ester), 1156, 1137, 1065, 1023, 962 [ν(C–C)], 935, 886, 852, 814 [δ(CHAr), outof-plane], 742 [δrocking(C2,5H2)]. 1H NMR spectrum, δ, ppm: 0.93 t (6H, CH2CH2CH2CH3, J = 7.2 Hz), 1.18 m (4H, CH2CH2CH2CH3), 1.63 m (4H, CH2CH2CH2· CH3), 4.08 s (4H, C2(5)CH2), 4.20 t (2H, CH2CH2· CH2CH3, J = 7.2 Hz), 5.65 s (4H, 2NH2), 6.64–7.60 m (8HAr, C6H4), 10.93 s (2H, NH). Mass spectrum: m/z 553.2764 [M + H]+ (calculated C28H37N6O6+: 553.2769). REFERENCES 1. Lomidze, K.Sh. and Koz’minykh, V.O., Book of Abstracts, Vserossiiskaya nauchnaya konferentsiya “Izyskanie i izuchenie novykh farmakologicheskikh sredstv” (All-Russian Sci. Conf. “Search and Study of New Pharmacological Agents”), Perm, 1989, p. 41. 2. Tarasova, V.A., Kuz’min, A.V., Mukovoz, P.P., and

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Koz’minykh, V.O., Bash. Khim. Zh., 2014, vol. 21, no. 4, p. 15. Koz’minykh, V.O. and Tarasova, V.A., Russ. J. Org. Chem., 2014, vol. 50, no. 11, p. 1687. doi 10.1134/ S1070428014110244. Koz’minykh, V.O., Mukovoz, P.P., and Kirillova, E.A., Vestn. Orenburg. Gos. Univ., 2009, no. 5, p. 155. Bellamy, L.J., Infrared Spectra of Complex Molecules, New York: Halsted Press, 1975. Fittig, R., Lieb. Ann. Chem., 1888, Bd 249, S. 182. Mukovoz, P.P., and Koz’minykh, V.O., Vestn. YuzhnoUral’sk. Gos. Univ., 2009, no. 23, p. 4. Mukovoz, P.P., PhD Thesis (Chem. Sci.), Yaroslavl, 2010. Dolomanov, O.V., Bourhis, L.J., Gildea, R.J., Howard, J.A.K., and Puschmann, H., J. Appl. Crystallogr. (A), 2009, vol. 42, p. 339. doi 10.1107/ S0021889808042726. Mukovoz, P.P., Dvorskaya, O.N., and Koz’minykh, V.O., Izv. Vuzov, Ser. Khim. i Khim. Tekhnol., 2011, vol. 54, no. 5, p. 96.

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