HETEROCYCLES

Short Paper | Regular issue | Vol. 89, No. 5, 2014, pp. 1211-1220
Received, 14th February, 2014, Accepted, 12th March, 2014, Published online, 24th March, 2014.
DOI: 10.3987/COM-14-12960

■ A Facile One-Pot Synthesis of Model Diethyl 6,6'-Dioxotetrahydro-5,5'-bi(1,2,4-triazine)-5,5'-dicarboxylates

Mustafa M. El-Abadelah,* Hanan H. Mohammed, Mohammed M. Abadleh, Salim S. Sabri, and Firas F. Awwadi

Department of Chemistry, Faculty of Science, The University of Jordan, Amman 11942, Jordan

Abstract

The reaction of diethyl aminomalonate with nitrile imine 1,3-dipolar species 1a,b follows a stereospecific path to deliver the racemic tetrahydro-6,6'-dioxo-5,5'-bi(1,2,4-triazine)-5,5'-dicarboxylates 4a,b, whilst the corresponding diastereomeric meso forms (5R, 5'S) could not be detected in the reaction product. Structural assignments for these novel heterocyclic dimers are based on microanalytical and spectral (MS, NMR) data, and further confirmed by X-ray diffraction analysis of single crystal for 4a.

4,5-Dihydro-1,2,4-triazin-6-ones constitute valuable heterocycles as scaffolds for combinatorial chemistry. They possess significant biological activities such as antimicrobial, antibacterial, fungicide, pesticide, herbicide, crop protection and blood platelet aggregation inhibition.1-3 Some derivatives were also reported to exhibit antitumor activity against leukemia / lymphoma, ovarian cancer, small and large lung cancer cells, and breast cancer.4,5
The reaction of α-amino esters with hydrazonoyl chlorides, precursors of nitrile imine 1,3-dipolar species, was reported6 to constitute an efficient one-pot synthesis of chiral 4,5-dihydro-1,2,4-triazin-6-ones having a wide variety of substituents appended at N-1, C-3 and C-5 positions. Those triazin-6-ones, incorporating an alkoxycarbonyl group at carbon-5 locus (exemplified by 3 / see Scheme 1) are hitherto undescribed in the literature; such ester moiety is convertible to the carboxy group which, in turn, can be manipulated for the installation of carbon and / or hetero-atom substituents where desired, and thus might lead to enhancement of their biological activities. Modeled on our previous findings,6 we envisaged that employment of aminomalonic ester 2, in place of α-amino esters, in the reaction with hydrazonoyl chlorides 1a,b, would lead to the respective targeted 6-oxo-4,5-dihydro-1,2,4-triazine-5-carboxylates 3a,b (see Scheme 1). In the present work this expectation was, however, not realized and the main isolable reaction products were identified as the respective 6,6'-dioxo-tetrahydro-5,5'-bi(1,2,4-triazine)-5,5'-dicarboxylates (4a,b), dimers of their presumed monomeric precursors 3a,b (Scheme 1). Herein, we wish to report on the synthesis, spectral and stereochemical properties of model bis-triazine derivatives 4a,b, accessible via a facile one-pot synthetic route outlined in Scheme 1.

In the presence of triethylamine, the reaction of diethyl aminomalonate 2 with N-arylhydrazonoyl chlorides 1a,b is envisaged to yield the respective ethyl 6-oxo-4,5-dihydro-1,2,4-triazine-5-carboxylates (3a,b) as stable cyclo-condensation end products (Scheme 1). However, the 1H- and 13C-NMR spectral data of the isolable products lack the methine C(5)-H proton's signal as well as the 13C(5)-H carbon signal (absent in the DEPT experiments) that are characteristic of 3a,b. Conversely, the 13C-NMR spectra revealed the presence of an additional low intensity signal (absent in the DEPT experiments) at δ ≈ 65 ppm; this signal is tentatively assigned to the equivalent quaternary hetero-ring carbons (C-5 / C-5') of the presumed structure for the dimeric products 4a,b (Scheme 1). The MS and NMR spectral data and microanalyses for the new compounds 4a,b are in accordance with the assigned structures; details are given in the Experimental section. Each of the dimeric products 4a,b incorporates two identical stereocenters (C-5 and C-5') that are constructed from symmetric reactants (1a,b and 2) in symmetric environment. Accordingly, each product is optically inactive, being either a racemate or a meso form; this is inferred from the NMR spectra of 4a,b whereby signal doubling was not observed indicating that the different protons and carbons associated with the heteroring A are virtually equivalent, but not diastereomeric, to their counterparts in ring A'.
The stereochemical aspects of 4a were indicated by 1H-NMR using europium(III) tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorate] as the chiral lanthanide shift reagent (LSR).6-8 After addition of Eu(hfc)3 (molar ratio of [Eu(hfc)3] / [substrate] = 0.64), the signal of the C(3)-acetyl methyl protons (s, δ = 2.48 ppm) was resolved into two diastereotopic singlets (at 2.54 and 2.56 ppm) of equal integrated peak areas. Likewise, the methyl (t, δ = 1.27 ppm) and methylene (q, δ = 4.28 ppm) protons' signals belonging to the C(5)-ethyl ester group, were resolved into two diastereotopic triplets (1.28 and 1.29 ppm) and quartets (4.31 and 4.34 ppm), respectively. These results strongly support that 4a is a racemic mixture: (5R,5'R) + (5S,5'S). Hence, it can be concluded that the reaction of aminomalonate with nitrile imines proceeds in a stereospecific manner to deliver racemic tetrahydro-5,5'-bi(1,2,4-triazinones), while the diasteromeric (5R,5'S) meso counterparts were not detected.
An additional diagnostic criterion for the dimeric structure came from the MS spectral data. Thus, the measured HRMS (ESI) spectrum of 4a displayed, in the molecular ion region, an isotopic cluster of three distinct peaks: [M+H], [M+H+2] and [M+H+4] with relative intensity ratios (relative abundance) of 9 : 6 : 1, respectively, indicative of the presence of two chlorine atoms in the molecule, and is supportive of the dimeric structure for 4a. Corresponding isotopic peaks are also displayed in the MS of 4b with relative ratios of 1 : 2 : 1, indicative of the presence of two bromine atoms in 4b. Eventually, the cyclic products (from 2 and 1a,b) were identified as 1,1'-diaryl-6,6'-dioxo-tetrahydro-5,5'-bi(1,2,4-triazine)-5,5'-dicarboxyates (4a,b) as evidenced from their elemental analyses, MS, 1H- and 13C- NMR spectral data, and confirmed by single crystal X-ray structure determination for 4a (Table 1 and Table 2; Figure 1 and Figure 2 / vide infra).
The production of the dimeric heterocycles 4a,b is probably initiated by the formation of the monomeric 6-oxo-4,5-dihydro-1,2,4-triazine-5-carboxylates 4a,b; the latter transient intermediates are then transformed into 4a,b, for which a plausible radical-mediated pathway involving a single electron transfer is postulated in the annexed mechanism (Scheme 2).
The instability of 3 in basic media might be due to the tendency of their resonance stabilized enolate anions [3A] to form radical species [3R] by the action of oxygen in basic solution; the resulting relatively stable radicals [3R] are liable to experience dimerization, thereby producing the respective dimeric products 4 (Scheme 2). This mode of oxidative dimerization is modeled on, and reminiscent of the conversion of indoxyl to the indigo dyestuff by the action of oxygen in basic solution, and for which an eminently reasonable mechanism, was previously suggested for the conversion of indoxyl anion to indoxyl radical, followed by radical coupling to produce the leucoindigo (which is further oxidized to indigo).9

Molecular structure of 4a. A crystal structure determination was performed to confirm the structure of 4a (and by inference that of 4b). A summary of data collection and refinement parameters is given in Table 1, while selected bond lengths and angles are provided in Table 2. The molecular structure of 4a in the crystal is displayed in Figure 1. The asymmetric unit of 4a contains one half molecules, the second half of 4a is generated by inversion through a center located at the middle of C5–C5A bond (Figure 1), where C5A

is the symmetry equivalent of C5. The molecular unit of 4a is stabilized by two intramolecular crystallographically equivalent N4– H4…O6A hydrogen bonding interactions (Figure 1), hydrogen bonding interaction parameters are 0.846 (0.037), 2.080 (0.042), 2.711(0.004) Å and 130.90 (3.77)° for N4–H4 Å, H4…O6A Å, N4…O6A Å and (N4–H4…O6A)°, respectively. These strong hydrogen bond interactions distort the molecular structure; the O6 atom deviates from the plane of the aromatic ring by 0.164 Å toward H4.
Two types of intermolecular interactions connect the molecular units of 4a to form the final 3D structure; these include the non-classical C-H…O hydrogen bonding interaction and C (carbonyl)…O interactions. C15 (carbonyl)… O13 distance is 3.154 Å which is 0.07 Å less than the sum of van der Waals radii; C (carbonyl)…O interactions collaborate with C14–H14A…O15 to form chain structures run parallel to the a-axis (Figure 2). C14–H14A…O15 hydrogen bonding interactions are 2.651, 3.472 and 143.79 for H14A…O15, C14…O15 and C14–H14A…O15, respectively.10
In conclusion, construction of carbon-carbon sigma bonds via oxidative cross-coupling of sp3-hybridized C–H bonds is of great interest and has been achieved using transition metal salts and / or oxidants.11 Dimers of carbonyl compounds have been reported in their oxidation by high valent metal salts in the absence of radical trapping agents.12 The development of new methodologies in cross-coupling reactions using C-H bonds as substrates is welcomed. Noticeably, the reaction presented here is a special case of metal-free and oxidant-free cross–dehydrogenative coupling of sp3-hybridized C-H bonds under mild conditions whereby the transformation of reactants 1 and 2 into dimers 4 (Scheme 1) constructs three consecutive HN – C=N, ArN – C=O and C5 – C5' sigma bonds in one-pot operation. The scope, stereochemistry, and synthetic applications of this intermolecular oxidative dimerization sequence are currently under investigation.

EXPERIMENTAL
The following chemicals, purchased from Acros, were used in this study: diethyl aminomalonate, 3-chloro-2,4-pentanedione, p-bromoaniline and p-chloroaniline. Melting points were determined on a Gallenkamp electrothermal melting-temperature apparatus in open capillary tubes. Elemental analyses were performed on a Euro Vector elemental analyzer, model EA 3000. 1H- and 13C-NMR spectra were recorded on a 500 MHz spectrometer (Bruker Avance-III), with TMS as the internal standard. Chemical shifts are expressed in δ units; J values for 1H-1H coupling constants are given in Hertz. High resolution mass spectra (HRMS) were acquired (in positive mode) using the electrospray ion trap (ESI) technique by collision-induced dissociation on a Bruker APEX-4 (7 Tesla) instrument. The samples were dissolved in dichloromethane, diluted in spray solution (methanol-water 1 : 1 v/v + 0.1 % formic acid) and infused using a syringe pump with a flow rate of 2 µL / min. External calibration was conducted using arginine cluster in a mass range m/z = 175 – 871.

N'-Aryl-2-oxopropanehydrazonoyl chlorides (1a,b). These hydrazonoyl chlorides, employed in this study, were prepared via the Japp-Klingemann reaction13 involving direct coupling interaction between the appropriate arenediazonium chloride and 3-chloro-2,4-pentanedione.6,14 The melting points, as given below, are in accordance with the literature values (not given here):
N'-(4-chlorophenyl)-2-oxopropanehydrazonoyl chloride (1a),6,14,15 mp 178–179 oC;
N'-(4-bromophenyl)-2-oxopropanehydrazonoyl chloride (1b),16,17 mp 166–167 oC.

General procedure for the synthesis of diethyl 1,1'-diaryl-6,6'-dioxo-tetrahydro-5,5'-bi(1,2,4-triazine)-5,5'-dicarboxylates (4a,b). To a solution of the appropriate hydrazonoyl chloride (1a,b / 0.01 mole) in EtOH (40 mL) was added a solution of triethylamine [(5 g), 0.05 mole] in EtOH (10 mL). After that, diethyl aminomalonate hydrochloride 2 [(2.54 g), 0.012 mole] in EtOH (20 mL), was added to the reaction mixture. Stirring was continued at ~ 0-5 oC for 2 h, and then at rt for 12 h. The reaction mixture was then diluted with cold H2O (100 mL), the resulting solid product was collected by suction filtration, washed with cold water (2 × 20 mL), dried, and recrystallized from EtOH, or CHCl3 / n-hexane.

(±) Diethyl 3,3'-diacetyl-1,1'-bi(4-chlorophenyl)-6,6'-dioxo-4,4',5,5'-tertahydro-5,5'-bi(1,2,4-triazine)-5,5'-dicarboxylate (4a). Yield 74%; mp 192 – 193 °C. 1H NMR (500 MHz, CDCl3): δ = 1.27 (t, J = 7 Hz, 6H, 2 CH3CH2O), 2.48 (s, 6H, 2 CH3C=O), 4.28 (q, J = 7 Hz , 4H, 2 OCH2Me), 7.46 (d, J = 8.5 Hz, 4H, 3''- H, 5''- H / 3'''- H, 5'''- H), 7.57 (d, J = 8.5 Hz, 4H, 2''- H, 6''- H / 2'''- H, 6'''- H), 8.37 (br s, 2H, N(4)-H / N(4')-H, exchangeable with D2O).13C NMR (125 MHz , CDCl3) : δ = 13.9 (2 CH3CH2O), 23.8 (2 CH3C=O), 63.6 (2 OCH2Me), 65.1(C- 5 / C-5'), 126.4 (C-2'', C-6'' / C-2''', C-6'''), 129.0 (C- 3'', C- 5'' / C- 3''', C- 5'''), 133.3 (C- 4'' / C- 4'''), 138.9 (C- 1''/ C- 1'''), 139.1 (C- 3 / C- 3'), 158.1 (C- 6 / C- 6'), 166.7 (2 CO2Et), 191.5 (2 Me-C=O). HRMS (ESI): m/z Calcd. for C28H2735Cl2 N6O8, [M+H]+: 645.12619, found: 645.12634. Calcd. For C28H2735Cl 37ClN6O8, [M+2+H]+: 647.12408, found: 647.12404. Calcd. for C28H2737Cl2N6O8, [M+ 4+H]+: 649 .11910, found: 649.11895. Calcd. for C28H2635Cl2 N6O8Na, [M+Na]+: 667.10814, found: 667.10847.Calcd. for C28H2635Cl 37Cl N6O8Na, [M+2+Na]+: 669.10602, found: 669.10649. Calcd for C28H2637Cl2 N6O8Na, [M+4+Na]+: 671.12144, found: 671.12157. Anal. Calcd for C28H26Cl2N6O8 (645.45) : C, 52.10; H, 4.06; Cl, 10.99; N, 13.02. Found: C, 52.18; H, 3.98; Cl, 10.82; N, 13.10.
(±) Diethyl 3,3'-diacetyl-1,1'-bi(4-bromophenyl)-6,6'-dioxo-4,4',5,5'-tertahydro-5,5'-bi(1,2,4-triazine)-5,5'-dicarboxylate (4b). Yield 76%; mp 198 - 200 °C. 1H NMR (500 MHz, CDCl3) : δ = 1.27 (t, J = 7.1 Hz , 6H, 2CH3CH2O), 2.48 (s, 6H, 2CH3C=O), 4.28 (q, J = 7.1 Hz , 4H, 2 OCH2Me), 7.52 (d, J = 8.6 Hz, 4H,2''- H, 6''- H / 2'''- H, 6'''- H), 7.61 (d, J = 8.6 Hz, 4H, 3''- H, 5''- H / 3'''- H, 5'''- H), 8.36 (br s, 2H, N(4)-H / N(4')-H, exchangeable with D2O). 13C NMR (125 MHz, CDCl3) : δ = 13.9 (2 CH3CH2O), 23.8 (2 CH3C=O), 63.6 (2 OCH2Me), 65.1 (C- 5 / C- 5'), 121.3 (C- 4'' / C- 4'''), 126.7 (C-2'', C-6'' / C-2''', C-6'''), 131.9 (C- 3'', C- 5'' / C- 3''', C- 5'''), 139.1 (C- 1''/ C- 1'''), 139.4 (C- 3 / C- 3'), 158.1 (C- 6 / C- 6'), 166.7 (2 CO2Et), 191.5 (2 Me-C=O). HRMS (ESI): m/z Calcd. for C28H2779Br2 N6O8, [M+H]+: 733.02516, found: 733.02448. Calcd. for C28H2779Br 81BrN6O8, [M+2+H]+: 735.02338, found: 735.02268. Calcd. for C28H2781Br2 N6O8, [M+4+H]+: 737.02204, found: 737.02039. Calcd. for C28H2679Br2N6O8Na, [M+Na]+: 755.00711, found: 755.00617. Calcd. for C28H2679Br 81BrN6O8Na, [M+2+Na]+: 757.00532, found: 757.00486. Calcd. for C28H2681Br2 N6O8Na, [M+4+Na]+: 759.00398, found: 759.00398. Anal. Calcd for C28H26Br2N6O8 (734.35): C, 45.80; H, 3.57; Br, 21.76; N, 11.44. Found: C, 45.62; H, 3.51; Br, 21.54; N, 11.27.

X-Ray structure analysis of (±)- 4a. Crystals were grown by allowing a clear hot solution of (±)- 4a in EtOH in an open vessel to stand at room temperature for 4 – 5 days. A suitable needle-like slightly yellowish crystal, with approximate dimensions of 0.15 x 0.1 x 0.05 mm3, was epoxy mounted on a glass fiber. Data were collected at room temperature (293 K) using an Oxford Xcalibur diffractometer. Data were acquired and processed to give SHELX-format-hkl files using CrysAlisPro software.18 Cell Parameters were determined and refined using CrysAlisPro.18 A multi-scan absorption correction was applied with minimum and maximum transmission factors of 1.00000 and 0.61885, respectively. The structure was solved by Direct Methods and refined by full-matrix least-squares on F2.19 All nonhydrogen atoms were refined anisotropically with the hydrogen atoms placed on the calculated positions using riding model, except H4 (Figure 1) which was found using Fourier difference maps and were refined isotropically. Data collection parameters and refinement results are given in Table 1. CCDC 969128 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data request/cif.

ACKNOWLEDGEMENTS
We thank the Deanship of Scientific Research at The University of Jordan, Amman (Jordan), for financial support.

References

1. R. M. Abdel-Rahman, J. M. Morsy, S. El-Edfawy, and H. A. Amine, Pharmazie, 1999, 54, 667; R. M. Abdel-Rahman, J. M. Morsy, F. Hanafy, and H. A. Amine, Pharmazie, 1999, 54, 347.
2. R. M. Abdel-Rahman, Pharmazie, 2001, 56, 18; and 275; Z. El-Gendy, J. M. Morsy, H. A. Allimony, W. R. Ali, and R. M. Abdel-Rahman, Pharmazie, 2001, 56, 376; E. El Ashry, N. Rashed, M. Taha, and E. Ramadan, Adv. Heterocycl.Chem., 1994, 59, 41. CrossRef
3. H. Neunhoeffer, P. F. Wiley, In The Chemistry of 1,2,3-Triazines and 1,2,4-Triazines, Triazines and Pentazines, vol. 33 in the series "The Chemistry of Heterocyclic compounds", ed. by A. Wiessberger and E. C. Taylor, Wiley, New York, 1978, pp. 1001-1004.
4. Z. El-Gendy and R. M. Abdel-Rahman, Indian J. Heterocycl. Chem., 1995, 4, 293; R. M. Abdel-Rahman, M. Saeda, M. Fawzy, and M. El-Baz, Pharmazie, 1994, 49, 729; E. Pomarnacka, Anta Pol. Pharm., 1998, 55, 481; R. M. Abdel-Rahman, Pharmaco, 1991, 46, 379.
5. B. S. Holla. B. S. Rao, R. Gonsalves, B. K. Sarojini, and K. Shridhara, Pharmaco, 2002, 57, 693; N. S. Habib, R. Soliman, K. Ismail, A. M. Hassan, and M. T. Sarg, Boll. Chim. Farm., 2003, 142, 396.
6. M. M. El-Abadelah, A. Q. Hussein, and B. A. Thaher, Heterocycles, 1991, 32, 1879. CrossRef
7. R. R. Frazer, M. A. Petit, and J. K. Sanders, J. Chem. Soc. (D), 1971, 1450; CrossRef A. F. Cockerill, G. L. O. Davis, R. C. Harden, and D. M. Racham, Chem. Rev., 1973, 73, 553; CrossRef R. R. Frazer, ″Asymmetric Synthesis″, vol. 1, ed. by J. D. Morrison, Academic Press, New York, 1983, pp. 173–000; T. J. Wenzel and J. Zaia, Anal. Chem., 1987, 59, 562. CrossRef
8. T. P. Andersen, A.-B. A. Ghattas, and S. O. Lawesson, Tetrahedron, 1983, 39, 3419. CrossRef
9. G. A. Russell and G. Kaupp, J. Am. Chem. Soc., 1969, 91, 3851. CrossRef
10. D. Braga, F. Grepioni, L. Maini, and M. Polito, Struct. Bond, 2009, 132, 25. CrossRef
11. W.-J. Yoo and C.-J. Li, Top. Curr. Chem., 2010, 292, 281, and refs. cited therein. CrossRef
12. A. Citterio, C. Finzi, R. Santi, and S. Strologo, J. Chem. Res., 1988, (S) 156; (M) 1280; N. J. Galakatos, J. E. H. Hancock, O. M. Morgan, M. R. Roberts, and J. K. Wallace, Synthesis, 1978, 472; CrossRef M. G. Vinogradov, P. A. Direi, and G. I. Nikishin, Zh. Org. Khim., 1978, 14, 2043; W. J. de Klein, Recl. Trav. Chim. Pays-Bas, 1977, 94, 22; H. Inoue, M. Sakata, and E. Imoto, Bull. Chem. Soc. Jpn., 1973, 46, 2211; CrossRef H. A. P. de Jong, C. R. H. I. de Jonge, H. J. M. Sinnige, W. J. de Klein, W. G. B. Huysmans, and W. J. Mijis, J. Org. Chem., 1972, 37, 1960. CrossRef
13. R. R. Phllips, Org. React., 1959, 10, 143; H.-C. Yao and P. Resnick, J. Am. Chem. Soc., 1962, 84, 3514; CrossRef G. C. Barrett, M. M. El-Abadelah, and M. K. Hargreaves, J. Chem. Soc. (C), 1970, 1986.
14. N. F. Eweiss and A. Osman, J. Heterocycl. Chem., 1980, 17, 1713, and refs. cited therein. CrossRef
15. R. Fusco and R. Romani, Gazz. Chim. Ital., 1946, 76, 419.
16. V. A. Galishev, V. N. Chistokletov, and A. A. Petrov, Zh. Obshch. Khim., 1975, 45, 1695.
17. A. S. Panevin, Yu. G. Trishin, V. A. Galishev, A. A. Baturin, V. N. Chistokletov, and A. A. Petrov, Zh. Obshch. Khim., 1984, 54, 1037; Ya. V. Zachinyaev, M. L. Petrov, A. N. Frolkov, V. N. Chistokletov, and A. A. Petrov, Zh. Org. Khim., 1980, 16, 938; A. Yu. Platonov, T. N. Timofeeva, I. G. Trostyanskya, E. V. Luzikova, M. A. Kazankova, and V. N. Chistokletov, Zh. Obshch. Khim., 1982, 52, 2172.
18. CrysAlis PRO, Version 1.171.35.11, Agilent Technologies, Yarnton, England, 2011.
19. SHELXTL (XPREP, XL, XP, XCIF), Version 6.10, Bruker AXS Inc., Madison, WI, 2002.