HETEROCYCLES

Paper | Regular issue | Vol. 78, No. 11, 2009, pp. 2755-2768
Received, 2nd June, 2009, Accepted, 31st July, 2009, Published online, 3rd August, 2009.
DOI: 10.3987/COM-09-11768

■ The Synthesis, Structure and Reactivity of 1-Thioxotetrahydropyridazino[1,2-a][1,2,4]triazin-4(1H)-one

Sandra Jarrett,* Ainka Brown, and Marvadeen Singh-Wilmot

Department of Chemistry, Mona Campus, University of the West Indies, Mona, Kingston 7, Jamaica

Abstract

The synthesis of 1-thioxotetrahydropyridazino[1,2-a][1,2,4]triazin-4-(1H)-one 3 in five steps from tert-butyl carbazate and its transformation into 3-benzylidene and 1-amino derivatives are described. Its crystal structure is presented showing it to be an axially chiral molecule that exists as a racemate in the solid state.

INTRODUCTION
An interest in determining the bioactive conformation of the naturally occurring hypotensive guanidine, caracasanamide 1,1 led us to design triazinone 2 as one of a number of conformationally restricted analogues.

Compound 2 was based on a gauche conformation of 1a attained by rotation about the C2-C3 bond of the flexible butyl chain that links the cinnamyl amide and prenyl guanidine moieties. By creating the C-N and N-N bonds as shown in Figure 1, we essentially locked the molecule into the novel 3-amino[1,2,4]triazinone structure 2. If the gauche representation approximates the bioactive conformation of caracasanamide 1, then the rigidification achieved in 2 could result in an enhanced binding affinity and greater activity as there would now be less of the attendant loss of entropy2 that occurs when a flexible molecule has to undergo conformational change in order to bind with its receptors.

In our bid to synthesize 2, the thioxotetrahydropyridazinotriazinone 3 emerged as a key intermediate. This molecule is interesting in its own right. It is a novel hexahydropyridazine derivative and the bicyclic counterpart of the 3-thioxo-1,2,4-triazin-6-ones 4a-c. Prepared3 by Böhme and Strahl via the isomerization and cyclization of thiocyanatoacetic hydrazides, 4a-c are the only such thioxotriazinones to have hitherto been reported. By contrast, hexahydropyridazine derivatives have attracted a lot of attention.

hey have been shown to exhibit significant biological activity exemplified by the herbicidal 1,2,4-tetrahydro[1,2-a]triazolopyridazinedithiones,4 the antinflammatory 2-cyanotetrahydropyridazine- 1-carboxylates5 and the inducible nitric oxide synthase inhibiting hexahydropyridazine- 1-caboximidamides, carbothioamides and carbothioimidic acid esters.6 Moreover, N,N'-diacylhexahydropyridazines have featured in the field of peptidomimetics wherein they have been utilized in the synthesis of peptide sequences containing the unnatural azahomoproline residue.7,8 Methods for the synthesis of hexahydropyridazines include the Diels Alder reaction9 between 1,3-butadienes and azodicarboxylic acid esters, high pressure hydrogenation10 of pyridazines and the reaction of 1,4-dihaloalkanes with hydrazine dicarboxylates.8,11
For compound 3 we chose the last of these approaches, with the expectation that sulfur could be introduced by way of a thiocarbonylation reaction. We now report the synthesis of 1-thioxotetrahydropyridazino[1,2,4]triazin-4(1H)-one (3), its crystal structure and reactivity.

RESULTS AND DISCUSSION
Our approach to 3 (Scheme 1) made use of the orthogonally protected hexahydropyridazine 7 which we synthesized using essentially the methodology described by Boussard and co-workers.7,8 Treatment of commercially available tert-butylcarbazate (5) at 0 ºC with benzyl chloroformate in the presence of triethylamine, gave the unsymmetrical hydrazine dicarboxylate 6 (83%). Deprotonation of 6 using NaH in DMF and annulation with 1,4-dibromobutane furnished 7 in 73% yield. Removal of the Boc group (82%) followed by acylation with N-Cbz-glycyl chloride (prepared from N-Cbz-glycine,12 oxalyl chloride and DMF cat.) afforded the doubly Cbz-protected N-glycyl hexahydropyridazine 9 (62%). Catalytic hydrogenolysis of 9 carried out at atmospheric pressure removed both of the benzyloxycarbonyl (Cbz) groups. The resultant N-glycylhexahydropyridazine (10), a straw coloured oil, proved to be quite unstable and seemed to polymerize on standing at room temperature to give a highly insoluble solid. Consequently, 10 had to be used straight away in the next step – ring closing thiocarbonylation using thiocarbonyl diimidazole in MeCN. In this way, the thioxohexahydropyridazino-triazinone 3 was obtained (71% yield over two steps) as a cream solid. The structure of 3 was supported by the 1H and 13C NMR spectral data, notable features being the 13C resonances at 162.5 and 178.9 ppm that distinguished the carbonyl and thiocarbonyl groups respectively.

Single crystal X-ray diffraction studies13 carried out at room temperature show that compound 3 crystallizes as a racemate in the monoclinic space group P21/c. A view of the two independent molecules in the unit cell is given in Figure 2. The axial chirality that gives rise to this racemic compound can be considered to arise from a torsional barrier to rotation about the N-N bond caused by repulsion between the electron lone pairs of the nitrogen atoms. Thus inversion of the fused six membered rings is precluded resulting in the atropisomerism observed in Figure 2. The hexahydropyridazine ring in 3 adopts a quasi chair conformation in which both nitrogens are essentially planar. This is indicated by the average bond angle, αav around each nitrogen atom: αav(N1) = 120º, αav(N2) = 118.71º, αav (N1A) = 119.94º, αav (N2A) = 119.1º (Table 2). The non-planar thioxotriazinone ring adopts a twist boat conformation with torsion angles C(1)-N(1)-N(2)-C(4) of -52.7º and C(7)-N(1)-N(2)-C(5) of -30.8º (C(1A)-N(1A)-N(2A)-C(4A) is +52.9º and C(7A)-N(1A)-N(2A)-C(5A) is +30.0º). This is comparable to the corresponding torsion angles (55.9º and 27.7º respectively) reported by Kaftory and co-workers14 for the structurally related hexahydropyridazino[1,2-a]pyridazine-1,4-dione. Importantly, the twisted conformation of the thioxotriazinone ring in 3 allows the electron lone pairs of the N-N group to avoid co-planarity. The N-CO, N-N and N-C bond lengths (Table 1) are all in the range seen for related compounds14 with flat, non-coplanar hydrazine nitrogens. Crystal packing diagrams of 3 show two non-interacting, infinite one dimensional chains that have an inversion relationship and feature alternating atropisomers linked via intermolecular N-H····O=C hydrogen bonds in a sinusoidal pattern (Figures 3 and 4).

Our synthetic strategy for triazinone 2 was contingent on compound 3 being able to react in two ways. The cyclic thiourea moiety must undergo guanylation and this was considered achievable via the S-methyl isothiourea.15,16 Furthermore, a Knoevenagel reaction between Boc-protected 3 and an aryl aldehyde should establish a benzylidene moiety such as that found in 2. To test our ideas, we set out to prepare the isobutylaminotriazinone 12 and the benzylidene 14 (Scheme 2). The S-methyl isothiouronium iodide 11 derived from 3 by its treatment with methyl iodide was subjected to reaction with isobutylamine in acetonitrile in a sealed tube. The reaction did not yield 12 but instead, 11 underwent demethylation of the type observed by Sandin et al.16 and reverted to 3. This is likely to have occurred by nucleophilic attack on the methyl group by the iodide ion with displacement of thiourea. Use of an isothiouronium salt having the less nucleophilic trifluoroacetate counterion proved useful as triazinone 12 was obtained in 40% yield by heating a mixture of the cyclic isothiourea 11b (obtained by treatment of 11 with saturated aqueous NaHCO3), one equivalent of trifluoroacetic acid and an excess of isobutylamine in a sealed tube at 165 ºC. It was anticipated that the electron withdrawing Boc group in 13 would engender enolate formation and indeed this occurred as the Knoevenagel reaction between 13 and veratraldehyde took place in the presence of sodium hydride in tetrahydrofuran.

Interestingly it was the deprotected product 14 that was obtained in 43% yield. The concomitant loss of the Boc group during the condensation mirrored the observations of Gallina16 and Bergman17 who reported the loss of an N-acetyl group via intramolecular acyl transfer in similar condensation reactions between aldehydes and diketopiperazines. The Z- geometry of the product 14 was confirmed by its NOESY spectrum which displayed cross-peaks between NH and the aromatic protons, 5"-H and 6"-H. That 14 was isolated in the Z- configuration might reflect a greater thermodynamic stablility of the Z- over the E- form and this would match the assertions made by Gallina,17 Bergman18 and Sammes19 about 3-ylidenepiperazine-2,5-diones. Attempts at guanylation of 14 have not yet furnished our synthetic target 2 as treatment of the S-methyl derivative of 14 with prenylamine and also with the more nucleophilic isobutylamine in the presence of TFA has been unsuccessful. Use of copper (I) halides20 as well as nickel (0)21 species in this effort might be useful and will be explored.

CONCLUSION
We have presented thioxotriazinone 3, its aminotriazinone and 5-benzylidene derivatives 12 and 14 respectively, as new hexahydropyradizine derivatives synthesized en route to a conformationally restricted analogue of the antihypertensive agent caracasanamide 1. They are also perhydro derivatives of the pharmacologically important class of [1,2,4]triazin-6-ones, members of which have exhibited antihypertensive as well as antibacterial, antifungal, antiasthmatic and bronchidilatory properties.22 Pharmacological evaluation of compounds 3, 12 and 14 will therefore be undertaken and the results reported at a later date.

EXPERIMENTAL
NMR spectra were obtained on a Bruker Vector 2000-200 spectrometer using tetramethylsilane (TMS) as internal standard. IR spectra were run on a Bruker Vector 22 FTIR spectrometer. Melting points are uncorrected and were determined on a Reichert melting point apparatus. Analytical thin layer chromatography (TLC) was performed using 250 µm silica and visualization was achieved with UV light as well as KMnO4 and vanillin spray reagents. Flash chromatographic separation was carried out on 230-400 mesh silica. THF (from Na/benzophenone), CH2Cl2 (from P2O5) and MeCN (from K2CO3) were distilled immediately prior to use. DMF was dried over 4Å sieves. Unless otherwise stated, reactions were carried out under nitrogen utilizing oven-dried glassware. Elemental analyses and high resolution mass spectrometry were carried out by MEDAC Ltd., Egham, Surrey, U.K.

1-Benzyl tetrahydropyridazine-(2H)-carboxylate (8)
1-Benzyl-2-tert-butyl tetrahydropyridazine dicarboxylate (7)7 (5.67 g, 18 mmol) was added in portions to a 25% TFA:CH2Cl2 solution (100 mL) whilst cooling in an ice salt bath. The resulting solution was then gradually brought to room temperature and stirred overnight (18 h). The solvent was removed in vacuo and the residue carefully treated with saturated NaHCO3(aq) to effect neutralization. This was followed by extraction with CH2Cl2. The organic phase was washed with H2O (2 x 20 mL), dried over anh. Na2SO4 and concentrated to give compound 8 as a tan oil (3.45 g, 88%). IR (neat) νmax 3032, 2941, 1700, 1624 cm-1; 1H NMR (200 MHz, CDCl3) δ 1.63 (4H, br s, -(CH2)2-), 2.92 (2H, t, -CH2-N), 3.58 (2H, t, -CH2-N), 5.14 (2H, s, -CH2-O), 7.31(5H, s, ArH); 13C NMR (50 MHz, CDCl3) δ 23.3, 24.3, 41.7, 45.7, 67.3 , 127.9, 128.4, 136.3, 155.4.

1-Benzyl-2-[(benzyloxycarbonyl)amino]acetyl tetrahydropyridazine carboxylate (9)
Oxalyl chloride (0.8 mL, 1.16 g, 9.2 mmol) was added dropwise to a suspension of N-carbobenzyloxyglycine12 (1.49 g, 8.7 mmol) in CH2Cl2 in the presence of DMF (0.1 mL) whilst cooling in an ice-salt bath. When effervescence ceased the resulting solution was stirred for 1 h then brought to room temperature. The solvent was removed and the residual acid chloride re-dissolved in CH2Cl2 (7 mL). This solution was then added to 1-benzyl tetrahydropyridazine-(2H)-carboxylate (8) (1.89 g, 8.6 mmol) and Et3N (1.3 mL, 943 mg, 9.3 mmol) in CH2Cl2 (50 mL) with cooling. The reaction was then allowed to stir at room temperature for 5 h. Removal of the solvent and chromatography using EtOAc-hexane (1:1) as eluent furnished the title compound as a viscous tan oil (2.37 g, 65%). [HRMS (FAB) calcd for C22H25N3O5 (MH+) 412.18724, found 412.188306]; IR (neat) νmax 3351, 1730, 1685, 1257 cm-1; 1H NMR (200 MHz, CDCl3) δ 1.65 (4H, br s,-CH2CH2-), 2.73 (1H, br m, CHHaN1), 2.99 (1H, br m, CHHaN2), 3.81 (1H, dd, J = 3.8, 17.9 Hz, CHbHN1), 4.17 (2H, m, HNCH2C=O), 4.46 (1H, d, J = 11.9 Hz, CHbHN2), 5.09 (2H, s, -CH2O-), 5.24 (2H, s, -CH2O-), 5.62 (1H, br s, NH), 7.31 (10H, br s Ar-H); 13C NMR (50 MHz, CDCl3) δ 23.2, 23.3, 42.2, 47.6, 66.8, 68.7, 128.0, 128.1, 128.5, 128.6, 128.7, 135.4, 136.4, 155.9, 156.2, 169.2.

1-Thioxotetrahydropyridazino[1,2-a][1,2,4]triazin-4(3H)-one (3)
A solution of 1-benzyl-2-[(benzyloxycarbonyl)amino]acetyltetrahydropyridazine carboxylate (9) (1.79 g, 4.4 mmol) in MeOH (35 mL) was hydrogenated (1 atm) in the presence of 5% palladium on carbon (99.4 mg). After 2.5 h the catalyst was removed by filtration and the mixture concentrated at room temperature under reduced pressure. The crude de-protected material was then immediately dissolved in MeCN (45 mL) and thiocarbonyldiimidazole (1.11 g, 6.3 mmol) introduced. The resulting bright orange solution was stirred at room temperature for 21 h followed by heating in a sealed tube for 3 h at 130 °C. Concentration in vacuo and subsequent purification by chromatography eluting with EtOAc-hexane (7:3) gave the thioxotriazinone 3 as a cream-coloured solid (581 mg, 71%); mp 163-165 ºC (CHCl3). (Anal. Calcd for C7H11N3OS: C, 45.39; H, 5.99; N, 22.67; S, 17.31. Found: C, 45.48; H, 6.08; N, 22.31; S, 16.83); IR (solid film) νmax 3317, 1682, 2947, 1682, 1511, 1320 cm-1, 1H NMR (200 MHz, CDCl3) δ 1.83 (4H, br m, -CH2CH2-), 3.76 (2H, m, C(O)NCH2), 3.83 (2H, d, J = 2.3 Hz, HN-CH2C=O), 4.24 (2H, m, C(S)NHCH2), 7.08 (1H, br s, NH); 13C NMR (50 MHz, CDCl3) δ 22.5, 23.3, 44.1, 45.2, 49.7, 162.4, 178.9.

2-tert-Butyloxycarbonyl-1-thioxotetrahydropyridazino[1,2-a][1,2,4]triazin-4(3H)-one (13)
Di-tert-butyldicarbonate (0.2 mL, 190 mg, 0.87 mmol) was added to a solution of thioxotriazinone 3 (0.128 mg, 0.69 mmol) and Et3N (72.6 mg, 0.1 mL, 0.72 mmol) in CH2Cl2 (2 mL). The resulting solution was heated at reflux until starting material was consumed. Removal of the solvent and flash chromatography using EtOAc-hexane (1:1) as eluent yielded the Boc-protected thioxotriazinone as a cream solid (145 mg, 74%); mp 143-145 °C (CHCl3). IR (solid film) νmax 2978, 1715, 1695, 1365, 1213 cm-1; 1H NMR (200 MHz, CDCl3) δ 1.58 (9H, s, (CH3)3C), 1.75 (2H, m, CH2CH2), 1.95 (2H, m, CH2CH2), 3.86 (2H, m, CH2NC=O), 4.17 (2H, m, NCH2C(O)N), 4.25 (2H, m, CH2NC=S); 13C NMR (50 MHz, CDCl3) δ 22.7, 23.3, 27.9, 43.4, 47.2, 50.0, 84.7, 151.5, 164.2, 177.4.

3-Z-(3,4-Dimethoxybenzylidene)-1-thioxohexahydropyridazino[1,2-a][1,2,4]triazin-4-one (14)
Sodium hydride (292 mg, 0.73 mmol) was added to a solution of 3,4-dimethoxybenzaldehyde (veratraldehyde) (35.2 mg, 0.21 mmol) and the N-Boc- thioxotriazinone 13 (60.8 mg, 0.21 mmol) in THF (5 mL) whilst cooling at 0 °C. After 10 min the solution was gradually brought to room temperature and stirred for 41 h whereupon the reaction was quenched by the dropwise addition of cold, saturated NH4Cl (aq). The mixture was taken up in EtOAc, dried, concentrated in vacuo then chromatographed using EtOAc- hexane (1:1) as eluent. The benzylidene 14 was obtained as a yellow solid (29.6 mg, 42%); mp 187-190 ºC (CHCl3-CH2Cl2). [HRMS (FAB) calcd for C16H19N3O3S (MH+) 334.1225, found 334.1229]; IR (solid film) νmax 3533, 2957, 1600, 1517, 1336 cm-1; 1H NMR (200 MHz, CDCl3) δ 1.88 (4H, br s, -CH2CH2), 3.91 (6H, s, OCH3), 3.92 (2H, m, CH2NC=S), 4.32 (2H, m, -CH2NC=O), 6.67 (1H, s, CH=C), 6.92 (1H, d, 5"-H, J = 8.3 Hz), 6.95 (1H, s, 2"-H), 7.02 (1H, dd, 6"-H, J = 1.8, 8.3 Hz), 8.38 (1H, br s, NH); 13C NMR (50 MHz, CDCl3) δ 22.4, 23.0, 44.4, 52.0, 55.9, 111.2, 111.9, 112.8, 121.0, 122.5, 125.5, 134.5, 149.6, 157.9, 171.8.

1-(Methylsulfanyl)-6,7,8,9 tetrahydropyridazino[1,2-a][1,2,4]triazin-4(3H)-one (11b)
Methyl iodide (912 mg, 0.4 mL, 6.4 mmol) was added to a solution of thioxotriazinone 3 (56.1 mg, 0.3 mmol) in MeCN (2 mL) and the mixture heated at 60 °C for 3 h resulting in the precipitation of the isothiouronium salt 11 as a white solid. After removal of the solvent in vacuo the residue was taken up in saturated NaHCO3 (aq) then the aqueous solution was extracted with CH2Cl2. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. Flash chromatography eluting with EtOAc-hexane (7:3) yielded the S-methyl compound 11b as a yellow semi-solid (46.4 mg, 78%). IR (solid film) νmax 2927, 1670 cm-1; 1H NMR (200 MHz, CDCl3) δ 1.70 (2H, m, CH2CH2), 1.73 (2H, m, CH2CH2), 2.30 (3H, s, SCH3), 3.51 (2H, m, CH2NC=O), 3.65 (2H, m, CH2NCS), 4.02 (2H, s, NCH2C=O); 13 C NMR (50 MHz, CDCl3) δ 13.4, 23.2, 23.4, 41.1, 49.8, 50.7, 157.7, 162.6.

1-(Isobutylamino)-6,7,8,9 tetrahydropyridazino[1,2-a][1,2,4]triazin-4(3H)-one (12)
A solution of isobutylamine (32.5 mg, 0.4 mmol) in MeCN (0.3 mL) was added to a solution of methylsulfanyltriazinone 11b (46.4 mg, 0.24 mmol) and TFA (37.4 mg, 0.3 mmol) in MeCN (1.7 mL). The mixture was then heated in a sealed tube at 165 °C for 5 h. Concentration in vacuo and chromatography of the crude residue eluting with CH2Cl2 – MeOH (9:1) yielded the isobutylaminotriazinone 12 as a yellow oil (0.0210 g, 40%). [HRMS (FAB) calcd for C11H20N4O (MH+) 225.17204, found 225.17204]; IR (solid film) νmax 2963, 1668, 1201 cm-1; 1H NMR (200 MHz, CDCl3) δ 0.96 (6H, d, J = 6.7 Hz, (CH3)2CH), 1.75 (2H, m, CH2-), 1.92 (3H, m, CH2-, (CH3)2CH), 3.02 (2H, d, J = 7.0 Hz, CH2NH), 3.49 (2H, br m, CH2NC=N), 3.75 (2H, br s, CH2NC=O), 3.94 (2H, s, NCH2C(O)N); 13C NMR (50 MHz, CDCl3) δ 19.9, 22.9, 23.4, 28.7, 42.4, 43.4, 51.7, 52.4, 156.9, 163.3.

X-Ray Crystallography
Colourless prisms of 1-thioxotetrahydropyridazino[1,2-a][1,2,4]triazin-4-(1H)-one (3) were harvested from a chloroform-dichloromethane mixture after slow evaporation at room temperature. A single crystal was mounted on a thin glass fiber using Super Glue®. Data were collected at room temperature on a Bruker AXS P4 Diffractometer using Mo-Kα radiation and a graphite monochromator. XSCANS software package was used to refine cell parameters and to collect and reduce data. The structure was solved and refined using the SHELXTL software package version 6.1.23 A partial structure was obtained by direct methods, and the remaining non-hydrogen atoms in the structure were located using difference Fourier techniques. H atoms on all carbons were placed at calculated positions and refined using a riding model but those on nitrogens were found from the difference map. All non-hydrogen atoms were refined with anisotropic parameters. Thermal ellipsoid plots were generated with XP in SHELXTL while H-bonding and packing plots were generated using Diamond version 3 with Pov-Ray interface for graphics. Additional crystallographic information including cell parameters and details concerning data collection and refinement are given in Table 2.

ACKNOWLEDGEMENT
The authors wish to thank the Office of Planning and Institutional Research, University of the West Indies, Mona, for financial support of this project.

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