X-Ray Supramolecular Structure, NMR Spectroscopy and Synthesis of 3-Methyl-1-phenyl-1H-chromeno[4,3-c]pyrazol-4-ones Formed by the Unexpected Cyclization of 3-[1-(Phenyl-hydrazono)ethyl]-chromen-2-ones

The molecular structures of nine 3-methyl-1-phenyl-1H-chromeno[4,3-c]pyrazol-4-one isomers, obtained by the oxidative cyclization of the corresponding 1-phenylhydrazono chromen-2-ones with copper acetate as catalyst, are reported. The molecular and supramolecular structures of the 8-chloro, 8-bromo- and 8-nitro isomers 2b-d, were established by X-ray diffraction. The halogenated isomers 2b and 2c are isomorphs, they crystallize as a triclinic system, space group P-1 with two molecules in the asymmetric unit. Compound 2d crystallizes as a monoclinic system, space group P21/m with two molecules in the unit cell. The 1-phenyl ring [Cg(4)] is almost perpendicularly positioned to the chromene-pyrazole ring system. This conformation is in agreement with the anisotropic NMR shielding effect exerted by the phenyl ring over H-9 in solution. The supramolecular architecture is almost controlled by C―H···A (A = O, π) and face to face π-stacking interactions. The observed π-stacking trend between chromene and pyrazole rings is given by the overlapping between the best donor and acceptor rings in each compound.

In this contribution the synthesis of 1-phenyl-chromeno [4,3-c]pyrazol-4-ones 2a-i through the oxidative cyclization of 3-(phenyl-hydrazono)-chromen-2-ones 1a-i with copper acetate as catalyst is reported (Scheme 1). The structures in solution by NMR as well as the molecular and supramolecular structures in the solid state, by monocrystal X-ray diffraction, are discussed.

Synthesis and Molecular Structure in Solution
In our efforts to crystallize hydrazone 1a from a saturated chloroform solution, crystals of 3-methyl-1-phenyl-1H-chromeno [4,3-c]pyrazol-4-one 2a were spontaneously formed instead in 30% yield at RT. It is worthy to note that the cyclization reaction of 1a is not expected, because of the absence of a 4-positioned good leaving group to allow pyrazole ring formation. To ascertain the scope and limitation of this transformation, several 3-(phenyl-hydrazono)-chromen-2-ones 1b-i were tested but cyclization did not proceed under the same conditions as for 1a. This result lead us to use Cu(CH 3 COO) 2 ·H 2 O as catalyst, since some examples of copper-catalyzed oxidative amination of alkynes [21] and azoles [22] via CH and NH coupling have recently been reported. Then, compounds 2a-i were prepared in poor to good yields (50-83%), starting from the corresponding 3-[1-(phenylhydrazono)-ethyl]-chromen-2-ones 1a-i, using Cu(CH 3 COO) 2 ·H 2 O as catalyst in 20:1 weight ratio under mild conditions. In comparison with reported methods, starting from 4-hydroxybenzopyranoarylhydrazones, the yields are lower or similar for 2a (76%) [17] and 2b (39%) [15], but in the case of 2c (78%) and 2d (83%) [23] they are significantly enhanced by the use of the copper catalyst.
The reaction should proceed by a simple intramolecular conjugate addition of the Ph-N to the α,βunsaturated-C=N + system, through the intermediate A, and the subsequent oxidation of the resulting dihydro-pyrazolone B (Scheme 2). This proposal is supported on similar reactions reported in acid media [24,25]. The formation of the key intermediate A' would be disfavored either by electro withdrawing (W) or by electrodonating (D) substituents, which would explain the necessary aid of the copper catalyst (Scheme 3).  Tables 1 and 2 for 1a-i and 2a-i, respectively. The 1 H-NMR spectra of compounds 2a-i is characterized by the loss of the H-4 signal, usually appearing as a singlet at δ 7.98-8.17, in the starting compounds 1a-i. In addition, the chemical shift of H-9 in 2a-i appears at δ 6.62-8.02, more shielded than the former H-5 (δ 6.97-8.51) in 1a-i, because of the anisotropic NMR shielding effect exerted by the phenyl group which should be almost perpendicular to the 1-phenylchromeno [4,3-c]pyrazol-4-one ring system in compounds 2a-f. The 13 C chemical shift of C-3a appears at 106-107 ppm in compounds 2a-i, whereas the former C-3, in the starting hydrazones 1a-i, is at 127.8-130.6 ppm. Subtle shielding is also observed for C-9a (former C-10) by 7.0 ppm, in agreement with the aromatic character of the newly formed pyrazole ring. The chemical shift of C-9b (former C-4) remains almost the same even when in this position was performed the ring closure. The saturation of the Me frequency in 1a (δ 2.20, s) gives a NOE effect on proton H-4 (δ 8.16, s) and NH proton (δ 9.43, s), suggesting an E configuration for the C=N double bond and thus the predominance in solution of the rotamer I (Scheme 4). Thus the transformation of 1a into 2a implies the breaking of the double -C=N-bond to a single -C-N-to allow the location of the atoms in the proper place for cyclization in agreement with the above mentioned copper-catalyzed oxidative amination.

Molecular and Supramolecular Structure in Solid State
1-Phenyl-chromeno [4,3-c]pyrazol-4-ones 2b-d were crystallized from saturated DMF solutions. The halogenated isomers 2b,c crystallize as a triclinic system, space group P-1 with two molecules in the asymmetric unit. Compound 2d crystallizes as a monoclinic system, space group P2 1 /m with two molecules in the unit cell. A summary of bond lengths and angles are listed in Table 3 and crystal data and structure refinement for 2b-d are listed in Table 4. As in other coumarin derivatives, the replacement of Cl by Br does not alter the crystal packing [26]. All the atoms of pyrazole and chromenone rings lie in a single plane within the limits of experimental error. The 1-phenyl ring in compounds 2b-d is sterically hindered and appears twisted by 71.9(2)º, 74.7(5)º and 92.1(2)º, respectively, from the three ring fused coplanar chromeno [4,3-c]pyrazol-4-one system in agreement with the conformation observed in solution (vide supra). The torsion angle between both planes is very close to that observed for 1-phenyl-1H-chromeno [4,3-c]pyrazol-4-one of 73.1(6)º [27]. However, in compound 2d the 1-phenyl ring [Cg(4)] is almost perpendicularly positioned, thus a symmetry plane cut the molecule through its equatorial plane and only one half of the phenyl ring is observed. This conformation is in agreement with the observed anisotropic NMR shielding effect exerted by the phenyl ring over H-9 in solution.
The molecular structures of the three isomers are very similar and the major differences among them arise from the nature of the 8-substituent, Figure 1. A brief comparison with the starting coumarins points out the lengthening of C9a-C9b bond length to 1.439(5) Å (mean value of 2b-d), from a mean reported value of 1.35 Å (C3-C4 in the former coumarins) [28], in agreement with a delocalized electronic character of the pyrazole ring. Because of the arrangement of the aromatic rings, the supramolecular architecture is almost controlled by C-H···A (A = O, π) and face to face π-stacking interactions, whose geometrical parameters are listed in Table 4. In the solid state C9-H9···Cg(4) and C9···Cg(4) distances, and C9-H9··· Cg(4) angle, suggest an intramolecular C-H···π interaction S(6) in 2d, Figure 2. Even when these geometric parameters are similar among 2a-d, only those corresponding to 2d lie are in the proper range to be considered as such [29]. Table 3. Selected bond lengths and angles from X-ray data of compounds 2b-d.

Atoms
Bond lengths (Å)   (3) 178  The first dimension (1-D) is directed by C13-H13···O4C4 interactions, between an aromatic hydrogen and the oxygen of the lactone group, developing C(10) chains along the direction of the c axis in 2b-d. Molecules of 2b,c self assemble in the bc plane and 2d in the ac plane through C7-H7···Cg(4) interactions forming C(8) chains. The 2-D assembly is thus described as a R 5 4 (25) ring, in agreement with the graph set notation conventions [30], Figure 2. 2-D assembled monolayers of 2b,c and 2d are face-to-face π-stacked developing the 3-D along the a and the b axis, respectively. A C(12) chain motif complements the 3-D in compounds 2b,c through the participation of C15-H15···O5 and C16-H16B···Cg(3) contacts running along the direction of the a axis ( Figure 3). The participation of the N-phenyl ring [Cg(4)] in π-stacking is restricted to C-H···π interactions because of its disposition out of the plane. In contrast, the remaining pyrazole [Cg(1)], pyrone [Cg (2)] and benzenoid [Cg (3)] rings are lying in the same plane and thus are appropriately positioned for πstacking. The geometric parameters associated with π-stacking interactions are listed in Table 5. Pyrazole ring is stacked with pyrone ring in compound 2a [Cg(1)···Cg (2)] [31], it further appears stacked with the Cl-or Br-substituted benzenoid ring [Cg(1)···Cg (3)] in compounds 2b and 2c. In both compounds, the π-stacking between pyrone and benzenoid rings, typical of coumarins, is also observed [Cg(2)···Cg (3)]. However, in the case of compound 2d only Cg(1) and Cg(3) are stacked, the EW group 8-NO 2 diminishes the charge transfer capability of the benzenoid ring, enabling the formation of π-stacked centrosymmetric pairs with pirazole ring, the best charge transfer donor ring. In the other hand, the donor-acceptor capabilities of the benzenoid ring changes on going from 2a to 2d, according with the increase of the EW nature of the 8-substituent. Thus, the observed π-stacking trend between the rings is given by the overlapping between the best donor and acceptor ring in each molecule. This trend is consistent with those observed for other CCDC deposited structures [32], whose molecular and supramolecular analysis is missing (LOLZER, LOLZOB, LOLZUH, LOMBAQ, LOMBEU). Compounds 2a-2d are functional isomers but only 2b and 2c are isomorphous, however the supramolecular structure of all of them is almost the same, varying only in the π-stacked rings and the propagating directions of the supramolecular motifs.

Materials and Methods
All chemicals and solvents were of reagent grade and used as received. The starting coumarins were synthesized as reported elsewhere [33]. Melting points were measured on an Electrothermal IA 9100 apparatus and were uncorrected. IR spectra were recorded neat using a Varian 3100 FT-IR EXCALIBUR series spectrophotometer. 1 H-and 13 C-NMR spectra were recorded on a Varian Mercury 300 ( 1 H, 300.08; 13 C, 75.46 MHz) instrument in CDCl 3 solutions, unless otherwise is specified, chemical shifts are in ppm and coupling constants in Hz, measured with SiMe 4 as internal reference. Mass spectra were obtained in a GC-MS system (Saturn 2100T) with an electron ionization mode (Hewlett-Packard 5972 series) using HP5. Elemental analyses were performed on a Perkin-Elmer 2400 elemental analyzer.

X-ray Data Collection and Structure Determination
Crystals suitable for X-ray analysis were obtained by slow crystallization from saturated DMF solutions. Single-crystal X-ray diffraction data for molecules 2b-d were collected on a Bruker Apex II area detector diffractometer at 293 K with Mo Kα radiation, λ = 0.71073 Å. A semiempirical absorption correction was applied using SADABS [37], and the program SAINT [37] was used for integration of the diffraction profiles. The structures were solved by direct methods using SHELXS97 [38] program of WinGX package [39]. The final refinement was performed by full-matrix least-squares methods on F 2 with SHELXL97 program [37]. H atoms on C, N and O were positioned geometrically and treated as riding atoms, with C-H = 0.93-0.98 Å, and with Uiso(H) = 1.2Ueq(C). Mercury was used for visualization, molecular graphics and analysis of crystal structures [40], software used to prepare material for publication was PLATON [41]. Crystallographic data (excluding structure factors) for the structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication CCDC numbers 766071 2b, 766070 2c, 766072 2d. Crystal data and details concerning data collection and structure refinement are given in Table 6.

Conclusions
3-Methyl-1-phenyl-1H-chromeno [4,3-c]pyrazol-4-one (2a) spontaneously crystallizes from CHCl 3 solutions of 3-[1-(phenyl-hydrazono)-ethyl]-chromen-2-one (1a) whereas the 6-substituted isomers 1b-i failed to do so, requiring Cu(CH 3 COO) 2 ·H 2 O as catalyst to yield the corresponding 1-phenylchromeno [4,3-c]pyrazol-4-ones 2b-i in moderate to good yields (50-83%) under mild conditions. The NMR data in solution and the X-ray data in the solid state are consistent with the N-phenyl ring almost perpendicular to the three fused rings chromeno-pyrazole system. In the solid state this geometrical arrangement of the aromatic rings determines the supramolecular architecture by C-H···A (A = O, π) and face to face π-stacking interactions which are very similar among 2b-d, varying only in the nature of the π-stacked rings and in the propagating direction. The observed π-stacking trend between chromeno and pyrazole rings is given by the overlapping between the best donor and acceptor rings in each molecule, modulated by the electronic character of the X and Y substituents.