NEW SPIRO (THIO) BARBITURATES BASED ON CYCLOHEXANONE AND BICYCLO [3.1.1]HEPTAN-6-ONE BY NONCONCERTED [1+5] CYCLOADDITION REACTION AND THEIR CONFORMATIONAL STRUCTURES

ABSTRACT. Crossed-aldol condensation reaction of aromatic aldehydes with ketones such as; acetone and cyclohexanone leads to the efficient formation of cross conjugated α,β-unsaturated ketones in excellent yield. The intermolecular and then intramolecular Michael addition reaction of α,β-unsaturated ketones derived from acetone and cyclohexanone with (thio)barbituric acids lead to synthesis new type of 7,11-diaryl-2,4diazaspiro[5.5]undecane-1,3,5,9-tetraone and 2,4-diaryl-1'H-spiro[bicyclo[3.3.1]nonane-3,5'-pyrimidine]2',4',6',9(3'H)-tetraone, respectively in good yield. Structure elucidation is carried out by H NMR, C NMR, FTIR, UV-Visible, mass spectroscopy and X-ray crystallography techniques. A possible mechanism of the formation is discussed. The structural conformation also demonstrated by coupling constants derived from dihedral angles between vicinal and geminal protons. The H NMR spectra of NH protons of spiro compounds derived from barbituric acid show a broad singlet peak instead, these protons in the spiro compounds derived from thiobarbituric acid show two distinct peaks.

As we searched in the literature, there are some reports about spiro barbiturates based on bis-arylideneacetones [36,45] and no report about spiro barbiturates based on 2,6-bisarylidenecyclohexanones.Based on these concepts, in this research, we report a new and facile route for the synthesis of 5,5-two substituted spiro-barbiturates by the condensation reaction of N-substituted and unsubstituted (thio)barbituric acids with dibenzalacetone and 2,6dibenzylidenecyclohexanone derivatives.

EXPERIMENTAL General
The drawing and nomenclature of compounds were done by ChemBioDraw Ultra 8.0 version software.Melting points were measured with a digital melting point apparatus (Electrothermal) and were uncorrected.IR spectra were determined in the region 4000-400 cm -1 on a NEXUS 670 FT IR spectrometer by preparing KBr pellets.The 1 H and 13 C NMR spectra were recorded on Bruker 300 FT-NMR at 300 and 75 MHz, respectively (Urmia University, Urmia, Iran). 1 H and 13 C NMR spectra were obtained on solution in DMSO-d 6 and/or in CDCl 3 as solvents using TMS as internal standard.The data are reported as (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or unresolved, bs = broad singlet, coupling constant(s) in Hz, integration).All reactions were monitored by TLC with silica gel-coated plates (EtOAc:cyclohexane, 8:10, v:v).The mass analysis performed using mass spectrometer (Agilent Technology (HP) type, MS Model: 5973 Network Mass Selective Detector Electron Impact (EI) 70 eV), ion source temperature was 230 ºC (Tehran University, Tehran, Iran).The electronic spectra were performed by T80 UV-Vis (PG Instruments Ltd) spectrometer (Urmia University, Urmia, Iran).Compounds 3 were synthesized based on reported literature [25].Compounds 1a-k, 2a', 2c', 4a''-4d'' and used solvents purchased from Merck and Across without further purification.
Representatively, the 1 H NMR spectrum of 7fa'b'' shows two singlets for N-CH 3 protons at δ 2.88 and 3.03 ppm, two doublet of doublets at δ 2.65 and 4.05 ppm for two diastereotopic methylene protons, a triplet at δ 3.75 ppm (essentially, it is doublet of doublets) for benzylic proton on chiral stereogenic center and a multiplet at δ 7.07-7.28ppm for aromatic phenyl protons. 13C NMR spectrum of this compound shows thirteen distinct peaks.One of the carbonyl peaks was extremely shifted to low field at δ 200.18 ppm that confirms the formation of saturated ketone (substituted cyclohexanone).The IR spectrum of this compound shows the C=O frequencies at 1717 and 1675 cm -1 that corresponds to carbonyl groups of spiro cyclohexanone and barbituric acid ring moieties, respectively.The UV-Visible spectra of some cross-conjugated dyes such as 3fa', 3ca' and some corresponding spiro compounds 7fa'b'', 7fa'd'' and 7ca'b'' is shown in Figure 2. Representatively, the 3fa' shows two absorption bonds at 320 and 384 nm that corresponds to π→π* (K-band) and weak n→π* (R-band), respectively.In contrast, in 7fa'b'', the allowed π→π* transition was disappeared and the only forbidden weak n→π* band at 304 nm was observed (see experimental section).Obviously, in dyes 3fa' and 3ca' the K-band undergoes a small bathochromic shift because of the enone conjugation.Instead, in 7fa'b'' and 7fa'd'' the K-bank hypsochromically shifted.These data also confirm the formation of the saturated cyclohexanone (decreasing the conjugated system) in 7fa'b'' and 7fa'd'' as representative.A small absorption at 402 nm for 7fa'd'', corresponds to n→π* band of thiocarbonyl group (Figure 2).

Plane of symmetry Axis of symmetry (C 2 )
A B (a  Two possible conformers (also diastereomers) of 7fa'a''-d'' is shown in Figure 3a.Representatively, compound 7fa'b'' can be serves as plane of symmetry (7fa'b''A form) and axis of symmetry, C 2 (7fa'b''B form) (Figure 3a).The Newman projection and observed structural conformers of 7fa'a''-d'' is shown in Figure 3b.Representatively, the predominant conformer and coupling constants (J) of 7fa'b''A is also shown in Figure 3c.The dependence of vicinal coupling constants on the dihedral angle, φ, based on Karplus curve -is described [57,58].For instance, in 7fa'b''A form, for H a at δ 4.04 ppm, the dihedral angle of φ ac and φ ab are equals to 180° and 60°, respectively.The corresponding J-values were obtained 14.4 and 4.2 Hz, respectively.For H b at δ 2.64 ppm, the J-values were obtained 14.7 Hz for two geminal protons H b and H c and 4.2 Hz for vicinal H b and H a , respectively (φ ab = 60°).For H c , the Jvalues were obtained 14.4 and 14.7 Hz for vicinal (J ca ) and geminal protons (J cb ), respectively.Scheme 4. Representatively, two intermolecular hydrogen bonds and tautomeric forms of 7ca'a'', 7ea'a'' and 7ga'a''.
These observations indicated that the bulky phenyl substituents lie in equatorial positions in 7 and cyclohexanone ring moiety has chair conformer (Figure 3b,c).In addition, the 1 H, 13 C NMR, IR, mass fragmentation data and conformational analysis confirms the assigned structure of 7fa'b''A (including a plane of symmetry, σ).These data indicated that representatively, 7fa'a''-7fa'd'' have plane of symmetry and are in 7fa'a''-7fa'd''A forms (Figure 3).No spiro barbiturates 7fa'a''-7fa'd''B forms consists of axis of symmetry (C 2 ) were observed based on NMR investigations.The chemical shifts of N-R 3 protons to be equivalent in (thio)barbituric acid ring moiety if the molecule have axis of symmetry (C 2 ).Another most interesting phenomenon in the spiro-barbiturate derivatives of 4a'' is the equivalence of the chemical shifts of two NH protons that appeared as an extremely broad singlet.This phenomenon presumably corresponds to the intermolecular hydrogen bond of NH protons in the molecule with oxygen atom on amidic carbonyl group of other molecule one (Scheme 4).Instead, this equivalency of two NH protons was not shown in the spirothiobarbiturate derivatives derived from 4c'' (Figure 4).Representatively, the equivalency of the NH protons of 7ca'a'' and 7ea'a'' are shown and comparised with the NH protons of 7ca'c'' and 7ea'c'' (thiobarbituric acid derivatives) in Figure 4. Representatively, the 1 H NMR spectrum of 7fb'b'' shows multiplets at δ 0.65-0.80ppm (1H), at δ 1.60-1.82ppm (4H) and at δ 2.93-2.97ppm (2H) for diastereotopic protons on spiro bicyclo scaffold. 1H NMR spectrum of this compound also show two singlets for N-CH 3 protons at δ 2.99 (3H) and 3.15 ppm (3H), a triplet at δ 3.71 ppm (1H, J = 10.8Hz), a doublet of doublets at δ 3.90 ppm (1H, J = 10.8Hz, J ≈ 3.5 Hz), a singlet at δ 4.43 ppm (1H) and a multiplet at δ 7.35-7.49ppm for aromatic phenyl protons.Obviously, the 13 C NMR spectrum of this compound shows fifteen distinct peaks.One of the carbonyl peaks was extremely shifted to low field at δ 215.0 ppm that confirms the formation of saturated ketone (substituted spiro bicyclo[3.3.1]nonan-9-onescaffold).The IR spectrum of this compound shows the C=O frequencies at 1743 and 1672 cm -1 that corresponds to carbonyl groups of spiro bicyclo[3.

X-Ray data for 7ca'b''
For the further study, the crystal structure and packing diagram of compound 7ca'b'' are shown in Figures 6 and 7, respectively.The cyclohexanone and barbituric acid rings have chair and nearly planar conformers, respectively.The torsion angle between two phenyls and cyclohexanone rings obtained in results of 79.93 and 95.57°, respectively.The summary of crystal date for 7ca'b'': crystal system, space group: tetragonal, P-42 1 c; unit cell dimensions: a = 21.5533(5), b = 21.5533(5), c = 9.4674(2) Å, α = 90.00,β = 90.00,γ = 90.00,cell volume: 4398.03Å 3 ; Z = 8.Single crystal of 7ca'b'' was obtained as colorless crystal by slow evaporation from methanol at room temperature.For the crystal structure determination, the single-crystal of the compound 7ca'b'' was used for data collection on a four-circle Rigaku R-AXIS RAPID-S diffractometer (equipped with a two-dimensional area IP detector).The graphite-monochromatized Mo K α radiation (λ = 0.71073 Å) and oscillation scans technique with ∆ω = 5˚ for one image were used for data collection.The lattice parameters were determined by the least-squares methods on the basis of all reflections with F 2 > 2σ(F 2 ).Integration of the intensities, correction for Lorentz and polarization effects and cell refinement was performed using CrystalClear (Rigaku/MSC Inc., 2005) software [59].The structures were solved by direct methods using SHELXS-97 [60] and refined by a full-matrix least-squares procedure using the program SHELXL-97 [60].H-atoms were positioned geometrically and refined using a riding model.The final difference Fourier maps showed no peaks of chemical significance.Crystallographic data were deposited in CSD under CCDC-800579 registration number and are available free of charge upon request to CCDC, 12 Union Road, Cambridge, UK (fax: +44-1223-336033, e-mail: deposit@ccdc.cam.ac.uk).

CONCLUSION
In summary, the crossed-aldol condensation reaction of aromatic aldehydes bearing electron donating and electron withdrawing substituents with acetone and cyclohexanone afforded crossconjugated type dyes.The inter-and then intramolecular Michael addition reaction of these dyes with (thio)barbituric acids afforded new type of spiro (thio)barbiturates and bicyclo spiro (thio)barbiturates, respectively.The structures of spiro (thio)barbiturates derived from acetone revealed that the spiro cyclohexanone moiety has chair conformer and two phenyl (and/or aryl) groups on cyclohexanone lies in equatorial position.The crystal structure of the one of spiro compounds derived from acetone show that the cyclohexanone and barbituric acid rings have chair and nearly planar conformers, respectively, in solid state.