(Z)-tert-Butyl 2-(4-amino-9H-fluoren-9-ylidene)acetate

The title compound, C19H19NO2, obtained as an almost equimolar mixture (as shown by 1H NMR) with the E isomer through a Wittig reaction between 4-amino-9H-fluoren-9-one and the stabilized ylide Ph3P=CHCO2C(CH3)3, was obtained pure in the Z configuration following crystallization from toluene. The molecule shows a planar arrangement of the ring system and the new double bond, whereas the carbonyl O atom forms a 45.1 (3)° dihedral angle with it. The molecules are linked by N—H⋯O hydrogen bonds, forming cyclic structures with R 4 4(24) graph-set motifs. These motifs are connected to each other, giving rise to a sheet structure parallel to the ab plane. The linkage within the sheets is further enhanced by π–π stacking interactions between the fluorene units [centroid–centroid distance = 3.583 (2) Å].

The title compound, C 19 H 19 NO 2 , obtained as an almost equimolar mixture (as shown by 1 H NMR) with the E isomer through a Wittig reaction between 4-amino-9H-fluoren-9-one and the stabilized ylide Ph 3 P CHCO 2 C(CH 3 ) 3 , was obtained pure in the Z configuration following crystallization from toluene. The molecule shows a planar arrangement of the ring system and the new double bond, whereas the carbonyl O atom forms a 45.1 (3) dihedral angle with it. The molecules are linked by N-HÁ Á ÁO hydrogen bonds, forming cyclic structures with R 4 4 (24) graph-set motifs. These motifs are connected to each other, giving rise to a sheet structure parallel to the ab plane. The linkage within the sheets is further enhanced bystacking interactions between the fluorene units [centroid-centroid distance = 3.583 (2) Å ].

D-HÁ
Data collection: CrysAlis CCD (Oxford Diffraction, 2008); cell refinement: CrysAlis RED (Oxford Diffraction, 2008); data reduction: CrysAlis RED; program(s) used to solve structure: SIR92 (Altomare et al., 1994); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: PLATON (Spek, 2003), ORTEP-3 (Farrugia, 1997) and DIAMOND (Brandenburg, 2008); software used to prepare material for publication: WinGX (Farrugia, 1999) and publCIF (Westrip, 2008 (Z)-tert-Butyl 2-(4-amino-9H-fluoren-9-ylidene)acetate M. Krokidis, D. Papaioannou and V. Nastopoulos Comment Retinoids, a large family of natural and synthetic compounds structurally related to vitamin A play an important role in a variety of biological functions including vision, development, reproduction and cell differentiation and have been applied successfully to the management of severe skin disorders (Sporn et al., 1994;Meyer et al., 1978). For example, acitretin (1) is presently regarded as the drug of choice for the treatment of psoriasis. However, retinoids are toxic compounds in large doses as well as teratogenic. Therefore, a huge array of analogs have been synthesized aiming at improving the therapeutic efficacy to toxicity index as well as to secure better selectivities for various therapeutic applications. These analogs usually involve changes in the lipophilic part of the molecules and/or the tetraene chain. As concerns the latter, double bonds have been for example replaced by the isosteric amide bond and/or incorporated into aromatic rings to restrict conformational freedom of the chain (Sporn et al.., 1994). Along this line, we have recently reported the synthesis of analogs like compound 2 (Magoulas & Papaioannou, 2003). We thought that the tetraene chain might be mimicked by compounds of the general formula 3, which could be readily assembled by joining commercially available cinnamic acids and an 4-amino-9H-fluoren-9-one derived α,β-unsaturated carboxylic acid (Fig. 1).
Examination of this reaction product by 1 H-NMR revealed that the two isomers were present in the ratio 1:0.8. Crystallization of this mixture of isomers from toluene provided one of the two isomers almost free of the other isomer. On the other hand, evaporation of the mother liquor and crystallization of the residue provided the other isomer almost free of the first one as shown by 1 H-NMR experiments and comparing the spectra of the two isomers with the one received from their mixture. In an attempt to identify which isomer is which, we decided to proceed with further recrystallizations of the almost pure isomers, obtained as described above. To our delight, the second recrystallization of the former isomer provided it in a suitable crystalline form to allow for an X-ray analysis. Unsuccessful were, however, our attempts to obtain the second isomer in an also suitable crystalline form for X-ray analysis.
We now wish to report the results of the X-ray crystallographic analysis of the former isomer which allowed us to determine unambiguously its configuration around the exocyclic double bond. As it can be seen from Figure 3, this compound actually has the Z configuration around the double bond (isomer 5 b) and therefore the other isomer should be the E isomer (5a).
The molecule shows an almost planar arrangement of the ring system and the new double bond (the maximum deviation from their mean plane being 0.091 (2) Å for atom C10), whereas the carbonyl O2 atom lies 0.602 (3)  graph-set motifs (Bernstein et al.., 1995). This bonding pattern results in a network of connected R 4 4 (24) rings lying on pleated layers parallel to the ab plane (Table 1 and Fig. 4). The tert-butyl moieties are packed between the layers.
The linkage inside each layer is further supported by weak π-π stacking interactions among the central five-membered ring and one of the attached six-membered rings of the fluorene moieties. Specifically, the C1'-C4'-C5'-C8'-C9 fulvene ring at (x, y, z) and the C1'-C1-C2-C3-C4-C4' aryl ring at (1/2+x, y, 3/2-z) are almost parallel forming between them a dihedral angle of 6.5 (2)°. The centroid separation of the two rings is 3.583 (2) Å and the perpendicular distance of the first centroid on the plane of the second ring is 3.421 (1) Å, corresponding to a centroid offset of 1.07 (2) Å.

Experimental
A mixture of 4-amino-9H-fluoren-9-one (0.78 g, 4 mmol) and ylide BCMP (3.16 g, 8.4 mmol) in anhydrous DMF (4 ml) was stirred at 100 o C for 4 days under an atmosphere of argon. The resulting solution was diluted with 30 ml e thylacetate (EtOAc) and then washed with H 2 O (3 x 10 ml). The organic layer was dried (Na 2 SO 4 ) and evaporated to dryness under reduced pressure. The residue was subjected to flash column chromatography using as eluant the solvent system PhMe/EtOAc (9.5:0.5).
The fractions with R f 0.3 in the same solvent system were pooled and evaporated to leave 1.1 g (95% yield) of pure compound in the form of a reddish oil. 1 H NMR of the product revealed the presence of the two geometrical isomers in the ratio 1:0.8 calculated on the basis of the integration of the two peaks at 8.839 and 8.329 p.p.m. where proton H-8 resonates for the isomers 5a and 5 b, respectively.The product was dissolved in the minimum volume of hot toluene. The resulting solution was then left to attain ambient temperature and then cooled at 5 o C for 2 days. The crystalline precipitate was collected, washed with ice-cold toluene and dried under reduced pressure. It weighed 60 mg. 1 H NMR of the crystals thus obtained showed them to be almost the pure isomer (5a:5 b=1:10) with H-8 resonating at 8.329 p.p.m.. The mother liquor from the crystallization was evaporated to dryness and the residue was crystallized also from toluene to provide 70 mg of the almost pure alternative isomer with H-8 resonating at 8.839 p.p.m.. Recrystallization of the first crystalline isomer finally gave reddish crystals suitable for X-ray analysis. This isomer had m.p. 386-387 K.

Refinement
The amine H atoms and that attached to C14 were located in difference Fourier maps and their positions were refined freely along with U iso (H) equal to 1.5U eq and 1.2U eq of their parent atoms, respectively. The methyl H atoms were constrained to an ideal geometry [C-H = 0.96 Å and U iso (H) = 1.5U eq (C)], but were allowed to rotate freely about the C-C bonds.
The remaining phenyl group H atoms were placed in geometrically idealized positions and constrained to ride on their parent C atoms [C-H = 0.93 Å and U iso (H) = 1.2U eq (C)]. Five low-angle reflections were omitted from the final cycles of refinement because their observed intensities were significantly lower than the calculated values, being apparently obscured by the beam stop.   (24) cyclic structures parallel to the ab plane and the π-π stacking interactions among the fluorene moieties (green dotted lines). For the sake of clarity, only the H-atoms involved in the bonding pattern (dashed lines) are drawn. [Symmetry codes: (i) -x, y+1/2, -z+3/2, (ii) x-1/ 2, y, -z+3/2, (iii) -x, -0.5+y, 1.5-z and (iv) 0.5+x, y, 1.5-z] (Z)-tert-butyl 2-(4-amino-9H-fluoren-9-ylidene)acetate  Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > σ(F 2 ) is used only for calculating Rfactors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.