(E)-13-(4-Aminophenyl)parthenolide

The title compound, C21H25NO3 [systematic name: (3aS,9aR,10aR,10bS,E)-3-[(E)-4-(4-aminobenzylidene)-6,9a-dimethyl-3a,4,5,8,9,9a,10a,10b-octahydrooxireno[2′,3′:9,10]cyclodeca[1,2-b]furan-2(3H)-one] was obtained from the reaction of parthenolide [synonym: 4,5-epoxygermacra-1(10),11(13)-dieno-12,6-lactone] with 4-iodoaniline under Heck reaction conditions. It was identified as the E-isomer (conformation about the exocyclic methylidene C=C bond; the conformation about the C=C bond in the ten-membered ring is also E). The molecule is built up from fused ten-, five- (lactone) and three-membered (epoxide) rings with a 4-aminophenyl group as a substituent. The ten-membered ring displays an approximate chair–chair conformation, while the lactone ring has an envelope conformation with the C atom bonded to the ring O atom as the flap. The dihedral angle between the benzene ring of the 4-aminophenyl moiety and the lactone ring mean plane is 23.50 (8)°. In the crystal, molecules are linked via N—H⋯O hydrogen bonds, between the amine group and the lactone and epoxide ring O atoms, forming chains propagating along the b-axis direction. Adjacent chains are linked via C—H⋯O interactions, forming an undulating two-dimensional network lying parallel to the plane (001). The absolute structure of the molecule in the crystal was confirmed by resonance scattering [Flack parameter = 0.03 (3)].

Parthenolide is a sesquiterpene lactone of the germacranolide class which occurs naturally in the plant feverfew (Tanacetum parthenium), and is believed to be the active chemical constituent responsible for the plant's biological activity (Hall et al., 1979). It has become a key intermediate for the synthesis of several novel antileukemic compounds over the past decade. From our research on antileukemia analogues of parthenolide, we have improved the poor water solubility properties of parthenolide and related sesquiterpenes by incorporating amino moieties at the exocyclic methylidene carbon via Michael addition (Neelakantan et al., 2009). Also, in a recent communication we have reported the synthesis and antileukemic activity of a melampolide sesquiterpene lactone, melampomagnolide B (Nasim et al., 2011).
The current study focuses on the synthesis of the title E-olefinic analogue of parthenolide which was obtained from the reaction of parthenolide with 4-iodoaniline utilizing Heck chemistry (Han et al., 2009). In order to obtain detailed information on the structural conformation of the title compound and to establish the geometry of the exocyclic double bond, a single-crystal X-ray structure determination has been carried out.
The title molecule, Fig. 1, contains an E-exocyclic olefinic bond C12═C13. The ten-membered ring displays an approximate chair-chair conformation, while the lactone ring has an envelope conformation with atom C9 as the flap. The dihedral angle between the benzene ring of the 4-aminophenyl moiety and the lactone ring mean plane is 23.50 (8) °.
The crystal structures of the structurally related 3-trifluoromethylphenyl and 2-trifluoromethylphenyl derivatives of parthenolide have been reported previously (Han et al., 2009). These molecules also have an E-conformation about the exocyclic olefinic double bond, and their absolute stereochemistries were also determined by resonance scattering. The lactone rings of these compounds have envelope conformations with the C-atom bonded to the O-atom as the flap, as in the title compound. The dihedral angles between the lactone ring mean plane and the aromatic rings of the 3-trifluoromethylphenyl and 2-trifluoromethylphenyl moieties are 40.52 (12) and 48.07 (12) °, respectively, compared to 23.50 (8)  Significant deviations from the ideal bond angle geometry around the carbon atoms, C12, C13 and C11, that are in the sp 2 state and involved in the double bonds are observed; the C12═C13-C16, C13═C12-C8 and O3═ C11-C12 bond angles with the respective values of 131.43 (14), 132.77 (14), and 129.80 (14)°, deviate from the ideal value of 120°.
In the crystal, molecules are linked via N-H···O hydrogen bonds ( Fig. 2 and Table 1), between the amine group and the lactone and epoxide ring O atoms, forming chains propagating along the b-axis. Adjacent chains are linked via C-H···O interactions (Table 1) forming undulating two-dimensional networks lying parallel to the plane (001).

Experimental
A mixture of parthenolide [Chemtek, Worcester, MA, USA](50 mg, 0.20 mmol), triethylamine (60 mg, 0.61 mmol), and 4-iodoaniline (48.56 mg, 0.22 mmol) in dimethylformamide (0.1 ml) was treated with palladium(II) acetate (0.5 mg, 0.002 mmol) and then stirred at 353 K for 24 h. Han et al. (2009) reported the synthesis of similar chiral molecules. The reaction mixture was cooled to room temperature, water (8 ml) was added, and the mixture was extracted with ethyl acetate (10 ml × 3). The separated organics were dried over Na 2 SO 4 and concentrated under reduced pressure. The obtained crude residue was purified using silica flash chromatography (7:3, hexanes/EtOAc) to afford the title compound, which was recrystallized from a mixture of hexanes and ethyl acetate(1:1) as yellow needle-like crystals (40 mg, 58 % yield; M.p. = 512-514 K). Spectroscopic data for the title compound are available in the archived CIF.

Refinement
All the H-atoms were located in difference electron density maps. The NH 2 H atoms were refined with U iso (H) = 1.5U eq (N). The C-bound H atoms were placed in idealized positions and refined as riding atoms: C-H = 0.98, 0.99, 1.00 and 0.95 Å for CH 3 , CH 2 , CH and C sp 2 H H atoms, respectively, with U iso (H) = 1.5U eq (C-methyl) and = 1.2U eq (C) for other H atoms.

Figure 2
A partial crystal packing plot of the title compound showing the N-H···O hydrogen bonds that join the molecules into chains parallel to the b axis (see Table 1 for details; H atoms not involved in these hydrogen-bonds have been omitted to enhance clarity). )-6,9a-dimethyl-3a,4,5,8,9,9a,10a,