4-Acetyl-3,3-diethyl-5-hydroxy-2-morpholino-2,3-dihydro-1-benzofuran

In the title compound, C18H25NO4, the benzofuran ring is almost planar and the morpholino ring displays a chair conformation. The packing of compound has a one-dimensional structure constructed through intermolecular O—H⋯O hydrogen bonds. The conformation is stabilized by intramolecular C—H⋯N and C—H⋯O interactions.

In the title compound, C 18 H 25 NO 4 , the benzofuran ring is almost planar and the morpholino ring displays a chair conformation. The packing of compound has a one-dimensional structure constructed through intermolecular O-HÁ Á ÁO hydrogen bonds. The conformation is stabilized by intramolecular C-HÁ Á ÁN and C-HÁ Á ÁO interactions.

Related literature
For biological activity, see: Araya-Maturana et al. (2002, 2006. For related structures, see: Dusausoy et al. (1973);Filarowski et al. (2005); Huang et al. (2004). For the synthesis, see: Castro et al. (1983). For hydrogen bonding, see: Desiraju (2002). For puckering parameters, see: Cremer & Pople, 1975 Table 1 Hydrogen-bond geometry (Å , ). The title compound, (I), is a structural model of its dimethyl analog (4-acetyl-3,3-dimethyl-5-hydroxy-2-morpholino-2,3dihidrobenzo[b] furan). The later compound has been reported to be inactive as inhibitor of cellular respiration (Araya-Maturana et al., 2002), despite the close analogy with inhibitors incorporating a carbonyl group in the ortho position with respect to a phenol function (Araya-Maturana et al., 2002). The lack of activity has been atributed to the non-planarity of the acetyl group with respect to the phenolic moiety. Additionally, the O,N-acetal moiety of the molecule allows its use as starting point for the synthesis of biologically active quinones and hydroquinones (Araya-Maturana et al., 2006).
The molecule of (I) displays a 2,3-dihydrobenzo[b]furanic skeleton, substituted at position 5 with an hydroxy group.
A morpholino, an acetyl and two gem ethyl groups at positions 2, 4 and 3,3 respectively, are also present in the molecule ( Fig. 1). While the aromatic ring is essentially planar, as expected by the π-conjugation, the furan ring is far from being planar, C2 is 0.331 (2) Å out of the plane formed by the remaining atoms in the ring, giving it an envelop conformation. The morpholino ring displays a classical chair conformation with puckering parameters (Cremer & Pople, 1975): Q = 0.580 (2) Å, θ = 1.88 (14)° and φ = 161 (5)°.
Surprisingly, the acetyl group at position 4 is not coplanar with the aromatic ring; the dihedral angle between the two least-squares planes is 66.84 (6)°, precluding the formation of an intramolecular hydrogen bond with the hydroxy group at position 5. This differs from the observation made in molecules like 2-hydroxy-6-methoxyacetophenone (Filarowski et al., 2005) or 2,6-di-hydroxy-acetophenone (Huang et al., 2004) where both, the acetyl and the phenyl ring are almost coplanar and, a rather strong (Desiraju, 2002) intramolecular hydrogen bond to the hydroxo group is defined. This is the case still for η 6 -2-hydroxyacetophenone-tricarbonylcrommium(0) (Dusausoy et al., 1973) where coordination to the metal could withdraw electron density from the aromatic ring, weakening conjugation to the acetyl carbonyl group.
It is interesting to note that the non-planarity have been previously predicted from solution data (Araya-Maturana et al., 2002), suggesting the steric repulsion with the gem ethyl groups at position 3 is stronger than the intramolecular hydrogen bond. Finally, the analysis establishes that the conformation of the molecule is preserved at this respect in solution.
The packing of the molecule displays an intermolecular hydrogen bond between hydroxy hydrogen atom and the morpholino oxygen atom of an adjacent molecule (-x + 1, y + 1/2, -z + 1/2), with O···O of 2.764 (1) Å. This head to tail interaction leads to the formation of zigzag chains along the b-axis (Fig. 2). The structure is stabilized by intramolecular interactions of the types C-H···N and C-H···O (details are given in Table 1).
The structure detemination supports the hypothesis that relates the lack of activity of the compound as a cell respiration inhibitor with the non planarity of the acetyl group in relation to the phenolic core.
supplementary materials sup-2 Experimental The title compound was prepared from reaction of 4-(2-ethyl-but-1-enyl)-morpholine with 2-acetyl-1,4-benzoquinone (see Scheme 2), following the procedure described for the 3,3-dimethyl analog (Castro et al., 1983). The reaction time was 2 h. X-ray quality crystals were obtained from the resulting solution after volume reduction and addition of a few drops of methanol.