Crystal structure of 5-benzyl-8-bromo-2-methyl-1,3-oxazolo[4,5-c][1,8]naphthyridin-4(5H)-one

The structure of an oxazolonaphthyridinone derivative unexpectedly formed during the synthesis of pyridodiazepinediones is reported.

The title compound, C 17 H 12 BrN 3 O 2 , was unexpectedly isolated during an attempt to synthesize pyridodiazepinediones and identified as an oxazolonaphthyridinone derivative. The almost planar oxazolonaphthyridinone ring (r.m.s. deviation = 0.016 Å ) makes a dihedral angle of 61.6 (2) with the phenyl ring. In the crystal, columns of molecules stacked along the a axis are formed by interactions between the six-membered rings of the oxazolonaphthyridone moieties [centroid-to-centroid distances = 3.494 (2)-3.906 (3) Å ], which further interact through C-HÁ Á Á contacts with the phenyl rings.

Chemical context
While benzodiazepine drugs have been amongst the most prescribed medication globally since their discovery in the 1950s, the search for structurally related biologically active compounds is of major relevance to the pharmaceutical industry (Washton & Zweben, 2011). Previous work in our group dealing with the construction of pyridodiazepinediones (PZDs; Van den Bogaert et al., 2010) led unexpectedly to the isolation of a tricyclic compound, which was later identified as oxazolonaphthyridinone (ONO) 6 ( Fig. 1). Commercially available 2-hydroxynicotinic acid 1 was converted to dihalonicotinic acid 3 via two sequential halogenation reactions (Van den Bogaert et al., 2010;Gero et al., 1989;Haché et al., 2002), after which a benzylamine substituent was introduced yielding the aza-anthranilic acid derivative 4. Next, ester compound 5 was prepared from intermediate 4 and tert-butyl glycinate using a standard coupling procedure. Finally, tert-butyl ester 5 was deprotected in situ and reacted with acetic anhydride in the presence of potassium carbonate, yielding tricyclic compound 6. After exploration and optimization of the revealed cascade reaction towards the closely related oxazoloquinolinone scaffold (Vrijdag et al., 2013), we decided to turn our attention to the remarkable tricyclic product 6 isolated during the initial investigation. The ONO structural motif contained in compound 6 is brought into relation with both antibacterial (Ratcliffe et al., 2015) and histamine 4 receptor antagonist (Ho et al., 2013) activities. Hence, new synthetic routes towards ONOs are currently being developed in our laboratory (Vrijdag et al., 2017). Here we present the molecular and crystal structure of the title compound 6.

Structural commentary
Crystals of 6 belong to the orthorhombic space group Pna2 1 with one molecule in the asymmetric unit (Fig. 2) (5) Å ] situated in the same plane (deviations from plane given in parenthesis). The dihedral angle between the mean planes through the oxazole and pyridine rings is 2.0 (2) . The dihedral angle between the oxazolonaphthyridine ring system and the phenyl rings is 61.6 (2) . Both H atoms of C17 are in close contact with the neighboring atoms N8 and O15 (H17AÁ Á ÁN8 = 2.36 Å and H17BÁ Á ÁO15 = 2.36 Å ). No classical hydrogen bonds are observed.
Cg3 is the centroid of the C18-C23 ring.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. All H atoms were placed in calculated positions with C-H = 0.95 Å for aromatic, C-H = 0.98 Å for CH 3 or C-H = 0.99 Å for CH 2 H atoms, and included in the refinement in a riding model with U iso (H) = 1.2 or 1.5U eq (C).  (Enraf-Nonius, 1989); data reduction: DREAR (Blessing, 1987); program(s) used to solve structure: SHELXS (Sheldrick, 2008); program(s) used to refine structure: SHELXL2014/7 (Sheldrick, 2015); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009). Absolute structure: No quotients, so Flack parameter determined by classical intensity fit Absolute structure parameter: 0.000 (12) Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.