A comparison of the structures of some 2- and 3-substituted chromone derivatives: a structural study on the importance of the secondary carboxamide backbone for the inhibitory activity of MAO-B

The structures of 2- and 3-substituted tertiary carboxamides and analogous pyrrolidine structures are compared.

The crystal structures of the 3-substituted tertiary chromone carboxamide derivative, C 17 H 13 NO 3 , N-methyl-4-oxo-N-phenyl-4H-chromene-3-carboxamide (1), and the chromone carbonyl pyrrolidine derivatives, C 14 H 13 NO 3 , 3-(pyrrolidine-1-carbonyl)-4H-chromen-4-one (3) and 2-(pyrrolidine-1-carbonyl)-4H-chromen-4-one (4) have been determined. Their structural features are discussed and compared with similar compounds namely with respect to their MAO-B inhibitory activities. The chromone carboxamide presents a -syn conformation with the aromatic rings twisted with respect to each other [the dihedral angle between the mean planes of the chromone system and the exocyclic phenyl ring is 58.48 (8) ]. The pyrrolidine derivatives also display a significant twist: the dihedral angles between the chromone system and the best plane formed by the pyrrolidine atoms are 48.9 (2) and 23.97 (12) in (3) and (4), respectively. Compound (3) shows a short C-HÁ Á ÁO intramolecular contact forming an S(7) ring. The supramolecular structures for each compound are defined by weak C-HÁ Á ÁO hydrogen bonds, which link the molecules into chains and sheets. The Cambridge Structural Database gave 45 hits for compounds with a pyrrolidinecarbonyl group. A simple statistical analysis of their geometric parameters is made in order to compare them with those of the molecules determined in the present work.

Molecular Conformations
As mentioned above, the compounds discussed in this work are presented in the Scheme. Compounds (2), (5) and (6) have previously been characterized. The ellipsoid plots for the remaining structures, e.g. for (1), (3) and (4), are given in Figs. 1-3. The results of the biological tests show that only (5) Figure 1 A view of the asymmetric unit of (1) with the atom-numbering scheme. Displacement ellipsoids are drawn at the 70% probability level.

Figure 2
A view of the asymmetric unit of (3) with the atom-numbering scheme. Displacement ellipsoids are drawn at the 70% probability level.

Figure 3
A view of the asymmetric unit of (4) with the atom-numbering scheme. Displacement ellipsoids are drawn at the 70% probability level. exhibits significant IMAO-B activity. Its isomer (6) is much less active while the remaining ones are inactive towards MAO-B, suggesting that substitution on position number 3 of the chromone is required and it must be a secondary carboxamide. As will be discussed, the presence of a tertiary amide induces significant conformational changes to the compounds that can explain the lack of activity for those compounds.
Compound (1) is a phenyl chromone carboxamide similar to (5) where the amidic hydrogen atom has been replaced by a methyl substituent. Since the nitrogen atom of the amide tends to be planar due to the partial sp 2 hybridization of the C-N bond and, owing to the high rotational barrier around that bond, amides often exhibit -anti/-syn conformations with respect to the C-N rotamer. The inactive chromone carboxamides (1) and (2) present -syn conformations whereas chomone (5) (active) and (6) (inactive) are in the -anti form.
In (5) and (6) the aromatic rings are roughly co-planar [dihedral angles between the mean planes of the aromatic rings are 10.77 (4) (Cagide et al., 2015) and 6.57 (7) , respectively], while in compounds (1) and (2) the aromatic rings are twisted with respect to each other [dihedral angles between the mean planes of the chromone and the exocyclic phenyl rings are 58.48 (8) and 73.86 (5) , respectively]. The twisting is probably driven by the minimization of steric hindrance that would arise from the proximity of the rings.

Intramolecular C-HÁ Á ÁO bonding
There is no intramolecular hydrogen bonding in compounds (1) and (2). This contrasts with what occurs in (5) and (6) where, due to the presence of the imidic nitrogen atom, the molecules display N-HÁ Á ÁO intramolecular S(6) rings and, due to the -anti configuration, they present weak C arom -HÁ Á ÁO hydrogen bonds (the carbonyl group of the amide acting as acceptor for the ortho-carbon atom of the benzyl ring), resulting in second S(6) rings (Cagide et al., 2015;Reis et al., 2014). In (3) there is a short intramolecular contact C312-H312Á Á ÁO4 in which the pyrollidine carbon atom acts as a donor to the carbonyl oxygen atom, O4, of the chromone, forming an S(7) ring. The search of the CSD (Groom & Allen, 2014) described below found five molecules containing a pyrrolidine carbonyl moiety that exhibit similar intramolecular hydrogen bonding. In conclusion, apart from precluding the formation of an intramolecular N-HÁ Á ÁA bond, substitution of the amidic hydrogen atom by a methyl group in the carboxamide or the insertion of a carboxypyrrolidine unit in the chromone causes a large change in the conformational geometry of the molecules that prevents a link to the active site of the MAO-B enzyme.

Supramolecular features
Details of the hydrogen bonding are given in Tables 1, 2 and 3.

Figure 4
Compound (1): the chain of R 2 2 (8) rings running parallel to the a axis. Hydrogen atoms not involved in the hydrogen bonding are omitted. linked bystacking between the chromone rings [centroidcentroid distance = 3.557 (2) Å ].
In compound (4) there is a short contact between C214-H21C and O4(Àx + 1, Ày + 1 2 , z À 1 2 ). This forms a C(9) chain which runs along the c axis, propagated by the twofold screw axis at ( 1 2 , 1 4 , z), Fig. 12. There is also a short contact between C8-H8 and O2(x + 1 2 , Ày À 1 2 , z) but in this case the angle at H8 is 121 and so this interaction will be relatively weak. It forms a C(7) chain parallel to the a axis propagated by the glideplane at 1 4 along the b axis, Fig. 13. There are no C-HÁ Á Á orinteractions.

Database survey
A search of the Cambridge Structural Database (Groom & Allen, 2014) gave 45 hits for the pyrrolidinecarbonyl group for structures with R 0.10 (see supplementary data for the search fragment). The mean value for the C-O bond length was 1.235 (2) Å with a range of 1.209-1.282 Å . The values for (3) and (4) are 1.239 (4) and 1.230 (2) Å , respectively. The mean C-N bond length is 1.335 (2) Å with a range of 1.294-1.361Å . The values for (3) and (4) are 1.337 (4) and 1.340 (3) Å , respectively. The values for these compounds are close to the mean values in each case.
The torsion angles around the C(carbonyl) and N(pyrrolidine) bond involving the carbonyl O atom lie in ranges between À9.15 and 8.023 with a mean value of close to zero and between À161.33 and 166.71 with a mean value close to 180 for both the C atoms attached to the N atom within the pyrolidine group. The respective torsion angles for (3) [À0.5 (5) and 171.9 (3) ] and those for (4) [1.1 (3) and À175.3 (2) ] are well within the ranges specified above.

Synthesis and crystallization
N-methyl-4-oxo-N-phenyl-4H-chromene-3-carboxamide, (1) was synthesized in a low yield (10%) by a one-pot reaction using 4-oxo-4H-chromene-3-carboxylic acid as starting material. The activation of the carboxylic acid was obtained by the coupling reagent bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP) and the amide obtained by reacting the ester derivative with N-methylaniline. The crude product was purified by flash chromatography (ethyl acetate and ethyl acetate/ CH 2 Cl 2 in an 4:1 ratio). Crystals suitable for X-ray diffraction were obtained from ethyl acetate.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 4. H atoms were treated as riding atoms with C-H(aromatic) = 0.95 Å and C-H(CH 2 ) = 0.99 Å with U iso = 1.2U eq (C), and C-H(methyl) = 0.98Å with U iso = 1.5U eq (C). The methyl hydrogen atoms were generated in idealized positions and checked on a final difference map.
Acta Cryst. (2015). E71, 1270-1277 research communications Table 4 Experimental details. (1) ( 3)   where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.30 e Å −3 Δρ min = −0.24 e Å −3 Special details Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes. 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 R-factors(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.