Crystallographic and spectroscopic characterization of 2-[(7-acetyl-4-cyano-6-hydroxy-1,6-dimethyl-8-phenyl-5,6,7,8-tetrahydroisoquinolin-3-yl)sulfanyl]-N-phenylacetamide

The heterocyclic portion of the tetrahydroisoquinoline unit is planar and an intramolecular N—H⋯N hydrogen bond and a C—H⋯π(ring) interaction help to determine the overall conformation. In the crystal, O—H⋯O hydrogen bonds form inversion dimers, which are connected by C—H⋯O hydrogen bonds, forming layers parallel to (10).

In the title molecule, C 28 H 27 N 3 O 3 S, the heterocyclic portion of the tetrahydroisoquinoline unit is planar and an intramolecular N-HÁ Á ÁN hydrogen bond and a C-HÁ Á Á(ring) interaction help to determine the overall conformation. In the crystal, a layer structure with the layers parallel to (101) is generated by O-HÁ Á ÁO and C-HÁ Á ÁO hydrogen bonds.

Chemical context
Tetrahydroisoquinolines exhibit important pharmacological activities including antitumor (Scott & Williams, 2002), antimicrobial (Bernan et al., 1994), and dopaminergic activities (Andujar et al., 2012). They are used as starting materials in the syntheses of pharmacologically active, constrained conformations of N-substituted-2-aminopyridines as antinociceptive agents (Dukat et al., 2004) and constrained conformations of nicotine to improve nicotine vaccines (Xu et al., 2002;Meijler et al., 2003;Carroll et al., 2007). These examples demonstrate the utility of the tetrahydroisoquinoline core and why these types of compounds are of great interest. In this context, we report here the synthesis and crystal structure of the title compound. ISSN 2056-9890

Structural commentary
The title compound crystallizes in space group P2 1 /n with one molecule in the asymmetric unit (Fig. 1). The C5/C6/C7/N1/ C8/C9 ring is approximately planar (r.m.s. deviation = 0.011 Å ) with the largest deviation of 0.020 (1) Å being for atom C6. The best planes through the C10-C15 and C23-C28 rings are inclined to the above plane by 85.19 (6) and 64.22 (7) , respectively. The orientation of the former ring is due in part to the C20-H20AÁ Á ÁCg3 (Cg3 is the centroid of the C10-C15 benzene ring) interaction while the intramolecular N3-H3AÁ Á ÁN1 hydrogen bond affects the orien-tation of the second ring (Table 1 and Fig. 1) and places the two rings on the same side of the tetrahydroquinoxaline unit. The acetyl group on C2 is in an equatorial position while the hydroxyl group on C3 is axial and these are syn to one another. The C10-C15 ring attached to C1 is close to equatorial and anti with respect to both other subsituents (Fig. 1). Although the O2-H2A hydroxyl group is favorably oriented for forming an intramolecular hydrogen bond with O1 as has been seen in some related molecules (Mague & Mohamed, 2020), the HÁ Á ÁO distance of ca 2.54 Å is long and a stronger, intermolecular interaction is favored (vide infra). A puckering analysis (Cremer & Pople, 1975) of the C1-C5/C9 ring yielded the following parameters: Q = 0.5267 (13) Å , = 128.52 (14) and ' = 286.46 (18) . The conformation of this ring approximates an envelope with C3 as the flap.

Figure 2
Packing viewed along the a-axis direction with intermolecular O-HÁ Á ÁO and C-HÁ Á ÁO hydrogen bonds depicted, respectively, by red and black dashed lines.

Figure 3
Packing viewed along the b-axis direction with intermolecular O-HÁ Á ÁO and C-HÁ Á ÁO hydrogen bonds depicted, respectively, by red and black dashed lines.

Figure 1
The title molecule with labeling scheme and 50% probability ellipsoids. The intramolecular hydrogen bond and C-HÁ Á Á(ring) interaction are depicted, respectively, by blue and green dashed lines.

Database survey
A search of the Cambridge Structural Database (CSD, updated to December 2020, Groom et al., 2016) found three analogs of the title molecule, one with a methyl group on sulfur (refcode AXUXOH; Dyachenko et al., 2010) and two with a 4-chlorophenyl group on C1 in place of the phenyl group, one with an ethyl group on sulfur (NAQRIJ; Mague et al., 2017a) and the other with a CH 2 CO 2 CH 3 group on sulfur (PAWCEY; Mague et al., 2017b). In all three, the acetyl group is equatorial and the hydroxyl group is axial while the phenyl or 4-chlorophenyl group is close to equatorial, as is the case with the title molecule. The puckering amplitudes of the cyclohexene ring in the second and third molecule are, respectively, 0.521 (2) and 0.524 (3) Å , which are essentially the same as in the title molecule. One notable difference between the four molecules is the orientation of the hydroxyl hydrogen. In AXUXOH there is an intramolecular hydrogen bond with the acetyl group leading to an HÁ Á ÁO distance of 2.23 Å . In the other three, intermolecular hydrogen bonding of the hydroxyl group predominates and the intramolecular HÁ Á ÁO distances are 2.55, 2.71 and 3.18 Å for the title molecule, PAWCEY and NAQRIJ, respectively.

Hirshfeld surface analysis
Hirshfeld surface analysis is an effective means of probing intermolecular interactions (McKinnon et al., 2007;Spackman & Jayatilaka, 2009), which can be conveniently carried out with Crystal Explorer 17 (Turner et al., 2017). A detailed description of the use of Crystal Explorer 17 and the plots obtained is given by Tan et al. (2019). From the surface mapped over d norm (Fig. 4a), the sites of the intermolecular O-HÁ Á ÁO and C-HÁ Á ÁO hydrogen bonds can be seen on the left side near the bottom and at the top, respectively. A weaker point of interaction is at O3 on the lower right of the diagram, which might indicate a weak, intermolecular C4-H4BÁ Á ÁO3 hydrogen bond since the OÁ Á ÁH distance is 2.605 (15) Å . The surfaces mapped over shape-index ( Fig. 4b) and curvedness (Fig. 5c) show a relatively flat region over the C23-C28 benzene ring in the latter and a red triangular area over the edge of the ring in the former. This is suggestive of a C-HÁ Á Á(ring) interaction and can be identified with the C20-H20AÁ Á ÁCg3 interaction noted in Section 2. The fingerprint plots derived from the Hirshfeld surface enable the apportionment of the intermolecular interactions into specific sets. The Hirshfeld surface of the title molecule mapped over (a) d norm , (b) shape-index, and (c) curvedness.

Spectroscopic characterization
The chemical structure of the compound has also been confirmed using analytical and spectroscopic methods. The FT-IR spectrum shows mainly the characteristic NH peak of the acetamide group at 3277 cm À1 and the C O bond of the amide group at 1667 cm À1 . In addition, characteristic peaks of the precursor are observed: OH at 3522 cm À1 , aromatic C-H at 3058 cm À1 , aliphatic C-H at 2920, 2970, 2991 cm À1 , nitrile at 2217 cm À1 and acetyl at 1694 cm À1 , also confirming the structure of the compound. With regard to the 1 H NMR spectrum, several characteristic signals can be clearly attributed to the title compound, such as a doublet of doublets between 4.09 and 4.19 ppm with a coupling constant of 16 Hz due to SCH 2 , and a singlet at 10.22 ppm due to NH. In addition, we note the presence of char-acteristic peaks related to the starting compound: multiplets between 7.17 and 7.29 ppm due to aromatic protons, singlets at 1.28, 1.92, 2.11 and 4.84 ppm referring to a methyl group attached to a pyridine ring, the CH 3 of the acetamide group and the hydroxy group, respectively. The doublets between 7.53-7.55 (J = 8 Hz) and 7.02-7.04 (J = 8 Hz) can be attributed to the aromatic protons.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. All hydrogen atoms were independently refined. Twelve reflections were not accessible due to the configuration of the goniometer and the low-temperature attachment.

Funding information
The support of NSF-MRI grant No. 1228232 for the purchase of the diffractometer and Tulane University for support of the Tulane Crystallography Laboratory are gratefully acknowledged.    (2) 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. 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 > 2sigma(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.