Crystal structure and Hirshfeld surface analysis of 2-{[7-acetyl-4-cyano-6-hy­droxy-8-(4-meth­oxyphen­yl)-1,6-dimethyl-5,6,7,8-tetra­hydro­isoquinolin-3-yl­]sulfan­yl}acetic acid ethyl ester

Al-Taifi, E.A.; Marae, I.S.; El-Ossaily, Y.A.; Mohamed, S.K.; Mague, J.T.; Akkurt, M.; Bakhite, E.A.

doi:10.1107/S2056989022000378

research communications

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ISSN: 2056-9890

Volume 78| Part 2| February 2022| Pages 220-224

https://doi.org/10.1107/S2056989022000378

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Crystal structure and Hirshfeld surface analysis of 2-{[7-acetyl-4-cyano-6-hydroxy-8-(4-methoxyphenyl)-1,6-dimethyl-5,6,7,8-tetrahydroisoquinolin-3-yl]sulfanyl}acetic acid ethyl ester

Elham A. Al-Taifi,^a ^* Islam S. Marae,^b Yasser A. El-Ossaily,^c Shaaban K. Mohamed,^d,^e ^* Joel T. Mague,^f Mehmet Akkurt ^g and Etify A. Bakhite ^b

^aChemistry Department, Faculty of Science, Sana'a University, Sana'a, Yemen, ^bChemistry Department, Faculty of Science, Assiut University, 71516 Assiut, Egypt, ^cChemistry Department, College of Science, Jouf University, PO Box 2014.Sakaka, Saudi Arabia, ^dChemistry and Environmental Division, Manchester Metropolitan University, Manchester, M1 5GD, England, ^eChemistry Department, Faculty of Science, Minia University, 61519 El-Minia, Egypt, ^fDepartment of Chemistry, Tulane University, New Orleans, LA 70118, USA, and ^gDepartment of Physics, Faculty of Sciences, Erciyes University, 38039 Kayseri, Turkey
^*Correspondence e-mail: elhamaltaifi@gmail.com, shaabankamel@yahoo.com

Edited by L. Van Meervelt, Katholieke Universiteit Leuven, Belgium (Received 3 January 2022; accepted 11 January 2022; online 25 January 2022)

In the title molecule, C₂₅H₂₈N₂O₅S, (alternative name ethyl 2-{[7-acetyl-4-cyano-6-hydroxy-8-(4-methoxyphenyl)-1,6-dimethyl-5,6,7,8-tetrahydroisoquinolin-3-yl]sulfanyl}acetate) the 4-methoxyphenyl group is disposed on one side of the bicyclic core and the oxygen atoms of the hydroxyl and acetyl groups are disposed on the other side. In the crystal, a layered structure parallel to the ac plane is generated by O—H⋯O and C—H⋯O hydrogen bonds plus C—H⋯π(ring) interactions.

Keywords: crystal structure; tetrahydroisoquinoline; ethyl ester; hydrogen bond; C—H⋯π(ring).

CCDC reference: 2141278

1. Chemical context

Some tetrahydroisoquinoline (THISQ) based compounds are of medicinal and biological importance, being used as antitumoral (Pingaew et al., 2014 ; Castillo et al., 2018 ), antifungal (Scott et al., 2002 ) and anti-inflammatory agents (Siegfried et al., 1989 ). Other tetrahydroisoquinolines were used as inhibitors including B-raf^V600E or p38 kinase inhibitors (Lu et al., 2016 ; Rosales et al., 2007 ). The THISQ core can easily be functionalized to build other heterocyclic rings on the carbocyclic ring (Xu et al., 2002 ; Carroll et al., 2007 ; Demers et al., 2008 , Marae et al., 2021a ). Recently, we have used some compounds related to THISQ as durable fluorescent dyes for cotton (Marae et al., 2021b ). The widespread importance of these compounds motivated us to further study the THISQ core. Here we report the synthesis and crystal structure determination of the title compound.

2. Structural commentary

The ethyl sulfanylacetate, acetyl and cyano groups and both methyl groups (C19 and C21) are in equatorial positions with respect to the bicyclic core, while the hydroxyl and anisole groups on the cyclohexane ring occupy an axial and bisectional position, respectively (Fig. 1). The C10–C15 benzene ring is inclined to the N1/C5–C9 pyridine ring by 82.57 (6)°. The C1–C5/C9 cyclohexane ring is in an envelope conformation, with atom C3 at the flap position [deviation from best plane = 0.367 (1) Å] and puckering parameters (Cremer & Pople, 1975 ) Q_T = 0.5180 (12) Å, θ = 53.85 (13)° and φ = 109.07 (17)°.

Figure 1
The title molecule with labelling scheme and 50% probability ellipsoids.

3. Supramolecular features

In the crystal of the title compound, chains of molecules extending along the a-axis direction are formed by O3—H3⋯O1 and C16—H16C⋯O2 hydrogen bonds (Table 1 and Fig. 2). These are connected into layers parallel to the ac plane by C21—H21A⋯O2, C22—H22A⋯O3 and C24—H24B⋯O4 hydrogen bonds as well as C22—H22B⋯Cg1 interactions (Table 1 and Fig. 3).

Table 1
Hydrogen-bond geometry (Å, °)

Cg1 is the centroid of the N1/C5–C9 pyridine ring.

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O3—H3⋯O1ⁱ	0.90 (2)	2.05 (2)	2.9283 (12)	164 (2)
C16—H16C⋯O2ⁱⁱ	0.98	2.47	3.1566 (15)	127
C21—H21A⋯O2ⁱⁱⁱ	0.98	2.51	3.3956 (15)	150
C22—H22A⋯O3^iv	0.99	2.44	3.1815 (15)	131
C22—H22B⋯Cg1^iv	0.99	2.58	3.4559 (15)	147
C24—H24B⋯O4^v	0.99	2.52	3.442 (2)	154
Symmetry codes: (i) x+1, y, z; (ii) ; (iii) ; (iv) ; (v) .

Figure 2
A portion of one chain viewed along the b-axis direction. O—H⋯O and C—H⋯O hydrogen bonds are depicted by red and black dashed lines, respectively.

Figure 3
Packing viewed along the c-axis direction giving an elevation view of one layer. Hydrogen bonds are depicted as in Fig. 2

while C—H⋯π(ring) interactions are indicated by green dashed lines.

4. Hirshfeld surface analysis

Hirshfeld surface analysis (Spackman & Jayatilaka, 2009 ) was carried out using CrystalExplorer17.5 (Turner et al., 2017 ). The Hirshfeld surface and their associated two-dimensional fingerprint plots were used to quantify the various intermolecular interactions in the title compound. In the Hirshfeld surface plotted over d_norm in the range −0.4903 (red) to +1.6396 (blue) a.u. (Fig. 4), the white areas indicate contacts with distances equal to the sum of van der Waals radii, and the red and blue areas indicate distances shorter (in close contact) or longer (distinct contact) than the van der Waals radii, respectively (Venkatesan et al., 2016 ). The bright-red spots indicate their roles as the respective donors and/or acceptors.

Figure 4
(a) Front and (b) back sides of the three-dimensional Hirshfeld surface of the title compound mapped over d_norm, with a fixed colour scale of −0.4903 (red) to +1.6396 (blue) a.u.

Fingerprint plots (Fig. 5b–e; Table 2) reveal that H⋯H (47.6%), O⋯H/H⋯O (19.7%), C⋯H/H⋯C (12.5%) and N⋯H/H⋯N (11.6%) interactions make the greatest contributions to the surface contacts. S⋯H/H⋯S (6.4%), N⋯C/C⋯N (0.7%), O⋯C/C⋯O (0.5%), O⋯O (0.5%) and C⋯C (0.4%) contacts also contribute to the overall crystal packing of the title compound. The Hirshfeld surface analysis confirms the importance of H-atom contacts in establishing the packing. The large number of H⋯H, O⋯H, C⋯H and N⋯H interactions suggest that van der Waals interactions and hydrogen bonding play the major roles in the crystal packing (Hathwar et al., 2015 ).

Table 2
Summary of short interatomic contacts (Å) in the title compound

Contact	Distance	Symmetry operation
O1⋯H3	2.051 (16)	−1 + x, y, z
H21A⋯O2	2.51	1 − x, 1 − y, −z
H22A⋯O3	2.44	1 − x, 1 − y, 1 − z
O4⋯H16A	2.60	x, y, 1 + z
H24B⋯H24B	2.44	−x, 1 − y, 1 − z
H11⋯N2	2.61	1 − x, − y, 1 − z
H18B⋯H2	2.49	1 − x, − y, −z
H21C⋯H16B	2.51	−x, 1 − y, −z
H25B⋯H25B	2.34	−x, 2 − y, 1 − z

Figure 5
Two-dimensional fingerprint plots for the title compound, showing (a) all interactions, and delineated into (b) H⋯H, (c) O⋯H/H⋯O, (d) C⋯H/H⋯C and (e) N⋯H/H⋯N interactions. The d_i and d_e values are the closest internal and external distances (in Å) from given points on the Hirshfeld surface.

5. Database survey

A search of the Cambridge Structural Database (CSD version 5.42, updated September 2021; Groom et al., 2016 ) for tetrahydroisoquinoline derivatives gave nine compounds very similar to the title compound. In the crystal of NAQRIJ (Mague et al., 2017 ), dimers form through complementary sets of inversion-related O—H⋯O and C—H⋯O hydrogen bonds. These are connected into zigzag chains along the c-axis direction by pairwise C—H⋯N interactions that also form inversion dimers. In KUGLIK (Langenohl et al., 2020 ), the heterocyclic amines are alternately connected to the hydrogen-bonding system along the c axis, which leads to the formation of syndiotactic polymer chains in this direction. In the crystal of DUSVIZ (Selvaraj et al., 2020 ), molecules are linked via C—H⋯O hydrogen bonds. In AKIVUO (Al-Taifi et al., 2021 ), a layered structure with layers parallel to (10 $[\overline{1}]$ ) is generated by O—H⋯O and C—H⋯O hydrogen bonds. In ULUTAZ (Naghiyev et al., 2021 ), molecules are linked via N—H⋯O and C—H⋯N hydrogen bonds, forming a three-dimensional network, and the crystal packing is dominated by C—H⋯π bonds. In CARCOQ (Lehmann et al., 2017 ), molecules are linked by O—H⋯O hydrogen bonds, forming chains propagating along the a-axis direction. The chains are linked by C—H⋯F hydrogen bonds, forming layers lying parallel to the ab plane. In POPYEB (Ben Ali et al., 2019 ), molecules are packed in a herringbone manner parallel to (103) and (10 $[\overline{3}]$ ) via weak C—H⋯O and C—H⋯π(ring) interactions. In ENOCIU (Naicker et al., 2011 ) various C—H⋯π and C—H⋯O bonds link the molecules together. In NIWPAL (Bouasla et al., 2008 ), the molecules are linked by N—H⋯O intermolecular hydrogen bonds involving the sulfonamide function to form an infinite two-dimensional network parallel to the (001) plane.

6. Synthesis and crystallization

7-Acetyl-4-cyano-1,6-dimethyl-6-hydroxy-8-(4-methoxyphenyl)-5,6,7,8-tetrahydro-isoquinoline-3(2H)-thione (5 mmol, 1.91 g) and sodium acetate trihydrate (1.36 g, 10 mmol) were suspended in 50 ml of absolute ethanol, then 0.55 ml of ethyl chloroacetate (5.3 mmol) were added and the mixture was refluxed for one h. During reflux, the yellow colour disappeared gradually over time to afford a colourless reaction mixture. The reaction mixture was then left to cool at room temperature and the formed precipitate was collected by fiitration, washed with water, dried in air and recystallized from ethanol to give the title compound as cubic crystals, yield 2.11 g (94%); m.p. 453–455 K. IR (cm⁻¹): 3454 (O—H); 3048 (C—H aromatic); 2970, 2913 (C—H aliphatic); 2215 (C≡N); 1743 (C=O, ester); 1697 (C=O, acetyl). ¹H NMR (CDCl₃, 400 MHz) δ: 6.80–6.86 (dd, J = 8 Hz, 4H, ArH), 4.24–4.26 (d, J = 8 Hz, 1H, C⁸H), 4.12–4.15 (q, J = 6 Hz, 2H, OCH₂), 3.89–3.92 (dd, 2H, SCH₂), 3.78 (s, 3H, OCH₃), 3.38 (s, 1H, OH), 3.09–3.12 (d, J = 12 Hz, 1H, C⁵H), 3.03–3.05 (d, J = 8 Hz, 1H, C⁷H), 2.89–2.92 (d, J = 12 Hz, 1H, C⁵H), 1. 90 (s, 3H, CH₃ at C-1), 1.80 (s, 3H, COCH₃), 1.34 (s, 3H, CH₃ at C-6), 1.18–1.21 (t, J = 6 Hz, 3H, CH₃ of ester group).

7. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 3. All C-bound H atoms were placed in geometrically idealized positions (C—H = 0.95–1.00 Å) while the hydrogen atom attached to O3 was found from a difference map, and was subsequently refined isotropically [O3—H3 = 0.903 (17) Å] with U_iso(H) = 1.5U_eq(O). All C-bound H atoms were included as riding contributions with isotropic displacement parameters 1.2 times those of the parent atoms (1.5 for methyl groups).

Table 3
Experimental details

Crystal data
Chemical formula	C₂₅H₂₈N₂O₅S
M_r	468.55
Crystal system, space group	Triclinic, P $[\overline{1}]$
Temperature (K)	150
a, b, c (Å)	10.0643 (6), 10.3592 (7), 12.0685 (8)
α, β, γ (°)	83.296 (1), 80.770 (1), 75.638 (1)
V (Å³)	1199.23 (13)
Z	2
Radiation type	Mo Kα
μ (mm⁻¹)	0.17
Crystal size (mm)	0.35 × 0.29 × 0.27

Data collection
Diffractometer	Bruker SMART APEX CCD
Absorption correction	Multi-scan (SADABS; Krause et al., 2015 )
T_min, T_max	0.82, 0.96
No. of measured, independent and observed [I > 2σ(I)] reflections	22695, 6509, 5177
R_int	0.023
(sin θ/λ)_max (Å⁻¹)	0.695

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.045, 0.133, 1.11
No. of reflections	6509
No. of parameters	305
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.71, −0.22
Computer programs: APEX3 and SAINT (Bruker, 2016 ), SHELXT2014/5 (Sheldrick, 2015a ), SHELXL2018/3 (Sheldrick, 2015b ), DIAMOND (Brandenburg & Putz, 2012 ) and SHELXTL (Sheldrick, 2008 ).

Supporting information

CCDC reference: 2141278

Crystal structure: contains datablocks I, global. DOI: https://doi.org/10.1107/S2056989022000378/vm2259sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989022000378/vm2259Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989022000378/vm2259Isup3.cml

checkCIF report

Computing details top

Data collection: APEX3 (Bruker, 2016); cell refinement: SAINT (Bruker, 2016); data reduction: SAINT (Bruker, 2016); program(s) used to solve structure: SHELXT2014/5 (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2018/3 (Sheldrick, 2015b); molecular graphics: DIAMOND (Brandenburg & Putz, 2012); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).

Ethyl 2-{[7-acetyl-4-cyano-6-hydroxy-8-(4-methoxyphenyl)-1,6-dimethyl-5,6,7,8-tetrahydroisoquinolin-3-yl]sulfanyl}acetate top

Crystal data top

C₂₅H₂₈N₂O₅S	Z = 2
M_r = 468.55	F(000) = 496
Triclinic, P1	D_x = 1.298 Mg m⁻³
a = 10.0643 (6) Å	Mo Kα radiation, λ = 0.71073 Å
b = 10.3592 (7) Å	Cell parameters from 9995 reflections
c = 12.0685 (8) Å	θ = 2.5–29.5°
α = 83.296 (1)°	µ = 0.17 mm⁻¹
β = 80.770 (1)°	T = 150 K
γ = 75.638 (1)°	Block, colourless
V = 1199.23 (13) Å³	0.35 × 0.29 × 0.27 mm

Data collection top

Bruker SMART APEX CCD diffractometer	6509 independent reflections
Radiation source: fine-focus sealed tube	5177 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.023
Detector resolution: 8.3333 pixels mm^-1	θ_max = 29.6°, θ_min = 1.7°
φ and ω scans	h = −13→13
Absorption correction: multi-scan (SADABS; Krause et al., 2015)	k = −14→14
T_min = 0.82, T_max = 0.96	l = −16→16
22695 measured reflections

Refinement top

Refinement on F²	Primary atom site location: dual
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.045	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.133	H atoms treated by a mixture of independent and constrained refinement
S = 1.11	w = 1/[σ²(F_o²) + (0.0848P)² + 0.0389P] where P = (F_o² + 2F_c²)/3
6509 reflections	(Δ/σ)_max < 0.001
305 parameters	Δρ_max = 0.71 e Å⁻³
0 restraints	Δρ_min = −0.22 e Å⁻³

Special details top

Experimental. The diffraction data were obtained from 3 sets of 400 frames, each of width 0.5° in ω, colllected at φ = 0.00, 90.00 and 180.00° and 2 sets of 800 frames, each of width 0.45° in φ, collected at ω = –30.00 and 210.00°. The scan time was 10 sec/frame.

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 F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > 2sigma(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger. H-atoms attached to carbon were placed in calculated positions (C—H = 0.95 - 1.00 Å) while that attached to oxygen was placed in a location derived from a difference map and its coordinates adjusted to give O—H = 0.87 %A. All were included as riding contributions with isotropic displacement parameters 1.2 - 1.5 times those of the attached atoms.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
S1	0.40179 (4)	0.33194 (3)	0.67126 (2)	0.02919 (11)
O1	−0.01601 (8)	0.26808 (9)	−0.00282 (7)	0.0261 (2)
O2	0.65454 (10)	0.31103 (10)	−0.03628 (7)	0.0325 (2)
O3	0.76674 (8)	0.24179 (8)	0.18545 (7)	0.02199 (18)
H3	0.8202 (16)	0.2524 (10)	0.1190 (13)	0.033*
O4	0.08897 (11)	0.46076 (12)	0.66388 (9)	0.0455 (3)
O5	0.13749 (11)	0.65264 (10)	0.58156 (8)	0.0357 (2)
N1	0.35085 (10)	0.41231 (10)	0.46279 (8)	0.0208 (2)
N2	0.67128 (14)	0.03469 (14)	0.60676 (11)	0.0424 (3)
C1	0.46954 (11)	0.29768 (11)	0.16884 (9)	0.0159 (2)
H1	0.500590	0.379658	0.134272	0.019*
C2	0.57706 (11)	0.17513 (11)	0.12120 (9)	0.0173 (2)
H2	0.531350	0.098468	0.129582	0.021*
C3	0.70498 (11)	0.13262 (11)	0.18391 (9)	0.0193 (2)
C4	0.65493 (12)	0.09343 (12)	0.30675 (10)	0.0223 (2)
H4A	0.620266	0.011333	0.310543	0.027*
H4B	0.734138	0.072924	0.350225	0.027*
C5	0.54209 (11)	0.20148 (11)	0.35998 (9)	0.0179 (2)
C6	0.52467 (11)	0.20985 (12)	0.47729 (9)	0.0199 (2)
C7	0.42631 (12)	0.31658 (12)	0.52466 (9)	0.0205 (2)
C8	0.36570 (11)	0.40524 (11)	0.35083 (9)	0.0177 (2)
C9	0.45724 (11)	0.29873 (11)	0.29599 (9)	0.0166 (2)
C10	0.33305 (11)	0.30117 (11)	0.12715 (9)	0.0176 (2)
C11	0.24375 (12)	0.22431 (12)	0.18378 (9)	0.0206 (2)
H11	0.263234	0.176107	0.253526	0.025*
C12	0.12671 (12)	0.21705 (12)	0.13990 (10)	0.0227 (2)
H12	0.065702	0.165748	0.180301	0.027*
C13	0.09882 (11)	0.28515 (12)	0.03646 (9)	0.0200 (2)
C14	0.18526 (12)	0.36397 (12)	−0.02017 (9)	0.0225 (2)
H14	0.165733	0.412138	−0.089914	0.027*
C15	0.30109 (12)	0.37198 (12)	0.02605 (9)	0.0212 (2)
H15	0.359409	0.427055	−0.012431	0.025*
C16	−0.03346 (13)	0.32073 (14)	−0.11635 (10)	0.0267 (3)
H16A	0.052176	0.288044	−0.166573	0.040*
H16B	−0.054905	0.418620	−0.120457	0.040*
H16C	−0.109566	0.291484	−0.139534	0.040*
C17	0.61828 (12)	0.20825 (12)	−0.00420 (10)	0.0227 (2)
C18	0.60948 (18)	0.11357 (16)	−0.08583 (12)	0.0404 (4)
H18A	0.654485	0.138974	−0.160555	0.061*
H18B	0.512060	0.117187	−0.089559	0.061*
H18C	0.656149	0.022519	−0.060849	0.061*
C19	0.81182 (13)	0.01430 (13)	0.13312 (11)	0.0280 (3)
H19A	0.849094	0.041750	0.056329	0.042*
H19B	0.767456	−0.059489	0.131300	0.042*
H19C	0.887278	−0.015108	0.179227	0.042*
C20	0.60828 (13)	0.11221 (13)	0.54794 (10)	0.0258 (3)
C21	0.27853 (12)	0.52205 (12)	0.29046 (10)	0.0236 (2)
H21A	0.327912	0.540938	0.215809	0.035*
H21B	0.259623	0.600477	0.333793	0.035*
H21C	0.190956	0.501257	0.282226	0.035*
C22	0.31143 (14)	0.50489 (13)	0.67068 (10)	0.0286 (3)
H22A	0.305095	0.534976	0.746654	0.034*
H22B	0.366449	0.558138	0.617296	0.034*
C23	0.16744 (14)	0.53363 (14)	0.63858 (10)	0.0303 (3)
C24	0.00183 (17)	0.68891 (18)	0.54348 (14)	0.0490 (4)
H24A	−0.072036	0.696185	0.608938	0.059*
H24B	−0.007797	0.619864	0.497063	0.059*
C25	−0.0099 (3)	0.8197 (2)	0.4757 (3)	0.0934 (9)
H25A	0.062343	0.810824	0.410224	0.140*
H25B	0.001445	0.886882	0.522048	0.140*
H25C	−0.101112	0.847711	0.450117	0.140*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
S1	0.0375 (2)	0.03615 (19)	0.01391 (15)	−0.00874 (14)	−0.00410 (13)	−0.00088 (12)
O1	0.0185 (4)	0.0418 (5)	0.0196 (4)	−0.0100 (4)	−0.0083 (3)	0.0052 (4)
O2	0.0360 (5)	0.0411 (6)	0.0226 (5)	−0.0181 (4)	0.0007 (4)	0.0018 (4)
O3	0.0192 (4)	0.0271 (4)	0.0219 (4)	−0.0090 (3)	−0.0012 (3)	−0.0056 (3)
O4	0.0337 (6)	0.0612 (7)	0.0426 (6)	−0.0229 (5)	−0.0002 (5)	0.0106 (5)
O5	0.0392 (5)	0.0333 (5)	0.0325 (5)	−0.0047 (4)	−0.0021 (4)	−0.0057 (4)
N1	0.0213 (5)	0.0254 (5)	0.0155 (4)	−0.0052 (4)	−0.0023 (4)	−0.0012 (4)
N2	0.0461 (7)	0.0444 (7)	0.0312 (6)	−0.0021 (6)	−0.0128 (6)	0.0117 (5)
C1	0.0158 (5)	0.0182 (5)	0.0142 (5)	−0.0049 (4)	−0.0033 (4)	0.0001 (4)
C2	0.0163 (5)	0.0195 (5)	0.0168 (5)	−0.0050 (4)	−0.0017 (4)	−0.0027 (4)
C3	0.0171 (5)	0.0204 (5)	0.0206 (5)	−0.0041 (4)	−0.0022 (4)	−0.0033 (4)
C4	0.0207 (5)	0.0217 (6)	0.0214 (6)	−0.0006 (4)	−0.0038 (4)	0.0020 (4)
C5	0.0174 (5)	0.0193 (5)	0.0177 (5)	−0.0061 (4)	−0.0037 (4)	0.0013 (4)
C6	0.0188 (5)	0.0237 (6)	0.0171 (5)	−0.0059 (4)	−0.0049 (4)	0.0034 (4)
C7	0.0230 (5)	0.0254 (6)	0.0145 (5)	−0.0091 (5)	−0.0029 (4)	0.0008 (4)
C8	0.0158 (5)	0.0223 (5)	0.0154 (5)	−0.0053 (4)	−0.0023 (4)	−0.0012 (4)
C9	0.0154 (5)	0.0203 (5)	0.0153 (5)	−0.0064 (4)	−0.0030 (4)	−0.0002 (4)
C10	0.0168 (5)	0.0206 (5)	0.0151 (5)	−0.0031 (4)	−0.0032 (4)	−0.0018 (4)
C11	0.0194 (5)	0.0267 (6)	0.0156 (5)	−0.0060 (4)	−0.0050 (4)	0.0033 (4)
C12	0.0183 (5)	0.0314 (6)	0.0193 (5)	−0.0099 (5)	−0.0038 (4)	0.0048 (5)
C13	0.0152 (5)	0.0271 (6)	0.0175 (5)	−0.0030 (4)	−0.0040 (4)	−0.0020 (4)
C14	0.0216 (5)	0.0291 (6)	0.0157 (5)	−0.0045 (5)	−0.0054 (4)	0.0031 (4)
C15	0.0218 (5)	0.0250 (6)	0.0175 (5)	−0.0086 (4)	−0.0036 (4)	0.0034 (4)
C16	0.0222 (6)	0.0387 (7)	0.0197 (6)	−0.0058 (5)	−0.0095 (5)	0.0020 (5)
C17	0.0189 (5)	0.0308 (6)	0.0182 (5)	−0.0050 (5)	−0.0016 (4)	−0.0040 (5)
C18	0.0571 (10)	0.0423 (8)	0.0242 (7)	−0.0115 (7)	−0.0059 (6)	−0.0121 (6)
C19	0.0229 (6)	0.0268 (6)	0.0309 (7)	0.0021 (5)	−0.0023 (5)	−0.0085 (5)
C20	0.0283 (6)	0.0292 (6)	0.0191 (6)	−0.0073 (5)	−0.0042 (5)	0.0043 (5)
C21	0.0238 (6)	0.0243 (6)	0.0194 (5)	0.0011 (5)	−0.0040 (5)	−0.0011 (4)
C22	0.0335 (7)	0.0344 (7)	0.0209 (6)	−0.0127 (5)	−0.0005 (5)	−0.0081 (5)
C23	0.0315 (7)	0.0387 (7)	0.0197 (6)	−0.0099 (6)	0.0045 (5)	−0.0059 (5)
C24	0.0383 (8)	0.0555 (10)	0.0449 (9)	0.0022 (7)	−0.0026 (7)	−0.0031 (8)
C25	0.0751 (16)	0.0498 (12)	0.139 (3)	0.0112 (11)	−0.0281 (16)	0.0228 (14)

Geometric parameters (Å, º) top

S1—C7	1.7672 (11)	C10—C11	1.3927 (15)
S1—C22	1.7966 (14)	C11—C12	1.3882 (16)
O1—C13	1.3742 (14)	C11—H11	0.9500
O1—C16	1.4355 (14)	C12—C13	1.3940 (15)
O2—C17	1.2116 (15)	C12—H12	0.9500
O3—C3	1.4223 (14)	C13—C14	1.3863 (16)
O3—H3	0.903 (17)	C14—C15	1.3944 (16)
O4—C23	1.2046 (17)	C14—H14	0.9500
O5—C23	1.3298 (17)	C15—H15	0.9500
O5—C24	1.457 (2)	C16—H16A	0.9800
N1—C7	1.3240 (15)	C16—H16B	0.9800
N1—C8	1.3439 (14)	C16—H16C	0.9800
N2—C20	1.1443 (17)	C17—C18	1.4956 (18)
C1—C9	1.5206 (14)	C18—H18A	0.9800
C1—C10	1.5278 (15)	C18—H18B	0.9800
C1—C2	1.5501 (15)	C18—H18C	0.9800
C1—H1	1.0000	C19—H19A	0.9800
C2—C17	1.5258 (15)	C19—H19B	0.9800
C2—C3	1.5421 (15)	C19—H19C	0.9800
C2—H2	1.0000	C21—H21A	0.9800
C3—C4	1.5290 (16)	C21—H21B	0.9800
C3—C19	1.5311 (15)	C21—H21C	0.9800
C4—C5	1.5028 (16)	C22—C23	1.5093 (19)
C4—H4A	0.9900	C22—H22A	0.9900
C4—H4B	0.9900	C22—H22B	0.9900
C5—C9	1.3941 (15)	C24—C25	1.488 (3)
C5—C6	1.4087 (15)	C24—H24A	0.9900
C6—C7	1.3972 (16)	C24—H24B	0.9900
C6—C20	1.4369 (16)	C25—H25A	0.9800
C8—C9	1.4053 (15)	C25—H25B	0.9800
C8—C21	1.4957 (15)	C25—H25C	0.9800
C10—C15	1.3893 (15)

C7—S1—C22	98.39 (6)	C13—C14—C15	119.48 (10)
C13—O1—C16	116.26 (9)	C13—C14—H14	120.3
C3—O3—H3	109.5	C15—C14—H14	120.3
C23—O5—C24	115.10 (12)	C10—C15—C14	121.43 (11)
C7—N1—C8	119.27 (10)	C10—C15—H15	119.3
C9—C1—C10	113.57 (9)	C14—C15—H15	119.3
C9—C1—C2	113.46 (9)	O1—C16—H16A	109.5
C10—C1—C2	106.92 (8)	O1—C16—H16B	109.5
C9—C1—H1	107.5	H16A—C16—H16B	109.5
C10—C1—H1	107.5	O1—C16—H16C	109.5
C2—C1—H1	107.5	H16A—C16—H16C	109.5
C17—C2—C3	111.24 (9)	H16B—C16—H16C	109.5
C17—C2—C1	108.37 (9)	O2—C17—C18	121.16 (12)
C3—C2—C1	112.73 (9)	O2—C17—C2	120.04 (11)
C17—C2—H2	108.1	C18—C17—C2	118.78 (11)
C3—C2—H2	108.1	C17—C18—H18A	109.5
C1—C2—H2	108.1	C17—C18—H18B	109.5
O3—C3—C4	106.22 (9)	H18A—C18—H18B	109.5
O3—C3—C19	110.37 (9)	C17—C18—H18C	109.5
C4—C3—C19	109.61 (10)	H18A—C18—H18C	109.5
O3—C3—C2	111.05 (9)	H18B—C18—H18C	109.5
C4—C3—C2	107.54 (9)	C3—C19—H19A	109.5
C19—C3—C2	111.84 (9)	C3—C19—H19B	109.5
C5—C4—C3	112.68 (9)	H19A—C19—H19B	109.5
C5—C4—H4A	109.1	C3—C19—H19C	109.5
C3—C4—H4A	109.1	H19A—C19—H19C	109.5
C5—C4—H4B	109.1	H19B—C19—H19C	109.5
C3—C4—H4B	109.1	N2—C20—C6	177.83 (14)
H4A—C4—H4B	107.8	C8—C21—H21A	109.5
C9—C5—C6	118.33 (10)	C8—C21—H21B	109.5
C9—C5—C4	121.92 (10)	H21A—C21—H21B	109.5
C6—C5—C4	119.67 (10)	C8—C21—H21C	109.5
C7—C6—C5	119.09 (10)	H21A—C21—H21C	109.5
C7—C6—C20	119.89 (10)	H21B—C21—H21C	109.5
C5—C6—C20	121.00 (11)	C23—C22—S1	114.39 (9)
N1—C7—C6	122.29 (10)	C23—C22—H22A	108.7
N1—C7—S1	116.98 (9)	S1—C22—H22A	108.7
C6—C7—S1	120.69 (9)	C23—C22—H22B	108.7
N1—C8—C9	122.66 (10)	S1—C22—H22B	108.7
N1—C8—C21	113.87 (10)	H22A—C22—H22B	107.6
C9—C8—C21	123.45 (10)	O4—C23—O5	124.65 (13)
C5—C9—C8	118.17 (10)	O4—C23—C22	124.79 (13)
C5—C9—C1	121.80 (10)	O5—C23—C22	110.53 (11)
C8—C9—C1	119.86 (9)	O5—C24—C25	107.60 (17)
C15—C10—C11	118.27 (10)	O5—C24—H24A	110.2
C15—C10—C1	120.46 (10)	C25—C24—H24A	110.2
C11—C10—C1	121.02 (9)	O5—C24—H24B	110.2
C12—C11—C10	121.02 (10)	C25—C24—H24B	110.2
C12—C11—H11	119.5	H24A—C24—H24B	108.5
C10—C11—H11	119.5	C24—C25—H25A	109.5
C11—C12—C13	119.91 (10)	C24—C25—H25B	109.5
C11—C12—H12	120.0	H25A—C25—H25B	109.5
C13—C12—H12	120.0	C24—C25—H25C	109.5
O1—C13—C14	124.12 (10)	H25A—C25—H25C	109.5
O1—C13—C12	116.04 (10)	H25B—C25—H25C	109.5
C14—C13—C12	119.84 (10)

C9—C1—C2—C17	−159.86 (9)	C21—C8—C9—C5	174.35 (10)
C10—C1—C2—C17	74.15 (10)	N1—C8—C9—C1	−179.57 (10)
C9—C1—C2—C3	−36.30 (12)	C21—C8—C9—C1	−0.96 (16)
C10—C1—C2—C3	−162.29 (9)	C10—C1—C9—C5	125.98 (11)
C17—C2—C3—O3	67.55 (12)	C2—C1—C9—C5	3.61 (14)
C1—C2—C3—O3	−54.40 (12)	C10—C1—C9—C8	−58.88 (13)
C17—C2—C3—C4	−176.63 (9)	C2—C1—C9—C8	178.74 (9)
C1—C2—C3—C4	61.42 (12)	C9—C1—C10—C15	143.67 (11)
C17—C2—C3—C19	−56.24 (13)	C2—C1—C10—C15	−90.40 (12)
C1—C2—C3—C19	−178.19 (9)	C9—C1—C10—C11	−42.15 (14)
O3—C3—C4—C5	64.88 (12)	C2—C1—C10—C11	83.77 (12)
C19—C3—C4—C5	−175.88 (10)	C15—C10—C11—C12	0.81 (17)
C2—C3—C4—C5	−54.09 (12)	C1—C10—C11—C12	−173.49 (10)
C3—C4—C5—C9	23.77 (15)	C10—C11—C12—C13	1.36 (18)
C3—C4—C5—C6	−153.08 (10)	C16—O1—C13—C14	9.11 (16)
C9—C5—C6—C7	−1.73 (16)	C16—O1—C13—C12	−170.76 (10)
C4—C5—C6—C7	175.24 (10)	C11—C12—C13—O1	177.43 (10)
C9—C5—C6—C20	179.59 (11)	C11—C12—C13—C14	−2.44 (18)
C4—C5—C6—C20	−3.44 (17)	O1—C13—C14—C15	−178.52 (11)
C8—N1—C7—C6	2.08 (18)	C12—C13—C14—C15	1.34 (18)
C8—N1—C7—S1	179.98 (8)	C11—C10—C15—C14	−1.94 (17)
C5—C6—C7—N1	−1.67 (18)	C1—C10—C15—C14	172.40 (10)
C20—C6—C7—N1	177.03 (11)	C13—C14—C15—C10	0.87 (18)
C5—C6—C7—S1	−179.50 (8)	C3—C2—C17—O2	−73.61 (14)
C20—C6—C7—S1	−0.80 (16)	C1—C2—C17—O2	50.84 (14)
C22—S1—C7—N1	−15.41 (11)	C3—C2—C17—C18	107.90 (13)
C22—S1—C7—C6	162.54 (10)	C1—C2—C17—C18	−127.65 (12)
C7—N1—C8—C9	0.94 (17)	C7—S1—C22—C23	69.08 (10)
C7—N1—C8—C21	−177.79 (10)	C24—O5—C23—O4	−3.71 (19)
C6—C5—C9—C8	4.47 (16)	C24—O5—C23—C22	178.31 (11)
C4—C5—C9—C8	−172.42 (10)	S1—C22—C23—O4	36.21 (17)
C6—C5—C9—C1	179.69 (10)	S1—C22—C23—O5	−145.80 (9)
C4—C5—C9—C1	2.79 (16)	C23—O5—C24—C25	−176.43 (17)
N1—C8—C9—C5	−4.26 (16)

Hydrogen-bond geometry (Å, º) top

Cg1 is the centroid of the N1/C5–C9 pyridine ring.

D—H···A	D—H	H···A	D···A	D—H···A
O3—H3···O1ⁱ	0.90 (2)	2.05 (2)	2.9283 (12)	164 (2)
C16—H16C···O2ⁱⁱ	0.98	2.47	3.1566 (15)	127
C21—H21A···O2ⁱⁱⁱ	0.98	2.51	3.3956 (15)	150
C22—H22A···O3^iv	0.99	2.44	3.1815 (15)	131
C22—H22B···Cg1^iv	0.99	2.58	3.4559 (15)	147
C24—H24B···O4^v	0.99	2.52	3.442 (2)	154

Symmetry codes: (i) x+1, y, z; (ii) x−1, y, z; (iii) −x+1, −y+1, −z; (iv) −x+1, −y+1, −z+1; (v) −x, −y+1, −z+1.

Summary of short interatomic contacts (Å) in the title compound top

Contact	Distance	Symmetry operation
O1···H3	2.051 (16)	-1 + x, y, z
H21A···O2	2.51	1 - x, 1 - y, -z
H22A···O3	2.44	1 - x, 1 - y, 1 - z
O4···H16A	2.60	x, y, 1 + z
H24B···H24B	2.44	-x, 1 - y, 1 - z
H11···N2	2.61	1 - x, - y, 1 - z
H18B···H2	2.49	1 - x, - y, -z
H21C···H16B	2.51	-x, 1 - y, -z
H25B···H25B	2.34	-x, 2 - y, 1 - z

Acknowledgements

JTM thanks Tulane University for support of the Tulane Crystallography Laboratory. Author contributions are as follows: synthesis and organic chemistry parts preparation, EAA, YAE, ISM; conceptualization and study guide, EAB, SKM; financial support, EAA; crystal data production and validation, JTM; paper preparation and Hirshfeld study, MA.

References

Al-Taifi, E. A., Maraei, I. S., Bakhite, E. A., Demirtas, G., Mague, J. T., Mohamed, S. K. & Ramli, Y. (2021). Acta Cryst. E77, 121–125. Web of Science CSD CrossRef IUCr Journals Google Scholar
Ben Ali, K. & Retailleau, P. (2019). Acta Cryst. E75, 1399–1402. Web of Science CSD CrossRef IUCr Journals Google Scholar
Bouasla, R., Berredjem, M., Aouf, N.-E. & Barbey, C. (2008). Acta Cryst. E64, o432. Web of Science CSD CrossRef IUCr Journals Google Scholar
Brandenburg, K. & Putz, H. (2012). DIAMOND, Crystal Impact GbR, Bonn, Germany. Google Scholar
Bruker (2016). APEX3, SADABS and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA. Google Scholar
Carroll, F. I., Robinson, T. P., Brieaddy, L. E., Atkinson, R. N., Mascarella, S. W., Damaj, M. I., Martin, B. R. & Navarro, H. A. (2007). J. Med. Chem. 50, 6383–6391. CrossRef PubMed CAS Google Scholar
Castillo, J.-C., Jiménez, E., Portilla, J., Insuasty, B., Quiroga, J., Moreno-Fuquen, R., Kennedy, A. R. & Abonia, R. (2018). Tetrahedron, 74, 932–947. CSD CrossRef CAS Google Scholar
Cremer, D. & Pople, J. A. (1975). J. Am. Chem. Soc. 97, 1354–1358. CrossRef CAS Web of Science Google Scholar
Demers, S., Stevenson, H., Candler, J., Bashore, C. G., Arnold, E. P., O'Neill, B. T. & Coe, J. W. (2008). Tetrahedron Lett. 49, 3368–3371. CrossRef CAS Google Scholar
Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171–179. Web of Science CrossRef IUCr Journals Google Scholar
Hathwar, V. R., Sist, M., Jørgensen, M. R. V., Mamakhel, A. H., Wang, X., Hoffmann, C. M., Sugimoto, K., Overgaard, J. & Iversen, B. B. (2015). IUCrJ, 2, 563–574. Web of Science CSD CrossRef CAS PubMed IUCr Journals Google Scholar
Krause, L., Herbst-Irmer, R., Sheldrick, G. M. & Stalke, D. (2015). J. Appl. Cryst. 48, 3–10. Web of Science CSD CrossRef ICSD CAS IUCr Journals Google Scholar
Langenohl, F., Otte, F. & Strohmann, C. (2020). Acta Cryst. E76, 298–302. Web of Science CSD CrossRef IUCr Journals Google Scholar
Lehmann, A., Lechner, L., Radacki, K., Braunschweig, H. & Holzgrabe, U. (2017). Acta Cryst. E73, 867–870. Web of Science CSD CrossRef IUCr Journals Google Scholar
Lu, B., Cao, H., Cao, J., Huang, S., Hu, Q., Liu, D., Shen, R., Shen, X., Tao, W., Wan, H., Wang, D., Yan, Y., Yang, L., Zhang, J., Zhang, L., Zhang, L. & Zhang, M. (2016). Bioorg. Med. Chem. Lett. 26, 819–823. CrossRef CAS PubMed Google Scholar
Mague, J. T., Mohamed, S. K., Akkurt, M., Bakhite, E. A. & Albayati, M. R. (2017). IUCrData, 2, x170390. Google Scholar
Marae, I. S., Bakhite, E. A., Moustafa, O. S., Abbady, M. S., Mohamed, S. K. & Mague, J. T. (2021a). ACS Omega, 6, 8706–8716. CrossRef CAS PubMed Google Scholar
Marae, I. S., Sharmoukh, W., Bakhite, E. A., Moustafa, O. S., Abbady, M. S. & Emam, H. (2021b). Cellulose, 28, 5937–5956. CrossRef CAS Google Scholar
Naghiyev, F. N., Grishina, M. M., Khrustalev, V. N., Khalilov, A. N., Akkurt, M., Akobirshoeva, A. A. & Mamedov, İ. G. (2021). Acta Cryst. E77, 195–199. Web of Science CSD CrossRef IUCr Journals Google Scholar
Naicker, T., Govender, T., Kruger, H. G. & Maguire, G. E. M. (2011). Acta Cryst. C67, o100–o103. Web of Science CSD CrossRef IUCr Journals Google Scholar
Pingaew, R., Mandi, P., Nantasenamat, C., Prachayasittikul, S., Ruchirawat, S. & Prachayasittikul, V. (2014). Eur. J. Med. Chem. 81, 192–203. CrossRef CAS PubMed Google Scholar
Rosales, A. & Bernado, V. (2007). Pyrazoloisoquinoline Derivatives. WIPO Patent WO2007/060198A12007. Google Scholar
Scott, J. D. & Williams, R. (2002). Chem. Rev. 102, 1669–1730. CrossRef PubMed CAS Google Scholar
Selvaraj, J. P., Mary, S., Dhruba, J. B., Huidrom, B. S., Panneerselvam, Y. & Piskala Subburaman, K. (2020). Acta Cryst. E76, 1548–1550. Web of Science CSD CrossRef IUCr Journals Google Scholar
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. Web of Science CrossRef CAS IUCr Journals Google Scholar
Sheldrick, G. M. (2015a). Acta Cryst. A71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Sheldrick, G. M. (2015b). Acta Cryst. C71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Siegfried, L., Helmut, V., Guenther, W., Thomas, S., Eckart, S., Dieter, L., Gunter, L. & Ger East, D. D. (1989). Chem. Abstr. 110, 75554g. Google Scholar
Spackman, M. A. & Jayatilaka, D. (2009). CrystEngComm, 11, 19–32. Web of Science CrossRef CAS Google Scholar
Turner, M. J., McKinnon, J. J., Wolff, S. K., Grimwood, D. J., Spackman, M. A., Jayatilaka, D. & Spackman, M. A. (2017). Crystal Explorer. University of Western Australia. Google Scholar
Venkatesan, P., Thamotharan, S., Ilangovan, A., Liang, H. & Sundius, T. (2016). Spectrochim. Acta A, 153, 625–636. Web of Science CSD CrossRef CAS Google Scholar
Xu, R., Dwoskin, L. P., Grinevich, V., Sumithran, S. P. & Crooks, P. A. (2002). Drug Dev. Res. 55, 173–186. Web of Science CrossRef CAS Google Scholar

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