Methyl trans-(±)-1-oxo-2-phenethyl-3-(thio­phen-2-yl)-1,2,3,4-tetra­hydro­isoquinoline-4-carboxyl­ate

Mehmet Akkurt; Selvi Karaca; Milen G Bogdanov; Meglena I Kandinska; Orhan Büyükgüngör

doi:10.1107/S1600536809017383

. 2009 May 14;65(Pt 6):o1287–o1288. doi: 10.1107/S1600536809017383

Methyl trans-(±)-1-oxo-2-phenethyl-3-(thiophen-2-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylate

Mehmet Akkurt ^a,^*, Selvi Karaca ^a, Milen G Bogdanov ^b, Meglena I Kandinska ^b, Orhan Büyükgüngör ^c

PMCID: PMC2969771 PMID: 21583149

Abstract

In the title compound, C₂₃H₂₁NO₃S, the piperidine ring of the tetrahydroisoquinolinone unit adopts a screw-boat conformation. The thiophene ring is disordered in a 0.700 (3):0.300 (3) ratio by an approximate 180° rotation of the ring around the C—C bond linking the ring to the tetrahydroisoquinolinone unit. The benzene ring of the tetrahydroisoquinolinone unit makes dihedral angles of 83.1 (2) and 62.38 (11)° with the major occupancy thiophene ring and the phenyl ring, respectively. The dihedral angle between the phenyl ring and the thiophene ring is 71.0 (2)°. In the crystal structure, molecules are linked together by intermolecular C—H⋯O and C—H⋯π interactions.

Related literature

For background to the biological and pharmacological applications of compounds containing a tetrahydroisoquinoline fragment, see: Bogdanov et al. (2007 ▶); Burdzhiev & Stanoeva (2006 ▶); Gitto et al. (2008 ▶); Humphries et al. (2009 ▶); Kandinska et al. (2006 ▶); Rothweiler et al. (2008 ▶). For reference structural data, see: Allen et al. (1987 ▶); Akkurt et al. (2008 ▶). For ring conformations, see: Cremer & Pople (1975 ▶).

Experimental

Crystal data

C₂₃H₂₁NO₃S
M _r = 391.48
Monoclinic,
a = 8.8841 (3) Å
b = 30.7095 (13) Å
c = 7.5757 (3) Å
β = 105.472 (3)°
V = 1991.95 (14) Å³
Z = 4
Mo Kα radiation
μ = 0.19 mm⁻¹
T = 296 K
0.65 × 0.47 × 0.22 mm

Data collection

Stoe IPDS 2 diffractometer
Absorption correction: integration (X-RED32; Stoe & Cie, 2002 ▶) T _min = 0.889, T _max = 0.960
13399 measured reflections
3986 independent reflections
3154 reflections with I > 2σ(I)
R _int = 0.036

Refinement

R[F ² > 2σ(F ²)] = 0.048
wR(F ²) = 0.137
S = 1.04
3986 reflections
273 parameters
36 restraints
H-atom parameters constrained
Δρ_max = 0.32 e Å⁻³
Δρ_min = −0.23 e Å⁻³

Data collection: X-AREA (Stoe & Cie, 2002 ▶); cell refinement: X-AREA; data reduction: X-RED32 (Stoe & Cie, 2002 ▶); program(s) used to solve structure: SIR97 (Altomare et al., 1999 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997 ▶); software used to prepare material for publication: WinGX (Farrugia, 1999 ▶).

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536809017383/is2413sup1.cif

e-65-o1287-sup1.cif^{(27.7KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536809017383/is2413Isup2.hkl

e-65-o1287-Isup2.hkl^{(191.4KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C2—H2⋯O1ⁱ	0.93	2.57	3.401 (3)	149
C15—H15⋯O1ⁱⁱ	0.93	2.55	3.420 (3)	155
C3—H3⋯Cg1ⁱⁱⁱ	0.93	2.78	3.688 (3)	165
C3—H3⋯Cg2ⁱⁱⁱ	0.93	2.77	3.688 (4)	167
C19—H19⋯Cg3^iv	0.93	2.89	3.692 (3)	145

Open in a new tab

Symmetry codes: (i) Inline graphic ; (ii) ; (iii) ; (iv) . Cg1, Cg2 and Cg3 are centroids of the S1A/C12/C13A/C14/C15, S1B/C12/C13B/C14/C15 and C1–C6 rings, respectively.

supplementary crystallographic information

Comment

Compounds containing tetrahydroisoquinoline fragment in their structure display a broad spectrum of biological activities. In particular, derivatives of this type have been recently recognized as being G-protein-coupled receptor 40 (GPR40) antagonists (Humphries et al.2009), inhibitors of the MDM2–p53 interaction (Rothweiler et al., 2008), potent anticonvulsant agents (Gitto et al., 2008), etc. Thus, the title compound (I) was synthesized as a part of our ongoing program related to anhydride-based synthesis of new heterocyclic compounds with potential pharmacological activities (Bogdanov et al., 2007; Burdzhiev & Stanoeva, 2006; Kandinska et al., 2006).

In the title molecule, (I), the thiophene ring is disordered over two sites and the major component of the disorder labelled with suffix A is shown in Fig. 1. The disorder corresponds to a rotation of approximately 180° rotation about the single C—C bond to which it is attached. All the bond lengths and angles of (I) are in normal ranges (Allen et al., 1987; Akkurt et al., 2008). The six-membered piperidine ring (N1/C1/C6–C9) of 3,4-dihydroisoquinolinone ring system adopts a screw-boat conformation, as shown with the Cremer–Pople puckering parameters [Cremer & Pople, 1975; Q_T = 0.4620 (18) Å, θ = 114.5 (2)° and φ = 90.8 (23)°]. The benzene ring (C1–C6) of 3,4-dihydroisoquinolinone ring system is essentially planar, with an r.m.s. deviation of 0.002 (2) Å for C2 and C5. This benzene ring makes dihedral angles of 83.1 (2), 83.1 (4) and 62.38 (11)°, with the thiophene rings A (C12/C13A/C14/C15/S1A) and B (C12/C13B/C14/C15/S1B), and the phenyl ring C (C18–C23), respectively. The dihedral angles between the phenyl ring C and the thiophene rings A and B are C/A = 71.0 (2) and C/B = 70.4 (4)°, respectively.

In the crystal structure, molecules are linked together by intermolecular C—H···O interactions (Table 1 and Fig. 2). The crystal structure is further stabilized by intermolecular C—H···π interactions (Table 1).

Experimental

The title compound (I) was synthesized by esterification reaction of trans-1-oxo-2-phenethyl-3-(thiophen-2-yl)-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid (20 g, 0.053 mol) in the presence of H₂SO₄ (4.3 ml) in methanol. The reaction mixture was refluxed for 3 h. and then left over night. The colourless crystals were filtered and washed with water/methanol mixture yielding 18.6 g (90%) of (I). Single crystals were obtained by slow evaporation of a chloroform–ethyl acetate (3:1) solution of (I) at room temperature (mp 401–402 K). Analysis, calculated for C₂₃H₂₁NO₃S (391.48): C 70.56, H 5.41 (%); found: C 70.24, H 5.38 (%). IR (CHCl₃) 1650 cm^-1 (C═O), 1740 cm^-1 (C═O). The ¹H NMR spectrum of (I) was obtained on a Bruker DRX-250 spectrometer at 250.13 MHz. Chemical shifts (δ) are expressed in parts per million (p.p.m.) from tetramethylsilane as an internal standard. ¹H NMR (250 MHz, deuterochloroform) δ = 2.90–3.05 (2H, m, CH₂-Phenyl), 3.18–3.30 (1H, m, CH₂—N), 3.69 (1H, s, –OCH₃), 4.05 (1H, s, H-4), 4.20–4.35 (1H, m, CH₂—N), 5.60 (1H, s, H-3), 6.80 (2H, d, J = 5 Hz, H—Th), 7.10 (1H, d, J = 4 Hz, H—Th), 7.15–7.35 (7H, m, H—Ph), 7.45–7.55 (1H, m, H—Ph), 8.15–8.20 (1H, dd, H—Ph).