N-[2-(2-Hy­droxy­eth­oxy)pheneth­yl]phthalimide

Er-Qun Yang; Jun-Tao Zhang; Xiao-Ping Cao; Jin-Zhong Gu

doi:10.1107/S1600536812018429

. 2012 May 5;68(Pt 6):o1636. doi: 10.1107/S1600536812018429

N-[2-(2-Hydroxyethoxy)phenethyl]phthalimide

Er-Qun Yang ^a, Jun-Tao Zhang ^a, Xiao-Ping Cao ^a,^*, Jin-Zhong Gu ^b

PMCID: PMC3379239 PMID: 22719437

Abstract

The title compound, C₁₈H₁₇NO₄, was obtained accidentally through acid-catalysed aromatization of a phthalimide-substituted 2-(1-hydroxyethyl)cyclohex-2-enone. It exhibits an intramolecular O—H⋯O_c (c = carbonyl) hydrogen bond and forms a three-dimensional network structure via π–π stacking interactions between adjacent benzene rings (phthalimide-to-phenylene and phthalimide-to-phthalimide), with centroid–centroid distances of 3.8262 (6) and 3.6245 (5) Å.

Related literature

For background to the titanium(IV) chloride-promoted Baylis–Hillman reaction, see: Basavaiah et al. (2010 ▶); Park et al. (2004 ▶); Qi et al. (2011 ▶); Reggelin et al. (2006 ▶); Veale et al. (2008 ▶). For protection of ketones as 1,3-dioxolanes, see: Chen et al. (2011 ▶); Shih & Swenton (1982 ▶). For background and a possible mechanism of the aromatization reaction, see: Patra et al. (2002 ▶); Lewin et al. (2008 ▶).

Experimental

Crystal data

C₁₈H₁₇NO₄
M _r = 311.33
Monoclinic,
a = 8.4799 (19) Å
b = 22.954 (5) Å
c = 8.5089 (19) Å
β = 110.077 (2)°
V = 1555.6 (6) Å³
Z = 4
Mo Kα radiation
μ = 0.09 mm⁻¹
T = 296 K
0.32 × 0.29 × 0.21 mm

Data collection

Bruker APEXII CCD diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2004 ▶) T _min = 0.970, T _max = 0.980
10978 measured reflections
2891 independent reflections
1867 reflections with I > 2σ(I)
R _int = 0.039

Refinement

R[F ² > 2σ(F ²)] = 0.054
wR(F ²) = 0.146
S = 1.04
2891 reflections
209 parameters
H-atom parameters constrained
Δρ_max = 0.27 e Å⁻³
Δρ_min = −0.25 e Å⁻³

Data collection: APEX2 (Bruker, 2004 ▶); cell refinement: SAINT (Bruker, 2004 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: SHELXTL (Sheldrick, 2008 ▶); software used to prepare material for publication: SHELXTL.

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536812018429/zl2473sup1.cif

e-68-o1636-sup1.cif^{(19.1KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812018429/zl2473Isup2.hkl

e-68-o1636-Isup2.hkl^{(141.9KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536812018429/zl2473Isup3.cml

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
O4—H4A⋯O2	0.82	2.14	2.941 (3)	164

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Acknowledgments

This work was supported financially by the National Natural Science Foundation of China (21061160494). The authors are also grateful to Yong-Liang Shao, Lanzhou University, for his helpful guidance in the preparation of the manuscript.

supplementary crystallographic information

Comment

N-[2-(2-Hydroxyethoxy)phenethyl]phthalimide (Fig. 1), was accidentally obtained as an unintended product from a total synthesis of malyngamides. In the first step N-[(formyl)methyl]phthalimide was reacted with cyclohex-2-enone via a titanium (IV) chloride promoted Baylis-Hillman reaction. The 2-(1-hydroxyethyl)cyclohex-2-enone obtained was then reacted with ethylene glycol with p-toluenesulfonic acid as the catalyst, with the aim to protect the keto group as a 1,3-dioxolane (Chen et al., 2011; Shih & Swenton, 1982). However, condensation with ethylene glycol proofed incomplete and through elimination of the hydroxy group and subsequent aromatization of the cyclohex-2-enone ring through a [1,5] shift of the double bond the title compound was obtained instead (Fig. 3). A similar reaction involving an aromatization of a cyclohex-2-enone obtained via a titanium (IV) chloride promoted Baylis-Hillman Reaction had been described earlier by e.g. Patra et al. (2002). This unexpected reaction offers itself as a good strategy for the synthesis of 2-substituted β-phenethylamines which are amino acid metabolites and important intermediates in medicinal chemistry (Lewin et al., 2008).

As shown in Fig. 2, an intramolecular O—H···O hydrogen bond is formed between the hydroxy group and one of the keto oxygen atoms (Table 1). In the crystal, the crystal packing is further stabilized by π-π interactions between phenyl rings in neighboring molecules (phthalimide to phenylene and phthalimide to phthalimide), with centroid to centroid distances of 3.8262 (6) Å and 3.6245 (5) Å.

Experimental

The title compound was produced in two steps. Using Baylis-Hillman reaction conditions (Basavaiah et al., 2010; Park et al., 2004), N-[2-hydroxy-2-(6-oxocyclohex-1-enyl)ethyl]phthalimide was prepared from N-[(formyl)methyl]phthalimide (Qi et al., 2011; Reggelin et al., 2006; Veale et al., 2008) and cyclohex-2-enone with titanium (IV) chloride in 56% yield. Then, to a stirred solution of N-[2-hydroxy-2-(6-oxocyclohex-1-enyl)ethyl]phthalimide (163 mg) in benzene (10 ml), ethylene glycol (4.40 ml) and p-toluenesulfonic acid (1 mg) were added and the mixture was refluxed for 20 h. The reaction mixture was poured into saturated NaHCO₃ solution (10 ml), extracted with Et₂O (3 × 20 ml) and then dried over MgSO₄. The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography on silica gel to give the title compound (128 mg, 72%) as a colourless solid. m.p. 403–404 K; ¹H NMR (CDCl₃, 400 MHz) δ: 7.85 (m, 2H, ArH), 7.71 (m, 2H, ArH), 7.22 (t, J = 7.4 Hz, 2H, ArH), 6.88 (m, J = 7.4 and 8.8 Hz, 2H, ArH), 4.07 (m, 4H, CH₂), 3.92 (m, 2H, CH₂), 2.98 (t, J = 8.4 Hz, 2H, CH₂); ¹³C NMR (CDCl₃, 100 MHz) δ: 168.6 (C), 157.0 (C), 134.0 (CH, overlapping signals), 132.1 (C), 130.9 (CH), 128.3 (CH), 126.0 (C), 123.4 (CH, overlapping signals), 120.8 (CH), 111.0 (CH), 69.5 (CH₂), 61.5 (CH₂), 37.9 (CH₂), 30.6 (CH₂); MS (ESI) m/z (%): 311 (M+, 30), 281 (9), 164 (100), 160 (53), 133 (73), 120 (57).