(4R)-3-Hy­droxy-7-isopropyl-4-methyl-5,6-di­hydro­benzo­furan-2(4H)-one

Frank W Heinemann; Alberto Herrera; Giuseppe Agrifoglio; Romano Dorta; Jesús Pastrán

doi:10.1107/S1600536814014524

. 2014 Jun 25;70(Pt 7):o824. doi: 10.1107/S1600536814014524

(4R)-3-Hydroxy-7-isopropyl-4-methyl-5,6-dihydrobenzofuran-2(4H)-one

Frank W Heinemann ^a, Alberto Herrera ^a, Giuseppe Agrifoglio ^b, Romano Dorta ^a, Jesús Pastrán ^b,^*

PMCID: PMC4120547 PMID: 25161599

Abstract

In the title compound, alternatively called α-hydroxy-γ-alkylidenebutenolide, C₁₂H₁₆O₃, two independent molecules (A and B) crystallize in the asymmetric unit in each of which the 5,6-dihydrobenzo ring has an envelope conformation. The torsion angle along the butadiene chain in the γ-alkylidenebutenolide core is −177.9 (2)° for molecule A and 179.9 (2)° for molecule B. In the crystal, O—H⋯O hydrogen bonds between hydroxyl and carbonyl groups of adjacent independent molecules form dimers with R ² ₂(10) loops.

Keywords: crystal structure

Related literature

For background to butenolides and their pharmacological activity, see: Rao (1964 ▶); Ma et al. (1999 ▶). For the synthesis of γ-alkylidenebutenolides, see: Park et al. (2012 ▶); Almeida et al. (2010 ▶); Xu et al. (2007 ▶); Langer et al. (2000 ▶, 2001 ▶). For related structures, see: Schneider & Viljoen (1997 ▶); Langer & Saleh (2000 ▶). For standard bond lengths, see: Allen et al. (1987 ▶) and for puckering parameters, see: Cremer & Pople (1975 ▶). graphic file with name e-70-0o824-scheme1.jpg

Experimental

Crystal data

C₁₂H₁₆O₃
M _r = 208.25
Monoclinic,
a = 9.0437 (3) Å
b = 13.2792 (6) Å
c = 9.8199 (5) Å
β = 104.694 (3)°
V = 1140.73 (9) Å³
Z = 4
Mo Kα radiation
μ = 0.09 mm⁻¹
T = 150 K
0.55 × 0.20 × 0.20 mm

Data collection

Bruker–Nonius KappaCCD diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2002 ▶) T _min = 0.682, T _max = 0.746
37926 measured reflections
2821 independent reflections
2564 reflections with I > 2σ(I)
R _int = 0.042

Refinement

R[F ² > 2σ(F ²)] = 0.037
wR(F ²) = 0.103
S = 1.09
2821 reflections
283 parameters
1 restraint
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.26 e Å⁻³
Δρ_min = −0.22 e Å⁻³

Data collection: COLLECT (Bruker–Nonius, 2002 ▶); cell refinement: EVALCCD (Duisenberg et al., 2003 ▶); data reduction: EVALCCD (Duisenberg et al., 2003 ▶); program(s) used to solve structure: SHELXTL (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL.

Supplementary Material

Crystal structure: contains datablock(s) I. DOI: 10.1107/S1600536814014524/jj2187sup1.cif

e-70-0o824-sup1.cif^{(32.3KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536814014524/jj2187Isup2.hkl

e-70-0o824-Isup2.hkl^{(138.5KB, hkl)}

Click here for additional data file.^{(4.5KB, cml)}

Supporting information file. DOI: 10.1107/S1600536814014524/jj2187Isup3.cml

CCDC reference: 1009320

Additional supporting information: crystallographic information; 3D view; checkCIF report

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

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O3—H3⋯O5ⁱ	0.87 (3)	1.81 (3)	2.627 (2)	157 (3)
O6—H6⋯O2ⁱⁱ	0.84 (3)	1.93 (3)	2.727 (2)	156 (3)

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Symmetry codes: (i) Inline graphic ; (ii) .

Acknowledgments

This work was financed by DID–USB (project S1–IN–CB–005–12).

supplementary crystallographic information

S1. Introduction

Butenolides are an important class of organic compounds present in natural products that have been studied for over 50 years (Rao, 1964). Most of them exhibit interesting pharmacological activities, such as antibacterial, anticancer, antibiotic and phospholipase A2 inhibition activity (Ma et al, 1999). During the last decades γ-alkylidenebutenolides have been considered as attractive synthetic targets due to their structural diversity and biological properties. As a result, several synthetic procedures have been developed for the preparation of these substances (Langer, et al., 2000; Langer, et al., 2001; Xu, et al., 2007; Almeida, et al., 2010; Park, et al., 2012). Also, α-Hydroxy-γ-alkylidenebutenolides are particularly suitable building blocks for analogues of pharmacologically relevant natural products (Langer & Saleh, 2000). Herein, we report the crystal structure of a bicyclic α-hydroxy-γ-alkylidenebutenolide based on l-Menthone, an inexpensive and accessible reagent from the chiral pool, which is also an important structural motif found in natural products. To the best of our knowledge, there is only one report on the preparation of a similar γ-alkylidenebutenolide, but no structural data were presented (Schneider & Viljoen, 1997).

S2. Experimental

S2.1. Synthesis and crystallization

Sodium hydride (60% dispersion in mineral oil, 2.44 g, 0.061 mmol) was stirred for 15 minutes in 200 mL of freshly distilled THF. Then a mixture of l-Menthone (7.71 g, 0.050 mmol) and di-ethyl oxalate (3.36 g, 0.023 mmol) in 100 mL of THF was added drop by drop. The resulting mixture was heated to reflux for 2 days. After this time, the solvent was removed by rotary evaporation. The crude reaction product was added to an ice-hydrochloric acid (1M) mixture and extracted with chloroform (3 x 50 mL). The organic layer was dried with MgSO₄, filtered and the solvent was removed under vacuum to afford orange oil, which was purified by Kugelrohr distillation (413 °K, 5 x 10^-2 mbar, bulbs cooled with dry ice), to obtain the desired product as a yellow oil that solidifies (1.95 g, 41%). Suitable crystals for X-ray diffraction analysis were obtained by slow diffusion of hexane into a saturated solution of the compound in dichloromethane cooled at 263 °K for 3 days. Elemental analysis calculated for C₁₂H₁₆O₃×1/3H₂O: C, 67.27 %, H 7.84 %. Found: C, 67.38 %, H 7.70 %.

S2.2. Refinement

The positions of the two oxygen bound hydrogen atoms H3 and H6 were taken from a difference fourier synthesis and their positional parameters were refined. All other H atoms were included in calculated positions (C–H = 0.93 Å for aromatic H, C–H = 0.96 Å for methyl H, C–H = 0.98 Å for methylene H, and C–H = 1.00 Å for tertiary H), and refined using a riding model with U_iso(H) = 1.2 Ueq or U_iso (H) = 1.5 Ueq (for methyl groups) of the carrier atom.

S3. Results and discussion

In the title compound,C₁₂H₁₆O₃, two independent molecules (A and B) crystallize in the asymmetric unit (Fig. 1). The 5,6-dihydrobenzo ring has an envelope conformation (puckering parameters Q, θ, and φ = 0.458 (2)Å, 126.4 (2)° and 295.8 (3)°, respectively; (Cremer & Pople, 1975)). The torsion angles along the butadiene chain in the γ-alkylidenebutenolide core are -177.9 (2)° for molecule A and 179.9 (2)° for molecule B. Bond lengths are in normal ranges (Allen et al., 1987). In the crystal O–H···O hydrogen bonds between hydroxyl and carbonyl groups of adjacent independent molecules form inversion dimers (Fig. 2).