2-Propynyl 2-hydroxy­benzoate

Stephan M Levonis; Milton J Kiefel; Todd A Houston; Peter C Healy

doi:10.1107/S160053680905421X

. 2009 Dec 24;66(Pt 1):o226–o227. doi: 10.1107/S160053680905421X

2-Propynyl 2-hydroxybenzoate

Stephan M Levonis ^a, Milton J Kiefel ^a, Todd A Houston ^a, Peter C Healy ^b,^*

PMCID: PMC2980208 PMID: 21580108

Abstract

The title compound, C₁₀H₈O₃, has been synthesized as part of our investigations into the generation of new antibacterial agents and serves as a building block for the synthesis of compound libraries. The compound crystallizes with two independent molecules in the asymmetric unit. The transoid propynyl ester groups are coplanar with the 2-hydroxybenzoate group with maximum deviations of −0.3507 (3) and 0.1591 (3) Å for the terminal carbons, with intramolecular O—H⋯O hydrogen bonding providing rigidity to the structure and ensuring that the reactivity of the alkyne is not compromised by steric factors. The propynyl group forms intermolecular C—H⋯O interactions with the phenolic O atom. Supramolecular chains along the b axis are found for both molecules with links by weak O—H⋯O intermolecular interactions in the first independent molecule and C—H⋯O interactions in the second.

Related literature

For background to Cu(I)-mediated azide–alkyne cycloadditions, see: Houston et al. (2008 ▶); Wilkinson et al. (2009 ▶). For the biological use of salicylates, see: Sox & Olson (1989 ▶). For background to boric acid-mediated esterification, see: Houston et al. (2004 ▶, 2007 ▶); Levonis et al. (2007 ▶). For stereochemistry, see: Wilkinson et al. (2006 ▶); Wiberg & Laidig (1987 ▶). For previous synthesis of the title compound and its anti-tumour activity, see: Jung et al. (1997 ▶).

Experimental

Crystal data

C₁₀H₈O₃
M _r = 176.16
Monoclinic,
a = 18.7150 (14) Å
b = 12.7972 (10) Å
c = 7.2310 (7) Å
β = 90.191 (8)°
V = 1731.8 (3) Å³
Z = 8
Mo Kα radiation
μ = 0.10 mm⁻¹
T = 296 K
0.36 × 0.30 × 0.12 mm

Data collection

Oxford-Diffraction GEMINI S Ultra diffractometer
Absorption correction: multi-scan (CrysAlis RED; Oxford Diffraction, 2009 ▶) T _min = 0.965, T _max = 0.988
10756 measured reflections
3081 independent reflections
1941 reflections with I > 2σ(I)
R _int = 0.031

Refinement

R[F ² > 2σ(F ²)] = 0.039
wR(F ²) = 0.098
S = 0.93
3081 reflections
235 parameters
H-atom parameters constrained
Δρ_max = 0.14 e Å⁻³
Δρ_min = −0.14 e Å⁻³

Data collection: CrysAlis CCD (Oxford Diffraction, 2009 ▶); cell refinement: CrysAlis RED (Oxford Diffraction, 2009 ▶); data reduction: CrysAlis RED; 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: PLATON (Spek, 2009 ▶) and publCIF (Westrip, 2010 ▶).

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S160053680905421X/tk2601sup1.cif

e-66-0o226-sup1.cif^{(22.5KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S160053680905421X/tk2601Isup2.hkl

e-66-0o226-Isup2.hkl^{(151.2KB, 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
O1—H1⋯O7	0.90	1.86	2.6193 (16)	141
O1—H1⋯O7ⁱ	0.90	2.55	3.2081 (17)	130
O11—H11⋯O17	0.90	1.82	2.6007 (18)	144
C10—H10⋯O11ⁱⁱ	0.95	2.38	3.310 (2)	165
C16—H16⋯O17ⁱⁱⁱ	0.96	2.48	3.291 (2)	143
C20—H20⋯O1^iv	0.95	2.46	3.340 (2)	154

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

Acknowledgments

We acknowledge support of this work by Griffith University, the Queensland University of Technology, the Eskitis Institute for Cell and Molecular Therapies, and the Institute for Glycomics.

supplementary crystallographic information

Comment

In an attempt to identify new antibacterial compounds, we have assembled a diverse range of azide and alkyne coupling partners for the purpose of creating compound libraries using Cu(I)-mediated azide-alkyne cycloadditions [CuAAC] (Houston et al., 2008; Wilkinson et al., 2009). Salicylates such as bismuth subsalicylate have been used for many years to treat diarrhea and other gastrointestinal disorders (Sox & Olson, 1989). We required a core salicylate scaffold that could be readily transformed into a variety of derivatives. Here, we describe the synthesis and X-ray crystal structure of 2'-propynyl 2-hydroxybenzoate (propargyl salicylate) (I) using our chemoselective method of boric acid-mediated esterification (Houston et al., 2004; 2007). Borate can activate hydroxycarboxylic acids such as salicylate toward esterification under mild conditions that are tolerant to acid-labile functional groups such as alkynes. This ester was previously synthesized by alkylation for the synthesis of cobalt carbonyl complexes and study of their anti-tumour activity (Jung et al., 1997).

Compound (I) was synthesized cleanly from salicylic acid and propargyl alcohol in 55% yield using 10 mol% boric acid in acetonitrile (Levonis et al., 2007) (Fig. 1), and crystallizes from toluene with two independent molecules in the asymmetric unit (Fig. 2). The ester group adopts the transoid arrangement (Wilkinson et al., 2006) as stereoelectronic requirements are met when the carbonyl bifurcates the methylene H atoms (Wiberg & Laidig, 1987). This allows both p →π and n →σ* overlap from the propargylated oxygen to the carbonyl. The propynyl groups are co-planar with the 2-hydroxybenzoate; with the intra-molecular O—H···O hydrogen bond between the phenolic proton and the carbonyl oxygen providing rigidity to the structure (Table 1). These factors result in the extension of the propynyl group away from the aromatic core and ensures that the reactivity of the alkyne when using the CuAAC method is not compromised by steric constraints. In the crystal lattice, the propynyl groups form inter-molecular C—H···O interactions with the phenolic oxygen (Table 1). Supramolecular chains along the direction of the b axis are found for both molecules with links by weak O1—H1···O7 (molecule A) and C16—H16···O17 (molecule B) inter-molecular interactions (Table 1, Fig. 3).

Experimental

To a stirred solution of salicylic acid (208 mg, 1.5 mmol) and propargyl alcohol (84 mg, 174 mL,3.0 mmol) in acetonitrile (3 ml) was added boric acid (9 mg, 0.15 mmol). The solution was heated and maintained at reflux for 16 h before concentrating in vacuo. Flash column chromatography was performed on silica using ethyl acetate as the mobile phase to yield 145 mg(55%) of (I) as a white solid. This was initially recrystallized from MeOH to furnish white needles (31%) for NMR analysis. A second recrystallization from toluene at 0°C produced single crystals suitable for X-ray diffraction analysis.

¹H NMR (CDCl₃ 300 MHz, 298 K) δ p.p.m. 2.53 (t, J = 2.4 Hz, 1H), 4.91 (s, 2H), 6.87 (ddd, J = 8.1, 7.35, 1.2 Hz, 1H), 6.96 (dd, J = 8.4, 0.9 Hz, 1H), 7.45 (ddd, J = 8.4, 7.2, 1.8 Hz, 1H), 7.85 (dd, J = 7.9, 1.8 Hz, 1H), 10.5 (s, 1H). ¹³C{¹H} NMR (CD₃OD, 75 MHz, 298 K) δ p.p.m. 53.7, 77.1, 78.3, 113.2, 118.5, 120.4, 130.9, 137.0, 162.9 170.5. MS(ESI–) 175.1 [M—H⁺]