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Synlett 2013; 24(7): 817-822
DOI: 10.1055/s-0032-1318500
letter
© Georg Thieme Verlag Stuttgart · New York

Phosphonated Benzoxazole Derivatives: Synthesis and Metal-Complexing Properties

Elodie Lagadic
a   Institute of Condensed Matter and Nanosciences (IMCN), Molecules, Solids and Reactivity (MOST), Université catholique de Louvain, Place Louis Pasteur L4.01.02, 1348 Louvain-la-Neuve, Belgium   Fax: +32(10)474168   Email: jacqueline.marchand@uclouvain.be
,
Frédéric Bruyneel
a   Institute of Condensed Matter and Nanosciences (IMCN), Molecules, Solids and Reactivity (MOST), Université catholique de Louvain, Place Louis Pasteur L4.01.02, 1348 Louvain-la-Neuve, Belgium   Fax: +32(10)474168   Email: jacqueline.marchand@uclouvain.be
,
Noémie Demeyer
a   Institute of Condensed Matter and Nanosciences (IMCN), Molecules, Solids and Reactivity (MOST), Université catholique de Louvain, Place Louis Pasteur L4.01.02, 1348 Louvain-la-Neuve, Belgium   Fax: +32(10)474168   Email: jacqueline.marchand@uclouvain.be
,
Marie-France Hérent
b   Louvain Drug Research Institute (LDRI), Université catholique de Louvain, Avenue Mounier 73.40, 1200 Bruxelles, Belgium
,
Yann Garcia
a   Institute of Condensed Matter and Nanosciences (IMCN), Molecules, Solids and Reactivity (MOST), Université catholique de Louvain, Place Louis Pasteur L4.01.02, 1348 Louvain-la-Neuve, Belgium   Fax: +32(10)474168   Email: jacqueline.marchand@uclouvain.be
,
Jacqueline Marchand-Brynaert*
a   Institute of Condensed Matter and Nanosciences (IMCN), Molecules, Solids and Reactivity (MOST), Université catholique de Louvain, Place Louis Pasteur L4.01.02, 1348 Louvain-la-Neuve, Belgium   Fax: +32(10)474168   Email: jacqueline.marchand@uclouvain.be
› Author Affiliations
Further Information

Publication History

Received: 30 January 2013

Accepted: 07 March 2013

Publication Date:
18 March 2013 (online)

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Abstract

Phosphonated benzoxazole derivatives are good candidates as ligands for metal complexes. Two regioisomers were synthesized with the phosphonate function at the C-4 and C-7 positions. Different alkyl chains were also introduced at the C-2 position to functionalize these two regioisomers and increase their complexation properties. The formation of coordination complexes of selected benzoxazoles with M2+ and M3+ metal cations has been screened in solution using HRMS (high-resolution mass spectrometry) as the analytical tool.

Key words

benzoxazole - phosphonate - regioselectivity - coordination complex - metal ligand

Supporting Information

    for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett.
  • Supporting Information
 

  • References and Notes

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  • 14 1H NMR, 13C NMR and 31P NMR spectra were recorded on Bruker Avance 300 and 500 spectrometers. Spectra were obtained in CDCl3 or CD3OD. Chemical shifts are reported in ppm relative to the solvent signals. High Resolution Mass Spectrometry (HRMS) analyses were performed on a LTQ-orbitrap XL hybrid mass spectrometer (Thermo Fisher Scientific, Bremen, Germany). Infrared spectra were performed on a FTIR-84005 equipment using ATR mode. Analytical grade solvents and commercially available reagents were used without further purification. Chromatography was carried with Rocc silica gel, 40–63 μm or 60–200 μm. Diethyl 2-Methylbenzoxazole-4-phosphonate (2): The glassware was flame-dried under an argon atmosphere. To a solution of 2-amino-3-hydroxybenzenephosphonic acid (1.00 g, 5.29 mmol) in anhyd MeCN (10.00 mL) was added triethyl orthoacetate (5.0 equiv, 4.90 mL). The mixture was heated at 80 °C overnight and then evaporated to give an orange oil. The crude product was purified by flash chromatography on silica gel (cyclohexane–EtOAc, 1:1, then EtOAc). The title compound was isolated as an orange oil with 78% yield (1.11 g). IR (film): 1677, 1568, 1415, 1244, 1230, 1020, 973, 790, 761 cm–1. 1H NMR (300 MHz, CD3OD): δ = 1.30–1.35 [m, 6 H, PO(OCH2CH 3)2], 2.69 (s, 3 H, Me), 4.16–4.22 [m, 4 H, PO(OCH 2CH3)2], 7.48 (td, 3 J H–H = 7.9 Hz, 4 J H–P = 3.7 Hz, 1 H, H-6), 7.74–7.85 (m, 2 H, H-5, H-7). 13C NMR (75 MHz, CD3OD): δ = 14.2 (s, Me), 16.6 [d, 3 J C–P = 6.3 Hz, PO(OCH2 CH3)2], 64.1 [d, 2 J C–P = 5.6 Hz, PO(OCH2CH3)2], 116.2 (d, 4 J C–P = 3.1 Hz, C-7), 119.6 (d, 1 J C–P = 190.2 Hz, C-4), 125.6 (d, 3 J C–P = 14.9 Hz, C-6), 130.1 (d, 2 J C–P = 7.8 Hz, C-5), 143.7 (d, 2 J C–P = 6.8 Hz, C-9), 152.4 (d, 3 J C–P = 15.9 Hz, C-8), 167.6 (s, C-2). 31P NMR (121 MHz, CD3OD): δ = 16.6 [s, PO(OEt)2]. HRMS (ESI): m/z [M + Na]+ calcd for C12H16NO4NaP: 292.0715; found: 292.0716. Diethyl 2-(N,N-Dimethyl-1-ethylen-1-amino)benzox-azole-4-phosphonate (3): The glassware was flame-dried under an argon atmosphere. To a solution of 2 (0.1 g, 0.4 mmol) in anhyd MeCN (2.0 mL) was added dimethylformamide diethylacetal (DMFDEA; 3.0 equiv, 0.2 mL). The mixture was heated at reflux overnight and then evaporated to give an orange oil. The crude product was purified by flash chromatography on silica gel (EtOAc, then EtOAc–i-PrOH, 95:5) to give the title compound as a yellow oil with 80% yield (0.09 g). IR (film): 1633, 1547, 1537, 1414, 1387, 1240, 1227, 1107, 1047, 1024, 968, 787, 764 cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.31–1.37 [m, 6 H, PO(OCH2CH 3)2], 2.98 (s, 6 H, Me), 4.12–4.27 [m, 4 H, PO(OCH 2CH3)2], 5.19 (d, 3 J H–H = 13.3 Hz, 1 H, C=CH), 7.15 (td, 3 J H–H = 7.8 Hz, 4 J H–P = 3.6 Hz, 1 H, H-6), 7.47 (ddd, 3 J H–H = 7.9 Hz, 4 J H–H = 5J H–P = 1.2 Hz, 1 H, H-7), 7.58 (d, 3 J H–H = 13.3 Hz, 1 H, CH=C), 7.70 (ddd, 3 J H–P = 13.8 Hz, 3 J H–H = 7.7 Hz, 4 J H–H = 1.1 Hz, 1 H, H-5). 13C NMR (125 MHz, CDCl3): δ = 16.4 [d, 3 J C–P = 6.5 Hz, PO(OCH2 CH3)2], 62.3 [d, 2 J C–P = 5.1 Hz, PO(OCH2CH3)2], 81.7 (s, C=C), 112.8 (d, 4 J C–P = 2.7 Hz, C-7), 116.2 (d, 1 J C–P = 186.9 Hz, C-4), 121.4 (d, 3 J C–P = 15.0 Hz, C-6), 128.6 (d, 2 J C–P = 8.4 Hz, C-5), 145.3 (d, 2 J C–P = 6.8 Hz, C-9), 149.3 (s, C=C), 149.9 (d, 3 J C–P = 16.0 Hz, C-8), 167.8 (s, C-2). 31P NMR (121 MHz, CDCl3): δ = 17.4 [s, PO(OEt)2]. HRMS (ESI): m/z [M + H]+ calcd for C15H22O4N2P: 325.1312; found: 325.1317. Diethyl 2-Formylbenzoxazole-4-phosphonate (4): To a solution of 3 (0.083 g, 0.255 mmol) in THF–H2O (1:1; 5.4/5.4 mL) was added sodium periodate (4.0 equiv, 0.218 g, 1.024 mmol). The reaction mixture was stirred at r.t. for 2 h. Then the crude mixture was extracted with CH2Cl2 (3 ×), dried over Na2SO4, filtered and evaporated to give the title compound as a yellow oil. It was used in the next step without further purification. 1H NMR (500 MHz, CDCl3): δ = 1.35–1.40 [m, 6 H, PO(OCH2CH 3)2], 4.20–4.36 [m, 4 H, PO(OCH 2CH3)2], 7.66 (td, 3 J H–H = 7.5 Hz, 4 J H–P = 3.3 Hz, 1 H, H-6), 7.88 (ddd, 3 J H–H = 8.4 Hz, 4 J H–H = 5J H–P = 0.9 Hz, 1 H, H-7), 8.03 (ddd, 3 J H–P = 14.2 Hz, 3 J H–H = 7.4 Hz, 4 J H–H = 0.9 Hz, 1 H, H-5), 10.09 (s, 1 H, CHO). 13C NMR (125 MHz, CDCl3): δ = 16.4 [d, 3 J C–P = 6.3 Hz, PO(OCH2 CH3)2], 62.9 [d, 2 J C–P = 5.5 Hz, PO(OCH2CH3)2], 116.4 (d, 4 J C–P = 3.0 Hz, C-7), 123.6 (d, 1 J C–P = 189.0 Hz, C-4), 128.8 (d, 3 J C–P = 14.9 Hz, C-6), 131.4 (d, 2 J C–P = 7.5 Hz, C-5), 141.3 (d, 2 J C–P = 6.2 Hz, C-9), 150.5 (d, 3 J C–P = 14.8 Hz, C-8), 157.8 (s, C-2), 179.5 (s, CHO). 31P NMR (121 MHz, CDCl3): δ = 13.6 [s, PO(OEt)2]. Diethyl 2-Hydroxymethylbenzoxazole-4-phosphonate (5): To a solution of crude 4 (0.072 g, 0.254 mmol) in MeOH (22.0 mL) was added NaBH4 (5.0 equiv, 0.038 g, 1.017 mmol). The solution was stirred for 2 h. Then cold H2O was added and the mixture was extracted with CH2Cl2 (3 ×), dried over Na2SO4, filtered and evaporated to give the title compound as a yellow oil with 84% yield for two steps (0.061 g). IR (film): 1749, 1633, 1608, 1570, 1414, 1392, 1246, 1049, 1020, 970, 789, 760 cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.31–1.37 [m, 6 H, PO(OCH2CH 3)2], 4.14–4.29 [m, 4 H, PO(OCH 2CH3)2], 5.01 (s, 2 H, CH2), 7.41 (td, 3 J H–H = 7.5 Hz, 4 J H–P = 3.5 Hz, 1 H, H-6), 7.70 (ddd, 3 J H–H = 8.3 Hz, 4 J H–H = 5 J H–P = 1.3 Hz, 1 H, H-7), 7.83 (ddd, 3 J H–P = 13.9 Hz, 3 J H–H = 7.5 Hz, 4 J H–H = 1.0 Hz, 1 H, H-5), 8.24 (br s, 1 H, OH). 13C NMR (125 MHz, CDCl3): δ = 16.4 [d, 3 J C–P = 6.4 Hz, PO(OCH2 CH3)2], 58.0 (s, CH2), 62.8 [d, 2 J C–P = 5.3 Hz, PO(OCH2CH3)2], 115.1 (d, 4 J C–P = 2.8 Hz, C-7), 120.0 (d, 1 J C–P = 189.1 Hz, C-4), 124.8 (d, 3 J C–P = 14.9 Hz, C-6), 129.4 (d, 2 J C–P = 7.6 Hz, C-5), 142.1 (d, 2 J C–P = 6.7 Hz, C-9), 150.9 (d, 3 J C–P = 15.6 Hz, C-8), 167.1 (s, C-2). 31P NMR (121 MHz, CDCl3): δ = 15.3 [s, PO(OEt)2]. HRMS (ESI): m/z [M + H]+ calcd for C12H17O5NP: 286.0839; found: 286.0841. Diethyl 2-[(Methoxycarbonyl)methyl(diethoxy-phosphoryl)]benzoxazole-4-phosphonate (6): To a solution of 5 (0.048 g, 0.17 mmol) in CH2Cl2 (1.00 mL) was added (diethoxyphosphoryl)acetic acid (1.1 equiv, 0.03 mL) and then N,N′-dicyclohexylcarbodiimide (DCC; 1.1 equiv, 0.038 g) and 4-(dimethylamino)pyridine (DMAP; 1.1 equiv, 0.023 g). The reaction mixture was stirred at r.t. overnight and then filtered to eliminate the N,N′-dicyclohexylurea (DCU) formed. The filtrate was evaporated and purified by flash chromatography on silica gel (MeCN–i-PrOH, 95:5). The title compound was isolated as a yellow oil with 98% yield (0.058 g). IR (film): 2905–2926, 1749, 1602, 1570, 1444, 1414, 1392, 1228–1290, 1161, 1111, 931–1047, 866, 731–789 cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.27–1.33 {m, 12 H, [PO(OCH2 CH 3)2]2}, 3.07 (d, 2 J H–P = 21.6 Hz, 2 H, COCH 2P), 4.13–4.26 {m, 8 H, [PO(OCH 2CH3)2]2}, 5.43 (s, 2 H, CH2O), 7.45 (td, 3 J H–H = 7.9 Hz, 4 J H–P = 3.4 Hz, 1 H, H-6), 7.71 (d, 3 J H–H = 8.2 Hz, 1 H, H-7), 7.88 (dd, 3 J H–P = 14.0 Hz, 3 J H–H = 7.4 Hz, 1 H, H-5). 13C NMR (125 MHz, CDCl3): δ = 16.3–16.4 [m, PO(OCH2 CH3)2], 34.0 (d, 2 J C–P = 133.8 Hz, COCH2P), 59.1 (s, CH2O), 62.8 [d, 2 J C–P = 5.3 Hz, PO(OCH2CH3)2], 63.0 [d, 2 J C–P = 6.2 Hz, PO(OCH2CH3)2], 115.2 (d, 4 J C–P = 2.8 Hz, C-7), 120.9 (d, 2 J C–P = 188.6 Hz, C-4), 125.5 (d, 3 J C–P = 14.9 Hz, C-6), 130.1 (d, 2 J C–P = 7.8 Hz, C-5), 141.7 (d, 2 J C–P = 6.3 Hz, C-9), 150.9 (d, 3 J C–P = 15.4 Hz, C-8), 161.2 (s, C-2), 165.1 (d, 2 J C–P = 5.9 Hz, CO). 31P NMR (121 MHz, CDCl3): δ = 15.3 [s, PhPO(OEt)2], 19.1 [s, CH2PO(OEt)2]. HRMS (ESI): m/z [M + H]+ calcd for C18H28NO9P2: 464.1239; found: 464.1231. Compounds 7–14 (Scheme 2) are described in the Supporting Information.
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