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(2-(1-Hydroxy-5-(hydroxy(phenyl)methyl)-1H-imidazol-2-yl)-
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was added by small portions. Aer 30 min at room temperature,
concentrated HCl (46 mL, 37%) was added slowly at 0 ꢂC. Then,
a new portion of NaBH3CN (3.5 g, 54 mmol) was added at room
temperature and one more time aer 2 hours (7.0 g, 109 mmol).
The reaction was stirred overnight and then concentrated under
reduced pressure. An aqueous solution of KOH (10%) was
added until pH ¼ 10 and then the product was extracted three
times with CH2Cl2 (100 mL). Organic layers were combined,
dried over MgSO4 and concentrated under reduced pressure.
The resulting crude was puried by column chromatography
(silica heptane–AcOEt 60 : 40–0 : 100) to afford the desired
ethyl)phosphonic acid (2e). From palladium dihydroxide on
charcoal (100 mg), 4c (0.80 g, 1.68 mmol) and ethanol (30 mL),
the desired product was obtained. Yield: 51% (0.27 g). 1H NMR
(400.13 MHz, D2O) d 1.21–1.27 (m, 1H), 1.84–1.92 (m, 2H), 2.01
(s, 3H), 2.96–3.03 (m, 2H), 6.04 (s, 1H), 7.29–7.38 (m, 5H). 13C
NMR (100.61 MHz, D2O) d 9.05 (s), 17.94 (d, 2JCP ¼ 3.6 Hz), 24.38
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(d, JCP ¼ 134.6 Hz), 65.11 (s), 123.52 (s), 126.02 (s), 127.50 (s),
3
128.23 (s), 128.78 (s), 139.37 (s), 140.71 (d, JCP ¼ 14.6 Hz). 31P
NMR (161.97 MHz, D2O) d 21.47 (s). HRMS (ESI) m/z [M + H]+
calcd for C13H18N2O5P 313.0953, found 313.0955.
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Method B. At 0 ꢂC, trimethylsilylbromide (1.27 mL, 10 mmol)
was added to a solution of benzyl phosphonate (4a, 4c and 4d, 1
mmol) in dichloromethane (10 mL). The reaction mixture was
allowed to stand up at room temperature and stirred for 14 h.
Aer concentration to dryness under vacuum, methanol (10
mL) was added and the resulting mixture was stirred at room
temperature for 2 h, thus concentrated in vacuo. Further puri-
cation was not required.
product. Yield: 50% (11.8 g). H NMR (400.13 MHz, CDCl3) d
1.34 (t, 3JHH ¼ 7.1 Hz, 6H), 3.68–3.71 (m, 2H), 4.06–4.14 (m, 4H),
4.73 (s, 2H), 5.85–5.96 (ddt, 2JPH ¼ 20.3 Hz, 3JHH ¼ 17.2 Hz, 4JHH
3
3
¼ 3.2 Hz, 1H), 6.77–6.89 (ddt, JPH ¼ 27.8 Hz, JHH ¼ 17.4 Hz,
3JHH ¼ 5.5 Hz, 1H), 7.33–7.37 (m, 5H). 13C NMR (100.61 MHz,
CDCl3) d 16.36 (d, 3JCP ¼ 6.4 Hz), 54.21 (d, 3JCP ¼ 23.2 Hz), 61.77
2
1
(d, JCP ¼ 5.6 Hz), 77.33 (s), 119.11 (d, JCP ¼ 187.8 Hz), 127.96
(s), 128.42 (s), 137.53 (s), 148.55 (d, JCP ¼ 4.9 Hz). 31P NMR
2
(161.97 MHz, CDCl3) d 17.84 (s).
(2-(5-Acetyl-1-hydroxy-1H-imidazol-2-yl)ethyl)phosphonic
acid (2a). Yield 96% (0.24 g). 1H NMR (400.13 MHz, D2O) d 2.00–
2.09 (m, 2H), 2.41 (s, 3H), 2.48 (s, 3H), 3.07–3.14 (m, 2H). 13C
General procedure
2
NMR (100.61 MHz, D2O) d 11.52 (s), 17.67 (d, JCP ¼ 3.6 Hz),
23.17 (d, 1JCP ¼ 137.5 Hz), 29.58 (s), 125.20 (s), 134.54 (s), 142.96
N-hydroxybenzylureas. Under N2, compound 9 (1.5 g, 5
mmol) was dissolved in dichloroethane (25 mL) and isocyanate
(2, 3 or 6 eq.) was added. The reaction mixture was stirred at
room temperature for 3 h (overnight for 8 days). The solution
was concentrated in vacuo and the resulting crude was used for
the next step without further purication.
(E)-Diethyl (3-(1-(benzyloxy)-3-ethylureido)prop-1-en-1-yl)-
phosphonate (8a). From ethylisocyanate (1.2 mL, 15 mmol), the
desired product was obtained. Yield: 100% (1.8 g). 1H NMR
3
(d, JCP ¼ 14.6 Hz), 190.80 (s). 31P NMR (161.97 MHz, D2O) d
24.08 (s). HRMS (ESI) m/z [M + H]+ calcd for C8H14N2O5P
249.0640, found 249.0637.
(2-(5-Benzoyl-1-hydroxy-1H-imidazol-2-yl)ethyl)phosphonic
acid (2c). Yield: 93% (0.29 g). 1H NMR (400.13 MHz, DMSO-d6) d
1.98–2.06 (m, 2H), 2.13 (s, 3H), 2.96–3.03 (m, 2H), 7.56–7.66 (m,
2H), 7.68–7.76 (m, 1H), 7.76–7.82 (m, 2H). 13C NMR (100.61
MHz, DMSO-d6) d 14.00 (s), 18.75 (s), 24.78 (d, 1JCP ¼ 135.4 Hz),
125.11 (s), 128.46 (s), 129.03 (s), 132.90 (s), 137.82 (s), 144.51 (d,
3JCP ¼ 15.4 Hz), 184.73 (s). 31P NMR (161.97 MHz, DMSO-d6) d
23.58 (s). HRMS (ESI) m/z [M + H]+ calcd for C13H16N2O5P
311.0797, found: 311.0797.
(400.13 MHz, CDCl3) d 1.03 (t, 3JHH ¼ 7.3 Hz, 6H), 1.33 (t, 3JHH
¼
7.2 Hz, 3H), 3.15–3.22 (m, 2H), 4.05–4.12 (m, 4H), 4.23–4.25 (m,
2H), 4.80 (s, 2H), 5.68 (t, 3JHH ¼ 5.5 Hz, 1H), 5.87 (ddt, 2JPH ¼ 19.6
Hz, 3JHH ¼ 17.2 Hz, 4JHH ¼ 1.4 Hz, 1H), 6.72–6.84 (m, 1H), 7.36–
7.41 (m, 5H). 13C NMR (100.61 MHz, CDCl3) d 15.07 (s), 16.33 (d,
(2-(5-(Furan-2-carbonyl)-1-hydroxy-1H-imidazol-2-yl)ethyl)-
phosphonic acid (2d). Yield: 97% (0.25 g). 1H NMR (400.13
MHz, D2O) d 1.97–2.06 (m, 2H), 2.30 (s, 3H), 3.05–3.12 (m, 2H),
6.49 (dd, 3JHH ¼ 3.1 Hz, 3JHH ¼ 1.0 Hz, 1H), 6.78 (d, 3JHH ¼ 3.1
3JCP ¼ 6.4 Hz), 34.94 (s), 54.22 (d, 3JCP ¼ 24.5 Hz), 61.80 (d, 2JCP
¼
5.6 Hz), 77.41 (s), 120.21 (d, 1JCP ¼ 186.9 Hz), 128.79 (s), 129.01 (s),
129.31 (s), 135.14 (s), 146.89 (d, 2JCP ¼ 5.0 Hz), 159.62 (s). 31P NMR
(161.97 MHz, CDCl3): d 17.24 (s). HRMS (ESI) m/z [M + H]+ calcd
for C17H28N2O5P 371.1740, found: 371.1736.
3
Hz, 1H), 7.55 (d, JHH ¼ 1.0 Hz, 1H). 13C NMR (100.61 MHz,
2
1
D2O) d 9.57 (s), 17.71 (d, JCP ¼ 3.7 Hz), 23.61 (d, JCP ¼ 136.1
Hz), 111.04 (s), 111.39 (s), 119.29 (s), 123.32 (s), 141.23 (d, 3JCP
¼ 14.6 Hz), 144.10 (s), 145.38 (s). 31P NMR (161.97 MHz, D2O) d
24.01 (s). HRMS (ESI) m/z [M + H]+ calcd for C10H14N2O5P
273.0640, found 273.0640.
(E)-Diethyl (3-(1-(benzyloxy)-3-phenylureido)prop-1-en-1-yl)-
phosphonate (8b). From phenylisocyanate (1.0 mL, 10 mmol),
1
the desired product was obtained. Yield: 100% (2.1 g). H NMR
(400.13 MHz, CDCl3) d 1.32 (t, 3JHH ¼ 7.0 Hz, 6H), 4.05–4.12 (m,
4H), 4.33–4.35 (m, 2H), 4.91 (s, 2H), 5.88–5.97 (m, 1H), 6.76–6.89
(m, 1H), 7.26–7.31 (m, 5H), 7.41–7.47 (m, 5H), 7.60 (s, 1H). 13C
NMR (100.61 MHz, CDCl3) d 16.33 (d, 3JCP ¼ 6.6 Hz), 51.72 (d, 3JCP
¼ 24.9 Hz), 61.87 (d, 2JCP ¼ 5.9 Hz), 77.95 (s), 119.31 (s), 120.70 (d,
1JCP ¼ 186.6 Hz), 123.74 (s), 128.93 (s), 129.02 (s), 129.37 (s),
129.44 (s), 134.71 (s), 137.53 (s), 146.22 (d, 2JCP ¼ 5.1 Hz), 156.68
(s). 31P NMR (161.97 MHz, CDCl3) d 16.99 (s). HRMS (ESI) m/z [M
+ H]+ calcd for C21H28N2O5P 419.1736, found 419.1736.
Synthesis of diethyl (oxiran-2-ylmethyl)phosphonate (12)
and diethyl (E)-(3-oxoprop-1-en-1-yl)phosphonate (10). Starting
materials 12 (ref. 23) and 10 (ref. 24) were prepared respectively
according to procedure described in literature.
Diethyl
(E)-(3-((benzyloxy)amino)prop-1-en-1-yl)phospho-
nate (9). (E)-diethyl (3-oxoprop-1-en-1-yl)phosphonate (15.2 g,
78.2 mmol, 1 eq.) was dissolved in MeOH (25 mL) and O-benzyl
ꢂ
hydroxylamine (8.19 mL, 78.2 mmol, 1 eq.) was added at 0 C.
(E)-Diethyl (3-(1-(benzyloxy)-3-(4-uorophenyl)ureido)prop-
1-en-1-yl)phosphonate (8c). From 4-uorophenylisocyanate (1.2
mL, 10 mmol), the desired product was obtained. Yield: 100%
The mixture was stirred for 1 h at room temperature. Aer
addition of MeOH (300 mL), NaBH3CN (14.8 g, 230 mmol, 3 eq.)
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RSC Adv., 2014, 4, 23770–23778 | 23775