Please do not adjust margins
Organic & Biomolecular Chemistry
Page 10 of 15
ARTICLE
(3-((4-(2-methoxy-2-oxoethyl)-2-oxo-2H-chromen-7yl)oxy)-
Journal Name
DOI: 10.1039/C6OB01080F
propyl)triphenylphosphonium bromide 5
114.2, 113.8, 102.7, 68.5 (d, JP-C = 16.9 Hz, 1C), 23.5 (d, JP-C = 3.3 Hz,
1C), 20.0 (d, JP-C = 54.0 Hz, 1C); HRMS (ESI+): calcd. for C32H28O5P+
[M]+ : 523.1674; found 532.1677. HPLC (system QC): tR = 26.3 min,
purity 96.6%.
Compound 4 (500 mg, 1.4 mmol) and PPh3 (4.05 g, 15.5 mmol, 11
equiv.) was suspended in dry ACN (20 mL) and the corresponding
medium refluxed for 24 h. The mixture was cooled, concentrated in
vacuo and washed several times with EtOAc to give (3-((4-(2-
methoxy-2-oxoethyl)-2-oxo-2H-chromen-7-yl)oxy)propyl)-
2-(7-(3-bromopropoxy)-2-oxo-2H-chromen-4-yl)acetic acid 8
To a cooled solution of 4 (547 mg, 1.5 mmol) in THF (7 ml) was
slowly added an aqueous solution (2 N) of lithium hydroxide (74 mg,
3.0 mmol, 2 equiv.). The resulting mixture was stirred at rt for 4 h,
then diluted with EtOAc (10 mL) and aq HCl 1 N (20 mL). The
organic layer that formed was extracted, dried over Na2SO4,
concentrated in vacuo and washed with Et2O to give 8 as a white
solid (434 mg, 83% yield). m.p. 128-130 °C; IR : ṽ = 2957, 1709, 1609,
1388, 1296, 1195, 1146, 1067, 1024 cm-1; 1H NMR (300 MHz,
(CD)3CO) : δ = 7.69 (d, J = 8.8 Hz, 1H), 6.98 (dd, J = 8.8 and 2.4 Hz,
1H), 6.94 (d, J = 2.4 Hz, 1H), 6.30 (s, 1H), 4.29 (t, J = 5.9 Hz, 2H), 3.91
(s, 2H), 3.70 (t, J = 6.6 Hz, 2H), 2.38 (p, J = 6.4 Hz, 2H); 13C NMR (75
MHz, (CD)3CO) : δ = 170.6, 162.9, 160.8, 156.5, 150.1, 127.3, 114.4,
113.8, 113.2, 102.3, 67.0, 37.9, 33.0, 30.7; HRMS (ESI-): calcd. for
C13H12Br79O3 [M-CO2-H]- : 294.9970; found 294.9968.
triphenylphosphonium bromide 5 as a white solid (863 mg, 93%
yield). m.p. 175-177 °C; IR : ṽ = 1715, 1610, 1433, 1390, 1261, 1135,
1
1112 cm-1; H NMR (300 MHz, CDCl3) : δ = 7.84-7.63 (m, 15H), 7.43
(t, J = 8.9 Hz, 1H), 6.84 (dd, J = 8.9 and 2.5 Hz, 1H), 6.70 (d, J = 2.4
Hz, 1H), 6.17 (s, 1H), 4.25 (t, J = 5.4 Hz, 2H), 3.77-3.59 (m, 7H), 2.28-
2.09 (m, 2H); 13C NMR (75 MHz, CDCl3) : δ = 169.4, 161.2, 160.9,
155.3, 148.2, 135.4 (d, JP-C = 3.0 Hz, 3C), 133.6 (d, JP-C = 10.0 Hz, 6C),
130.7 (d, JP-C = 12.6 Hz, 6C), 125.9, 118.5, 117.4, 113.5 (d, JP-C = 80.1
Hz, 3C), 112.1, 102.5, 67.2 (d, JP-C = 17.5 Hz, 1C), 52.8, 37.9, 22.7 (d,
JP-C = 3.3 Hz, 1C), 19.4 (d, JP-C = 54.1 Hz, 1C); HRMS (ESI+): calcd. for
C33H30O5P+ [M]+: 537.1831; found 537.1831. HPLC (system QC): tR =
28.4 min, purity 97.9%.
3-((4-(2-methoxy-2-oxoethyl)-2-oxo-2H-chromen-7-yl)oxy)-
N,N,N-trimethylpropan-1-ammonium bromide 6
2-(7-(3-bromopropoxy)-2-oxo-2H-chromen-4-yl)-N-(prop-2-yn-
To a solution of 4 (300 mg, 0.84 mmol) in dry EtOH (4 mL) was 1-yl)acetamide 9
added a 4.2 M solution of trimethylamine in EtOH (2.21 mL, 9.29
To a cooled solution of 8 (50 mg, 146 µmol), propargylamine (14 µl,
mmol, 11 equiv.). The resulting solution was stirred at 85 °C for 12
h. After completion of the reaction monitored by TLC, the mixture
was cooled to rt and concentrated under reduced pressure to give
the crude 3-((4-(2-ethoxy-2-oxoethyl)-2-oxo-2H-chromen-7-yl)oxy)-
N,N,N-trimethylpropan-1-aminium bromide. The crude product was
dissolved in dry MeOH (12 mL) and DIPEA (150 µL) was added. The
resulting mixture was refluxed for 48 h, cooled to rt, concentrated
under reduced pressure and washed several times with EtOAc to
give the desired salt 6 as a yellow solid (304 mg, 87% yield). m.p.
131-133 °C; IR : ṽ = 3478, 1717, 1611, 1392, 1263, 1200, 1141, 1064
219 µmol, 1.5 equiv.) and PyBOP (83 mg, 160 µmol, 1.1 equiv.) in a
mixture of ACN (1 mL) and DMF (100 µL) was added dropwise DIPEA
(36 µL, 219 µmol, 1.5 equiv.). The resulting mixture was stirred at rt
for 2 h and then diluted with EtOAc (5 mL) and aq HCl 1 N (5 mL).
The organic layer that formed was extracted, washed with NaHCO3
(5 mL), brine (5 mL), dried over Na2SO4 and concentrated in vacuo.
Flash column chromatography (cyclohexane/EtOAc, 40:60) Rf : 0.3
gave the desired product 9 as a white solid (43 mg, 78% yield). m.p.
141-143 °C; IR : ṽ = 3369, 3288, 2949, 1703, 1662, 1614, 1583, 1532,
1391, 1296, 1254, 1146, 1017 cm-1; 1H NMR (300 MHz, (CD3)2CO) : δ
= 7.81 (s, 1H), 7.73 (d, J = 8.8 Hz, 1H), 6.95 (dd, J = 8.8 and 2.5 Hz,
1H), 6.91 (d, J = 2.4 Hz, 1H), 6.26 (s, 1H), 4.28 (t, J = 5.9 Hz, 2H), 4.00
(dd, J = 5.5 and 2.5 Hz, 2H), 3.79 (s, 2H), 3.70 (t, J = 6.6 Hz, 2H), 2.66
(t, J = 2.6 Hz, 1H), 2.37 (p, J = 6.4 Hz, 2H); 13C NMR (75 MHz,
(CD3)2CO) : δ = 168.2, 162.8, 160.8, 156.4, 150.9, 127.5, 114.2,
113.9, 113.1, 102.2, 81.0, 72.2, 67.0, 39.9, 32.9, 30.7, 29.0; HRMS
(ESI+): calcd. for C17H17Br79NO4 [M+H]+ : 378.0341; found 378.0339.
1
cm-1; H NMR (300 MHz, CD3OD) : δ = 7.21 (d, J = 8.7 Hz, 1H), 7.01-
6.92 (m, 2H), 6.28 (s, 1H), 4.23 (t, J = 5.7 Hz, 2H), 3.91 (s, 2H), 3.72
(s, 3H), 3.68-3.60 (m, 2H), 3.23 (s, 9H), 2.42-2.30 (m, 2H); 13C NMR
(75 MHz, CD3CO) : δ = 171.3, 163.2, 162.8, 156.6, 151.1, 127.5,
114.5, 114.3, 113.8, 102.7, 66.4, 65.3, 53.8, 53.76, 53.70, 53.0, 38.1,
24.2; HRMS (ESI+): calcd. for C18H24NO5 [M]+ : 334.1654; found
334.1641. HPLC (system QC): tR = 19.7 min, purity > 99%.
(3-((4-(carboxymethyl)-2-oxo-2H-chromen-7-yl)oxy)propyl)-
triphenylphosphonium bromide 7
(3-((2-oxo-4-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)-2H-chromen
-7-yl)oxy)propyl)triphenylphosphonium bromide 10
To a solution of 5 (600 mg, 0.97 mmol) in a solution of MeOH (10
ml) and H2O (2 ml) was slowly added K2CO3 (403 mg, 2.92 mmol, 3
equiv.). The resulting mixture was stirred at rt for 4 h, then aq HCl 1
N (20 mL) and DCM (20 mL) was added. The organic layer that
formed was extracted, dried over Na2SO4, concentrated in vacuo
and washed with Et2O and acetone to give 7 as a white solid (586
mg, 89% yield). m.p. 145-147 °C; IR : ṽ = 2311, 1715, 1693, 1609,
1438, 1376, 1267, 1243, 1137, 1114, 1053, 1016 cm-1; 1H NMR (300
MHz, CD3OD) : δ = 7.92-7.72 (m, 15H), 7.59 (d, J = 8.9 Hz, 1H), 6.93
(dd, J = 8.9 and 2.4 Hz, 1H), 6.81 (d, J = 2.4 Hz, 1H), 6.21 (s, 1H), 4.26
(t, J = 5.3 Hz, 2H), 3.81 (s, 2H), 3.75-3.62 (m, 2H), 2.27-2.13 (m, 2H);
13C NMR (75 MHz, CD3OD) : δ = 172.48, 162.9, 162.8, 156.4, 151.61,
151.58, 136.3 (d, JP-C = 3.0 Hz, 3C), 134.8 (d, JP-C = 10.1 Hz, 6C), 131.6
Compound 9 (30 mg, 79 µmol) and PPh3 (62 mg, 238 µmol, 3 equiv.)
was suspended in dry ACN (1 mL). The mixture was stirred and
refluxed under Ar atmosphere. Refluxing was continued for 12 h.
The mixture was cooled, concentrated in vacuo and washed several
times with EtOAc to give 10 as a white solid (36 mg, 71% yield). m.p.
88-90 °C; IR : ṽ = 3207, 3044, 1709, 1669, 1609, 1437, 1383, 1268,
1139, 1112 cm-1; 1H NMR (300 MHz, CD3CN) : δ = 8.14 (br, 1H), 7.90-
7.60 (m, 16H), 6.84 (dd, J = 8.9 and 2.5 Hz, 1H), 6.77 (d, J = 2.4 Hz,
1H), 6.23 (s, 1H), 4.20 (t, J = 5.4 Hz, 2H), 3.90 (dd, J = 5.7 and 2.5 Hz,
2H), 3.76 (s, 2H), 3.60-3.46 (m, 2H), 2.42 (t, J = 2.5 Hz, 1H), 2.16-2.02
(m, 2H); 13C NMR (75 MHz, CD3CN) : δ = 168.9, 162.2, 161.5, 156.2,
151.5, 136.1 (d, JP-C = 3.0 Hz, 3C), 134.7 (d, JP-C = 10.1 Hz, 6C), 131.3
(d, JP-C = 12.6 Hz, 6C), 127.8, 119.7, 118.5, 114.1, 113.7 (d, JP-C = 84.7
10 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins