[3,5-13C2]4H-Pyran-4-one (9)9. To triethyl orthoformate
(4.74 g, 5.33 mL, 32 mmol) at -30 C (acetonitrile and dry ice)
(75.45 MHz, CDCl3) 162.8 (-CO-), 161.4 (enhanced, -CH-), 105.6
(d, J 79 Hz, -CH-), 67.2 (-CH2-), and 14.6 (-CH3).
◦
under argon, was added drop-wise over 15 min, a solution of
BF3·OEt2 (12.14 mL, 96 mmol) in DCM (13 mL). The reaction
mixture was warmed to 0 ◦C with stirring, and stirred for 20 min to
give a slurry of◦diethoxycarbenium fluoroborate. The mixture was
cooled to -78 C and [1,3-13C2]acetone (1.0 g, 14 mmol) added.
iPr2NEt (16.7 mL, 96 mmol) was then added drop-wise over 30 min
with efficient stirring and the resulting reaction mixture stirred at
-78 ◦C for 2.5 h. After that time, the reaction mixture was poured
into conc. NaHCO3 solution (120 mL), and stirred vigorously for
10 min at room temperature. The resulting mixture was extracted
with DCM (3 ¥ 50 mL). The combined organic layers were washed
successively with ice cold 1 M H2SO4 (17.5 mL), and cold water
(2 ¥ 50 mL) and dried (MgSO4). Removal of the solvent at reduced
pressure gave the crude enone product 8 as a brown oil (2.40 g,
quant.). dH (300 MHz, CDCl3) 7.52 (2H, dd, J 12.4, 6.7 Hz, -CH-
), 5.59 (2H, dd, J 159.3, 12.4 Hz, -13CH-), 3.88 (4H, q, J 7.1 Hz,
-CH2-), and 1.28 (6H, t, J 7.1 Hz, -CH3); dC (75.45 MHz, CDCl3)
163.3 (t, J 41 Hz, -CO-), 105.6 (enhanced, -CH-), 62.5 (-CH2-),
and 14.4 (-CH3).
A solution of the crude enone (0.58 g, 3.35 mmol) in ethanol
(20 mL) and 10% aqueous HCl (2 mL) was heated at 80 ◦C for 24 h.
After this time, the solvents were removed at reduced pressure and
the resulting residue dissolved in water (15 mL). The aqueous layer
was extracted with toluene (3 ¥ 15 mL), and the combined organic
layers washed with water (2 ¥ 15 mL). After filtering the aqueous
phase to remove any solids, it was treated with decolourising
charcoal and filtered through celite. Remov◦al of the solvent from
the aqueous phase at reduced pressure (at 40 C) gave [2,6-13C2]4H-
pyran-4-one 14 as an off-white solid (0.304 g, 92%). Mp 33–33.5 ◦C
◦
(lit unlabelled9 32.5 C); m/z (CI) 99 [(MH)+, 100%]; HRMS
(CI) [Found: (MH)+, 99.0360, 12C313C2H5O2 requires 99.0357]; dH
(300 MHz, CD3OD) 8.20 (2H, dm, J 202 Hz, 13C(2,6)H), and 6.33
(2H, m, C(3,5)H); dC (75.45 MHz, CD3OD) 156.8 (enhanced, C-2,
6), and 117.9 (s, C-3,5); nmax/cm-1 1623 (C O), 1577 (C C), 1325,
=
=
923 and 827 (CH).
Ethyl 4-hydroxy-[1,3,5-13C3]benzoate (10). A solution of [3,5-
13C2]4H-pyran-4-one 9 (1.57 g, 16 mmol) and diethyl [2-
t
13C]malonate 3 (2.34 g, 15 mmol) in dry BuOH (25 mL) was
A solution of the crude enone 8 (2.75 g, 16 mmol) in ethanol
(80 mL) and 10% aqueous HCl (8 mL) was heated at 80 ◦C
for 24 h. After this time, the solvents were removed at reduced
pressure and the resulting residue dissolved in water (50 mL).
The aqueous layer was extracted with toluene (3 ¥ 30 mL), and
the combined organic layers washed with water (2 ¥ 30 mL).
After filtering the aqueous phase to remove any solids, it was
treated with decolourising charcoal and filtered through celite.
Removal of the solvent from the aqueous phase at reduced pressure
heated to reflux under argon. KOBut (16 mmol, 16 mL of a 1 M
solution in tBuOH) in dry tBuOH (30 mL) was added drop-wise.
The resulting mixture was heated under reflux for 3 h, after which
time HCl (1 M, 30 mL) was added. The reaction solution was
heated under reflux for a further 1 h, the solvent was then removed
at reduced pressure, and water (40 mL) added. The aqueous phase
was extractedwithdiethylether (3 ¥ 30 mL). The combined organic
phase was washed with water (2 ¥ 30 mL), brine (30 mL), dried
(MgSO4) and solvent removed at reduced pressure to give 10 as an
orange solid (1.88 g, 74%). Mp 113–113.5 ◦C (lit unlabelled8 112–
114 ◦C); m/z (CI) 170 [(MH)+, 100%], 142 [(M - Et)+, 18]; HRMS
(CI) [Found: (MH)+, 170.0808, 12C613C3H10O3 requires 170.0809];
dH (400 MHz, CDCl3) 7.97 (2H, br d, J 8.7 Hz, C(2,6)H), 6.88 (2H,
dm, J 159.2 Hz, 13C(3,5)H), 4.36 (2H, q, J 7.3 Hz, -CH2-), and
1.39 (3H, t, J 7.3 Hz, -CH3); dC (100 MHz, CDCl3) 169.7 (-CO-),
161.4 (C-4), 131.8 (dt, J 59, 6 Hz, C-2,6), 123.0 (enhanced, t, J
2 Hz, C-1), 115.1 (enhanced, d, J 2 Hz, C-3,5), 60.9 (-CH2-), and
◦
(at 40 C) gave [3,5-13C2]4H-pyran-4-one 9 as an off-white solid
◦
(1.37 g, quant.). Mp 32–32.5 C (lit unlabelled9 32.5 ◦C); m/z
(CI) 99 [(MH)+, 100%]; HRMS (CI) [Found: (MH)+, 99.0357,
12C313C2H5O2 requires 99.0357]; dH (300 MHz, DMSO-d6) 8.13
(2H, ddd, J 6.5, 4.8, 2.1 Hz, C(2,6)H), and 6.29 (2H, dd, J 171.7,
6.5 Hz, 13C(3,5)H); dC (75.45 MHz, DMSO-d6) 177.1 (t, J 54 Hz,
-CO-), 156.9 (d, J 72 Hz, C-2, 6), and 117.3 (enhanced, C-3,5);
n
max/cm-1 1619 (C O), 1590 (C C), 1326 (CH), 1091 (C-O), 918
= =
and 848 (CH).
14.4 (-CH3); nmax/cm-1 3207 (OH), 1714 (C O), 1667 and 1569
=
(ArH), 1277 (OH), 1229, 1165, 1098 and 1016 (C–O), 840 and
762 (CH).
[2,6-13C2]4H-Pyran-4-one (14)9. To triethyl [13C]orthoformate
(1 g, 1.12 mL, 6.7 mmol) at -30 ◦C (acetonitrile and dry ice)
under argon, was added drop-wise over 15 min, a solution of
BF3·OEt2 (2.54 mL, 20.1 mmol) in DCM (3 mL). The reaction
mixture was warmed to 0 ◦C with stirring, and stirred for 20 min
to give a slurry of diethoxycarbenium fluoroborate. The mixture
was then cooled to -78 ◦C and acetone (0.24 mL, 3.35 mmol)
Ethyl 3,5-dibromo-4-hydroxy-[1,3,5-13C3]benzoate (11). To a
solution of ethyl [1,3,5-13C3]4-hydroxybenzoate 10 (0.878 g,
5.2 mmol) and sodium acetate (1.94 g, 24 mmol) in AcOH (20 mL),
was added drop-wise over 20 min a solution of bromine (3.54 g,
22 mmol) in AcOH (5 mL) at room temperature. The reaction
mixture was stirred for 1.5 h at room temperature. After the
addition of water (40 mL) to the reaction mixture, the aqueous
phase was extracted with DCM (3 ¥ 40 mL). The combined organic
layers were washed with sodium metabisulfite solution (2 ¥ 30 mL),
water (30 mL), brine (30 mL) and dried (MgSO4). Removal of
the solvent at reduced pressure gave the di-bromo product 11
as an orange/yellow solid (1.68 g, 99%). Mp 150–150.5 ◦C (lit
unlabelled15 108–108.5 ◦C); m/z (CI) 328 [(MH79Br81Br)+, 100%],
326 [(MH79Br2)+, 30], 330 [(MH81Br2)+, 27]; HRMS (CI) [Found:
(MH)+, 327.8998, 12C613C3H8O379Br81Br requires 327.8999]; dH
(400 MHz, CDCl3) 8.16 (2H, dt, J 2.8, 1.7 Hz, C(2,6)H), 4.37
(2H, q, J 7.1 Hz, -CH2-), and 1.40 (3H, t, J 7.1 Hz, -CH3); dC
i
was added. Pr2NEt (3.5 mL, 20.1 mmol) was then added drop-
wise over 30 min with efficient stirring and the resulting reaction
◦
mixture stirred at -78 C for 2.5 h. After that time, the reaction
mixture was poured into conc. NaHCO3 solution (30 mL), and
stirred vigorously for 10 min at room temperature. The resulting
mixture was extracted with DCM (3 ¥ 15 mL). The combined
organic layers were washed successively with ice cold 1 M H2SO4
(4.2 mL), and cold water (2 ¥ 15 mL) and dried (MgSO4). Removal
of the solvent at reduced pressure gave the crude enone 13 as a
brown oil (0.58 g, quant.). dH (300 MHz, CDCl3) 7.52 (2H, dd, J
181.4, 12.5 Hz, -13CH-), 5.57 (2H, dd, J 12.5, 3.2 Hz, -CH-), 3.88
(4H, dq, J 7.0, 2.9 Hz, -CH2-), and 1.28 (6H, t, J 7.0 Hz, -CH3); dC
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 785–788 | 787
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