Organic Syntheses, Vol. 78, pp. 113-122
Checked by Tina M. Marks, Nathan X. Yu, and Edward J. J. Grabowski.
1. Procedure
A. Diethyl
[2-13C]malonate
(Note
1).
A flame-dried, 100-mL, round-bottomed Schlenk
flask equipped with a
rubber septum and a
magnetic
stirring bar is purged with
argon. The flask is charged
with
15 mL of anhydrous tetrahydrofuran
(THF) (Note
2) and
5.8
mL (28 mmol, 2.5 equiv) of hexamethyldisilazane
(Note
3). After the solution is cooled to 0°C in an
ice-water
bath,
9.4 mL (23.5 mmol,
2.1 equiv) of a solution of butyllithium (2.5 M in
hexanes) (Note
4) is added slowly via a syringe to the stirred
solution. The
ice bath is removed and the mixture is allowed
to warm to room temperature. After the solution is stirred for 30 min, it is cooled
to −78°C using an
acetone-dry ice bath and equilibrated
for 5 min at the same temperature. Then
1.00 g
(11.2 mmol, 1 equiv) of ethyl [2-13C]acetate
(Note
5) is added within 5 min via a syringe, and the acetate-containing
flask is rinsed with
0.5 mL of anhydrous
THF. Stirring is continued at −78°C for 20 min, and
1.07
mL (11.2 mmol, 1 equiv) of ethyl chloroformate
(Note
6) is added within 5 min via a syringe. The mixture is
stirred for 1 hr at −78°C, and
5 mL
of 6 M hydrochloric acid (HCl) is added in one portion
(Note
7). The mixture is allowed to warm to room temperature,
and after the addition of 20 mL of water, the pH of the solution is adjusted to 1-2
with 2 M HCl. The mixture is extracted with
diethyl
ether (3 × 50 mL), and the combined organic
phases are washed successively with 2 M HCl, water, and
brine
(30 mL each). The HCl and water phases are combined and
reextracted with ether (50 mL). The organic layer is washed with
brine
(20 mL) and added to the combined organic phases. The
combined extracts are dried over
anhydrous sodium
sulfate (Na
2SO
4), filtered and concentrated
under reduced pressure with a
rotary evaporator (200 mbar/35°C,
150 mm/35°C). The crude product is distilled in a microdistillation apparatus at 90
mbar (67.5 mm) to give
1.66 g(
10.3 mmol,
92%)
of
diethyl [2-13C]malonate
as a colorless liquid (Notes
8 and
9).
2. Notes
1. The procedure follows closely that of Mueller and Leete
2 with slight improvements by the submitters.
3.
Hexamethyldisilazane
(98%), purchased from Lancaster Synthesis Inc.
or Aldrich Chemical Company, Inc., was used as received.
5.
Ethyl [2-13C]acetate
is commercially available (Aldrich Chemical Company, Inc.),
but expensive. The compound can be prepared by O-ethylation
4,5,6 of the cheaper
sodium [2-13C]acetate (Aldrich
Chemical Company, Inc.) or via
[2-13C]acetyl
chloride.
7
6.
Ethyl chloroformate
(97%), purchased from Aldrich Chemical Company, Inc.,
was used as received.
7. The solution should be quenched prior to warming to room temperature.
Solutions of lithiated
ethyl acetate decompose rapidly at 0°C.
8
8. The receiver is cooled to −10°C. Cooling to −78°C
is not advisable because obstruction may occur. The product (
bp 123-125°C/90 mbar, 67.5 mm) can be separated from the hydrolysis
products
trimethylsilanol and traces of
hexamethyldisiloxane.
9 At the end, the apparatus is rinsed with
diethyl ether to obtain all the product.
9. The spectral data are as follows:
1H NMR (300 MHz, CDCl
3) δ:
1.27 (t, 6 H, J = 7.2), 3.34 (d, 2 H, J = 132), 4.19
(q, 4 H, J = 7.2);
13C
NMR (75 MHz, CDCl
3) δ: 14.1, 41.7 (
13C),
61.5, 166.7 (d, J = 59); MS (EI): 161 [M+] (3), 134 (40), 116 (100),
106 (7), 89 (52), 61 (31); IR (KBr) cm
−1: 3465 (br),
2986, 2942, 1754, 1733, 1467,
1448, 1410, 1369, 1319, 1267,
1189, 1151, 1097, 1035, 949,
866, 844, 787, 666, 603.
10. Because of the relatively high melting point of the solvent (23-26°C),
it is not advisable to put the condenser directly on the flask. With the addition
funnel between the flask and the condenser, most of the
tert-butyl alcohol
is condensed as a liquid and does not collect as a solid on the cold condenser.
11.
tert-Butyl alcohol
(=99.7%), purchased from Fluka Chemical Corp.
or Fisher Scientific, was used as received.
12.
4H-Pyran-4-one
is commercially available (98+%, Aldrich Chemical Company, Inc.),
but the substance is expensive. It can be synthesized by decarboxylation of
chelidonic acid monohydrate (Lancaster Synthesis Inc.)
following the procedure of De Souza and co-workers.
10
13.
Potassium tert-butoxide (99%),
purchased from Fluka Chemical Corp. or Aldrich Chemical
Company, Inc., was used as received.
14. Flash chromatography was performed on
E.
Merck silica gel 230-400 mesh: 150 g of silica gel was loaded
on a 7- × 2-in size column using a minimum amount of
ethyl acetate
as loading solvent. The checkers used a 90-g silica column purchased from Biotage.
15. The spectral data are as follows:
1H NMR (300 MHz, CDCl
3) δ:
1.39 (t, 3 H, J = 7.2), 4.36 (q, 2 H, J = 7.2), 6.50
(s, 1 H), 6.85-6.93 (m, 2 H), 7.93-7.99 (m, 2 H);
13C NMR (75 MHz,
CDCl
3) δ: 14.4, 61.1, 115.3 (d, J
= 1.5), 122.7 (
13C), 132.0 (d, J = 60),
160.4 (d, J = 9.1), 167.2 (d, J = 77); MS (EI): 167 [M+] (30), 139 (23),
122 (100), 94 (11), 83 (10); IR (KBr) cm
−1: 3218 (br),
1672, 1602, 1583, 1441, 1370,
1306, 1286, 1239, 1169, 1104,
1018, 847, 768, 723, 697,
618.
16. The spectral data are as follows:
1H NMR (300 MHz, DMSO-d
6) δ:
6.77-6.85 (m, 2 H), 7.75-7.81 (m, 2 H), 10.2 (s, br,
≈0.8 H), 12.4 (s, br, ≈0.8 H); (The coupling
pattern of the aromatic protons is even at 600 MHz not clearly resolved.)
13C NMR (75 MHz, DMSO-d
6)
δ: 115.3, 121.6 (
13C), 131.7 (d,
J = 59), 161.8 (d, J = 8.5), 167.3 (d, J = 74);
MS (EI) 139 [M+] (100), 122
(94), 94 (20); IR
(KBr) cm
−1: 3394 (br), 2966, 2831,
2660, 2562, 1677, 1602, 1588,
1504, 1440, 1421, 1309, 1282,
1243, 1169, 1100, 933, 852,
766, 617, 548.
All toxic materials were disposed of in accordance with "Prudent Practices in the
Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
Previous syntheses of ring-labeled
4-hydroxybenzoic acid use
many steps and show low overall yields.
4-Hydroxy[3-13C]benzoic
acid was synthesized in six steps from
ethyl [1-13C]acetate
with
2.8% overall yield.
13 4-Hydroxy[3,5-13C2]benzoic acid
was prepared in five steps from
[1,3-13C2]acetone
with an overall yield of less than
4.5%.
12b 4-Hydroxy[2,6-13C2]benzoic
acid was generated microbiologically from
[1-13C]glucose
by using a mutant strain of
Klebsiella pneumoniae.
14 For 120 mg of product, 18 g of labeled
glucose was necessary.
Methyl
4-methoxy[3,5-13C2]benzoate was obtained
from
[1,3-13C2]acetone
in five steps with 32% overall
yield.
15 Baldwin
and co-workers
16 synthesized
methyl 4-methoxy[3,4,5-13C3]benzoate
in four steps from
[1,2,3-13C3]acetone
without indicating the overall yield.
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
4-Hydroxybenzoic-1-13C acid: Benzoic-1-13C
acid, 4-hydroxy- (14); (211519-30-1)
Diethyl malonate-2-13C: Propanedioic-2-13C
acid, diethyl ester (10); (67035-94-3)
1,1,1,3,3,3-Hexamethyldisilazane: Disilazane,
1,1,1,3,3,3-hexamethyl- (8); Silanamine, 1,1,1-trimethyl-N-(trimethylsilyl)-
(9); (999-97-3)
Butyllithium: Lithium, butyl-
(8,9); (109-72-8)
Ethyl acetate-2-13C: Acetic-2-13C
acid, ethyl ester (9); (58735-82-3)
Ethyl chloroformate: Formic acid, chloro-,
ethyl ester (8); Carbonochloridic acid, ethyl ester
(9); (541-41-3)
Ethyl 4-hydroxybenzoate-1-13C: Benzoic-1-13C
acid, 4-hydroxy-, ethyl ester (14); (211519-29-8)
tert-Butyl alcohol (8); 2-Propanol, 2-methyl-
(9); (75-65-0)
4H-Pyran-4-one (8,9); (108-97-4)
Potassium tert-butoxide: tert-Butyl alcohol,
potassium salt (8); 2-Propanol, 2-methyl-, potassium salt
(9); (865-47-4)
Diphenylacetic acid: Acetic acid, diphenyl-
(8); Benzeneacetic acid, α-phenyl- (9); (117-34-0)
4-Biphenylmethanol (9); (3597-91-9)
Sodium acetate-2-13C: Acetic-2-13C
acid, sodium salt (9); (13291-89-9)
Acetyl-2-13C chloride: Acetyl-2-13C
chloride (8,9); (14770-40-2)
Trimethylsilanol: Silanol, trimethyl-
(8,9); (1066-40-6)
Hexamethyldisiloxane: Disiloxane, hexamethyl-
(8,9); (107-46-0)
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