Checked by Paula M. Roach, Sung W. Rhee, and Robert M. Coates.
1. Procedure
A.
4-Benzyloxy-2-butanone. A
100-mL, three-necked, round-bottomed flask is equipped with a
magnetic stirring bar, a
condenser mounted with a nitrogen inlet, and a
pressure-equalizing dropping funnel (Note
1). The flask is charged with
4.40 g (0.050 mol) of 4-hydroxy-2-butanone (Note
2),
50 mL of dry toluene (Note
3), and
13.9 g (0.060 mol) of freshly prepared silver oxide (Note
4). The suspension is stirred and cooled in an
ice bath while
12.0 g (0.070 mol) of benzyl bromide (Note
5) is added over ca. 5 min. The ice bath is removed, and the mixture is allowed to stir for 18 hr at room temperature (Note
6). The suspension is filtered through Celite, the filter cake is washed with two
50-mL portions of toluene, and the combined filtrates are evaporated under reduced pressure. The remaining liquid, which weighs 9.6–10.4 g, is dissolved in
15 mL of 5% tetrahydrofuran in hexane. The cloudy solution is applied to a
5-cm × 47.5-cm column prepared with
380–385 g of silica gel (Note
7) packed in
5% tetrahydrofuran in hexane. The column is eluted with
5% tetrahydrofuran in hexane, and 250-mL fractions are collected and analyzed by TLC (Note
8). A total of 12 or 13 fractions (3–3.25 L) is collected first to separate
benzyl bromide,
dibenzyl ether, and other minor by-products. The product is then eluted with
0.5–1.0 L of tetrahydrofuran, the solvent is evaporated, and the remaining 6.0–6.5 g of liquid is distilled under reduced pressure. After separation of a 0.7–1.0 g forerun, bp 30–68°C (0.2 mm), consisting mainly of
benzyl alcohol,
3.87–4.33 g (
43–49%) of
4-benzyloxy-2-butanone, bp
77–79°C (0.2 mm),
nD25 1.5018 is collected (Note
9).
B.
5-Benzyloxy-3-hydroxy-3-methylpentanoic-2-13C acid. A
50-mL, three-necked, round-bottomed flask is equipped with a magnetic stirring bar, a
rubber septum, a condenser connected to a nitrogen inlet, and a pressure-equalizing dropping funnel. The apparatus is purged with
nitrogen and dried (Note
1), and the flask is charged with
1.79 g (2.4 mL, 0.0177 mol) of freshly distilled diisopropylamine and
6.5 mL of dry tetrahydrofuran (Note
10). The solution is stirred and cooled in an ice bath while
7.22 mL (0.0169 mol) of 2.34 M butyllithium in hexane (Note
11) is added from the dropping funnel over 30 min. After 30 min a solution of
0.439 g (0.00720 mol) of acetic acid-2-13C (Note
12) in
3 mL of tetrahydrofuran is added by syringe over ca. 10 min. The solution is stirred and cooled in an ice bath for 3.5 hr, after which
1.30 g (0.0073 mol) of 4-benzyloxy-2-butanone in
4 mL of tetrahydrofuran is added by syringe over 15 min. Stirring is continued for 2 hr at 0°C and 18 hr at room temperature. The reaction mixture is cooled in an ice bath, hydrolyzed by adding 4.5 mL of water, and concentrated under reduced pressure to remove most of the
tetrahydrofuran. The remaining aqueous suspension is basified by addition of
6 mL of aqueous 4% sodium hydroxide and extracted with
30 mL of diethyl ether. The ethereal layer is extracted with
40 mL of 4% sodium hydroxide, the combined alkaline extracts are cooled and acidified to pH 3 with ca.
10 mL of 18% hydrochloric acid, and the aqueous mixture is extracted with three
25-mL portions of ether. The combined ethereal extracts are dried over anhydrous
sodium sulfate and evaporated. The remaining viscous, yellow liquid weighs
0.95–1.01 g (
55–59%) and is used in part C without further purification (Note
13).
2. Notes
1. The apparatus was dried in an
oven at 125°C and allowed to cool while a stream of
nitrogen was passed through the condenser and out the dropping funnel. Alternatively the apparatus may be flushed with
nitrogen and flamed dry. A
nitrogen atmosphere was maintained within the apparatus during the subsequent operations.
2.
4-Hydroxy-2-butanone was purchased from Chemical Samples Company by the checkers and distilled, bp
56–58°C (5.0 mm). The submitters obtained the material from BASF Wyandotte Corporation, Parsippany, NJ 07054.
4. The
silver oxide was prepared by the following procedure. A solution of
6.9 g (0.172 mol) of sodium hydroxide in 200 mL of water was heated to 80–90°C and added to a solution of
30 g (0.177 mol) of silver nitrate in 200 mL of water, also heated to 80–90°C. The resulting hot suspension was quickly filtered, and the filter cake was washed with 200 mL of hot water,
200 mL of 95% ethanol, and
200 mL of absolute ethanol. The
silver oxide was dried at 1 mm and weighed
17.8–18.3 g (
87–89%).
6. The reaction is mildly exothermic, and the mixture becomes warm after the ice bath is removed. The checkers monitored the progress of the reaction by TLC on
silica gel with
5% methanol in chloroform as developing solvent. After 2 hr the spot at
Rf 0.42 for the starting alcohol has disappeared, and the formation of the spots at
Rf 0.70 and 0.47 for the product and
benzyl alcohol, respectively, appeared to be complete.
7. The checkers used
silica gel 60 having particle sizes from 0.05 to 0.2 mm (70–270-mesh ASTM), supplied by Brinkmann Instruments, Inc., Westbury, NY. The submitters used
450 g of silica gel with 90–200 mesh purchased from Gallard-Schlesinger Chemical Manufacturing Corp., Carle Place, NY 11514.
8. Thin-layer chromatograms were performed by the checkers on plates coated with
silica gel using
chloroform as developing solvent. The
Rf values for
benzyl bromide, dibenzyl ether,
4-benzyloxy-2-butanone, and
benzyl alcohol were 0.72, 0.61, 0.20, and 0.09, respectively. Chromatograms of the crude product showed spots for these four components and in addition three minor spots at
Rf 0.44, 0.40, and 0.36. The first six fractions (1.5 L) were combined and evaporated, affording
0.6–1.5 g of material judged to be mainly benzyl bromide. The following six or seven fractions (1.5–1.75 L) provided 1.6–3.2 g of material composed largely of
dibenzyl ether.
9. The submitters obtained
4.5 g (
51%) of product, bp
95°C (0.8 mm),
nD27 1.5029. A boiling point of
88–91°C (0.5 mm) and a refractive index of
nD28 1.5040 are reported for
4-benzyloxy-2-butanone.
2 The product was analyzed by the checkers. Anal. calcd. for C
11H
14O
2: C, 74.13; H, 7.92. Found: C, 73.87; H, 8.09. The product has the following spectral characteristics: IR (liquid film) cm
−1: 1725 and 1710 (split C=O), 1360, 1175, 1110, 1090, 740, 700;
1H NMR (CDCl
3) δ: 2.17 (singlet, 3, C
H3), 2.70 (triplet, 2,
J = 6, C
H2CH
2O), 3.78 (triplet, 2,
J = 6, CH
2C
H2O), 4.50 (singlet, 2, C
H2C
6H
5), 7.32 (singlet, 5, C
6H5).
12.
Acetic acid-2-13C of 90% isotopic purity was purchased by the checkers from Stohler Isotope Chemicals, Rutherford, NJ, and dried by distillation from
phosphorus pentoxide in the following manner. A
0.5-g portion of the labeled acetic acid was transferred to a
5-mL flask containing
0.1 g of phosphorus pentoxide. The flask (A) was attached to a vacuum system (see
f.htmigure 1), chilled with a
dry ice-acetone bath until the mixture solidified, and evacuated to 0.01 mm. The stopcock was closed, the cooling bath was moved to the receiver (flask B), and flask A was allowed to warm to room temperature. The distillation was completed by heating flask A to 60°C.
Nitrogen was introduced into the system and flask B removed and stoppered. The recovery of acetic acid-2-
13C was
0.42–0.44 g (
84–86%).
Figure 1
13. The submitters carried out the procedure in Section B at five times the scale described with
1.96 g (0.0321 mol) of acetic acid-2-13C and obtained
4.01 g (
56%) of product. The spectral properties of the product are as follows: IR (liquid film) cm
−1: 1710 (C=O);
1H NMR (CDCl
3) δ: 1.31 (doublet, ca. 2.4,
J = 4.5,
13CH
2CC
H3), 1.31 (singlet, ca. 0.6,
12CH
2CC
H3), 1.89 (multiplet, 2, C
H2CH
2O), 2.55 (doublet, ca. 1.6,
J = 128,
13C
H2CO
2H), 2.55 (singlet, ca. 0.4,
12C
H2CO
2H), 3.70 (triplet, 2,
J = 6, CH
2C
H2O), 4.52 (singlet, 2, C
6H
5C
H2), 7.35 (singlet, 5, C
6H5). The product may be purified further by Kugelrohr distillation with an oven temperature of 100–110°C (0.015 mm).
14. The
palladium black was purchased from Engelhard Industries Division, Engelhard Minerals and Chemicals Corporation, Iselin, NJ 08830. The checkers found that the hydrogenolysis may also be effected with
5% palladium on carbon, although 20 hr was required to achieve complete reaction.
15. The hydrogenation apparatus is available from Parr Instrument Company, Inc., Moline, IL 61265.
16. As a further precaution the checkers chilled the suspension in an ice bath prior to filtration.
17. The product was further purified by the checkers by recrystallization from ca.
1.5 mL of ether at 0°C. The recovery of white, crystalline mevalonolactone-2-
13C, mp
24–26°C, was
90–92%. The reported
2 melting point is
27–28°C. The spectral properties of the product are as follows: IR (liquid film) cm
−1: 3300 (OH), 1730 (C=O); 220–MHz
1H NMR (CDCl
3) δ: 1.40 (doublet, ca. 2.4,
J = 4.5,
13CH
2CC
H3), 1.40 (singlet, ca. 0.6,
12CH
2CC
H3), 1.90 (multiplet, 2, C
H2CH
2O), 2.54 and 2.67 (eight-line
ABX multiplet, ca. 1.6,
JAB = 17,
JAX = 132,
JBX = 127,
13C
HAHB), 2.54 and 2.67 (
AB doublet, 0.4,
J = 17,
12C
HAHB), 4.47 (multiplet, 2, CH
2C
H2O).
3. Discussion
Many of the procedures given above have been utilized for the preparation of
mevalonolactone labeled with isotopes of
carbon,
hydrogen, and
oxygen.
7,8,9,10,11 Mevalonolactone-14C has been prepared with the label at all six positions: 1-,
7,38 2-,
7,17,32,33 3-,
14 3'-,
27,39 4-,
7,24 and 5-
14C.
26 Preparations of singly and doubly labeled mevalonolactone-
13C have been reported recently: 2-,
35,40 3-,
41 4-,
42 43 3',4-,
7,24 3,4-,
35,43 and 4,5-
13C.
44 The procedure described here
35 for the preparation of
mevalonolactone-2-13C is both convenient and economical compared to the usual Reformatsky methods since acetic acid-2-
13C is utilized directly in the condensation reaction, rather than
methyl or ethyl bromoacetate. The overall yield of
mevalonolactone-2-13C is
46–52% based on
acetic acid-2-13C.
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
silica gel
palladium black
sodium ketyl of benzophenone
dimethyl or diethyl 3-hydroxy-3-methylglutarate
methyl or ethyl bromoacetate
2H-Pyran-2-one-13C, tetrahydro-4-hydroxy-4-methyl-
ethanol (64-17-5)
hydrochloric acid (7647-01-0)
acetic acid (64-19-7)
ammonia (7664-41-7)
Benzene (71-43-2)
methanol (67-56-1)
ether,
diethyl ether (60-29-7)
hydrogen (1333-74-0)
sodium hydroxide (1310-73-2)
chloroform (67-66-3)
silver oxide (20667-12-3)
silver nitrate (7761-88-8)
bromine (7726-95-6)
sodium sulfate (7757-82-6)
oxygen (7782-44-7)
formic acid (64-18-6)
barium oxide
nitrogen (7727-37-9)
carbon (7782-42-5)
potassium hydroxide pellets (1310-58-3)
toluene (108-88-3)
zinc (7440-66-6)
sodium,
sodium wire (13966-32-0)
palladium (7440-05-3)
Benzyl alcohol (100-51-6)
Dibenzyl ether (103-50-4)
hydrogen peroxide (7722-84-1)
xylene (106-42-3)
Diphenylacetic acid (117-34-0)
chromium trioxide (1333-82-0)
boron trifluoride (7637-07-2)
benzyl bromide (100-39-0)
butyllithium (109-72-8)
Tetrahydrofuran (109-99-9)
lithium aluminum hydride (16853-85-3)
4-hydroxy-2-butanone (590-90-9)
silver carbonate (534-16-7)
hexane (110-54-3)
4,4-dimethoxy-2-butanone (5436-21-5)
sodium borohydride (16940-66-2)
2-Butanol (78-92-2)
1,10-phenanthroline (66-71-7)
diisopropylamine (108-18-9)
Linalool (78-70-6)
phosphorus pentoxide (1314-56-3)
4-Benzyloxy-2-butanone (6278-91-7)
mevalonolactone
monomethyl 3-hydroxy-3-methylglutarate
lithium borohydride (16949-15-8)
3,5-dihydroxy-3-methylpentanal
3-methyl-1,3,5-pentanetriol (7564-64-9)
3-methyl-1-tetrahydropyranyloxy-5-hexen-3-ol
3,5-dihydroxy-3-methylpentanenitrile
4-(bromoacetoxy)-2-butanone
4-acetoxy-2-butanone (10150-87-5)
N-(diphenylmethyl)-3,4-epoxy-5-hydroxy-3-methylpentanamide
5-Benzyloxy-3-hydroxy-3-methylpentanoic-2-13C acid,
5-benzyloxy-3-hydroxy-3-methylpentanoic acid-2-13C (57830-65-6)
acetic acid-2-13C
Mevalonolactone-2-13C
Mevalonolactone-14C
(R,S)-Mevalonolactone-2-13C
Copyright © 1921-2002, Organic Syntheses, Inc. All Rights Reserved