Checked by Alan T. Johnson and James D. White.
1. Procedure
Caution! Hydrogen peroxide attacks the skin and may decompose violently. The first step should be carried out behind a safety screen, and the operator should wear safety glasses and rubber gloves. Air must not be admitted to the hot distillation residue in Step 2.
A.
2(5H)-Furanone. A
6-L, three-necked, round-bottomed flask equipped with two
condensers, a
dropping funnel, and a
12 × 55-mm magnetic stirring bar is charged with
480 g (5 mol) of furfural (Note
1) and
2.0 L of methylene chloride. The addition of
200 g of sodium sulfate (Note
2) and
150 g of N,N-dimethylethanolamine (Note
3) in one portion each is followed immediately by
460 g of formic acid (Note
4), carefully added in portions over a period of 2 min, after which
100 mL of 30% hydrogen peroxide (Note
5) is added in one portion. The mixture is stirred vigorously. After 5 min the mixture will reflux and another
800 mL of 30% hydrogen peroxide is added dropwise during 9 hr (Note
6) while stirring is continued. When the addition is complete, the mixture is vigorously stirred as long as it refluxes and then stirred gently overnight. The organic phase is separated, and the water phase is extracted with the
200 mL of methylene chloride that is used to wash out residues from the reaction flask.
The
methylene chloride phase is washed with two
150-mL portions of saturated sodium disulfite solution (Note
7) and dried over
magnesium sulfate and
sodium sulfate. After a negative peroxide test (Note
8), the solvent is removed. The crude product (
255 g) is fractionated through a
30-cm Vigreux column. The material boiling at
85–85°C (13 mm) is collected to give
210 g of
butenolide, which is yellow because of some high-boiling residues. Redistillation through the
30-cm Vigreux column and collection of the material boiling at
100–102°C (30 mm),
95–97°C (19 mm),
89–91°C (16 mm), or
79–81°C (9 mm) gives colorless
butenolide. In this way
170.2 g (
41%) of pure
butenolide is obtained.
B.
Furyl phosphorodichloridate. A
1-L flask, protected from moisture by a
calcium chloride tube, is charged with
42 g (0.5 mol) of 2(5H)-furanone,
85 g (0.55 mol) of phosphoryl chloride, and
100 mL of methylene chloride. A solution of
65 g (0.5 mol) of ethyldiisopropylamine in
60 mL of methylene chloride is added dropwise during 4 hr at ambient temperature (Note
9). The resulting mixture is stirred overnight (12 hr), after which
6.5 g of the amine in
10 mL of methylene chloride is added in one portion and stirring is continued for 20 hr (Note
10). The solvent is removed on a
rotary evaporator and
200 mL of dry ether (Note
11) is added cautiously, followed by
100 mL of pentane (in that order), to the dark residue to precipitate the amine hydrochloride. The flask is stoppered and shaken for 1–2 min. The
hydrochloride is filtered by suction and washed immediately with
100 mL of dry ether and
200 mL of pentane or petroleum ether (Note
12). The bottle is tightly stoppered and the filtrate is allowed to stand in the
refrigerator (+4°C) overnight. The clear brown ethereal phase is decanted from a dark lower phase, and the solvent is evaporated. The residue (ca.
100 g) is distilled at the
water pump. In order to obtain pure, color-stable, yellow dichloridate it is usually necessary to distill it twice. The first distillation is done rapidly, collecting the material that boils at
73–98°C (9 mm) to give
65–75 g of product, which usually darkens within a few days (Note
13) and (Note
14). Redistillation (Note
15), collecting the material that boils at
91–93°C (22 mm),
88–90°C (16 mm), or
73–76°C (9 mm), gives
60–65 g of pure product (Note
16). The yield is
60–65%.
C.
Furyl N,N,N',N'-tetramethyldiamidophosphate. To
180 mL of dry diethyl ether, chilled to −30°C, is added
56.7 g (4.2 equiv) (1.26 mmol) of dimethylamine (Note
17). This solution is added—during 1–2 hr from a
double-jacketed dropping funnel, protected from moisture by a
calcium chloride tube and connected to a
cryostat regulated to −30°C—to a stirred mixture (Note
18) of
60 g (0.30 mol) of the freshly distilled furyl phosphorodichloridate and
250 mL of ether in a
two-necked, 1-L flask equipped with a condenser, protected from moisture by a calcium chloride tube and connected to the cryostat. This flask is chilled in an
ice bath during the addition of the first 2 equiv of the
dimethylamine. After the addition of
dimethylamine is complete, stirring is continued for 20 hr while the mixture is warmed on a
water bath at 35°C. The
hydrochloride that forms is carefully filtered off with suction and washed with two
70-mL portions of dry ether. The combined
ether phases are evaporated to give ca.
65 g (
99%) of crude product. Distillation, discarding a yellow forerun and collecting the fraction boiling at
149–152°C (20 mm) or
131–134°C (7 mm) (Note
19), affords
52–58 g (
79–88%) of pure material (Note
20).
D.
3-Methyl-2(5H)-furanone. To
10.9 g (50 mmol) of furyl tetramethyldiamidophosphate in
90 mL of tetrahydrofuran (THF) (Note
21), chilled to −75°C, is added
21.9 mL (55 mmol) of a 2.51 M hexane solution of
butyllithium (Note
22) at a rate (6–10 min) such that the temperature reaches −60°C but does not exceed this level. The resulting mixture is chilled to −75°C for 10 min; then
8.9 g (63 mmol) of methyl iodide in
20 mL of tetrahydrofuran is added with a syringe during 7–8 min (Note
23) so that the temperature does not rise above −55°C. After the addition is complete, the temperature is raised to 0°C and the mixture is concentrated to ca. 40 mL. Water (30 mL) and
ethyl acetate (50 mL) are added, the phases are separated, and the dark inorganic phase is extracted with two
50-mL portions of ethyl acetate. The combined, yellow organic phases are washed with
brine and dried over
magnesium sulfate. The solvent is evaporated to give
10.5 g of crude
2-(3-methylfuryl) tetramethyldiamidophosphate, which need not be purified for the next reaction (Note
24).
To the phosphate in a
250-mL flask on a water bath at 25°C (Note
25) is added
20 mL of 98–100% formic acid (Note
26), and the resulting mixture is stirred until bubbling has ceased (30–40 min).
Benzene (50 mL) is added and most of the excess
formic acid is removed on an evaporator. To the residue are added
50 mL of ethyl acetate and
30 mL of a sodium chloride–sodium carbonate solution (Note
27). The organic phase is washed twice with the latter solution (i.e., a total of 3 × 20 mL), the combined inorganic phases are extracted once with
50 mL of ethyl acetate, the combined organic phases are dried over
magnesium sulfate, the solvent is removed, and the product is distilled to give
3.2 g (
64%) of
3-methyl-2(5H)-furanone, bp
97–101°C (19 mm).
2. Notes
1.
Practical-grade furfural from Fluka Chemical Corporation or Aldrich Chemical Company, Inc. was used without any purification. Very dark
furfural can be used, but it foams at the beginning of the reaction and leads to lower yields.
2.
Sodium sulfate is used to salt out the water phase;
brine is not effective. The yield without the sulfate is 5–10% lower.
4.
Formic acid (98–100%), obtained from Merck & Company, Inc., was used.
5.
"Perhydrol" (30%), obtained from Merck & Company, Inc., gave reproducible results without efforts to determine the activity of the
peroxide. An excess is used.
6. The process is a fine balance between oxidation and isomerization of the initially formed
2(3H)-furanone. Longer addition times produce better yields; however, the benefit is of marginal value.
7.
Sodium disulfite, Na2S2O5, from Merck & Company, Inc. was used. The saturated solution of disulfite should be the lower phase.
10. The reaction is reversible. In order to obtain pure (
97–98%) dichloridate it is essential to add the 6.5 g of
amine after the first equivalent has reacted.
12. The use of more
pentane or
petroleum ether gave a product of better stability and purity.
13. Once-distilled product was usually not color-stable for prolonged periods.
14. The distillation flask is allowed to cool before air is passed into it. A vigorous polymerization may occur if air is passed into the hot residue, which may be safely discarded after the addition of
acetone (an exothermic, but easily controlled reaction). Spectroscopic data for
furyl phosphorodichloridate are as follows:
1H NMR (60 MHz, CDCl
3, TMS) δ: 5.85 (m, 1 H, furan-
H3), 6.30 (m, 1 H, furan-H4), 7.05 (m, 1 H, furan-H5);
13C NMR (CDCl
3, TMS) δ: 92.5 (
3JPC = 7, furan-C3), 111.5 (
4JPC = 3, furan-C4), 137.1 (
4JPC = 3, furan-C5), 147.9 (
2JPC = 12, furan-C2). MS
m /
e [relative intensity (rel. int.)]: 202 (16), 200 (26), 119 (4), 117 (6), 83 (100), 55 (31). M
+ 201.9160: calcd. 201.9167 for C
4H
3Cl
2O
3P; observed 199.9195. calcd. 199.9197. IR cm
−1: 1610 (s), 1300 (s), 980 (s), 890, 870. Anal. calcd. for C
4H
3Cl
2O
3P: C, 23.9, H, 1.5. Found: C, 23.8, H, 1.5.
15. Pure, pale-yellow dichloridate is stable for months without extensive change of color if stored in
well-stoppered bottles in the refrigerator.
16. The purity of this product is
97–98%. It contains some
butenolide; therefore an excess of
dimethylamine is used in the subsequent step.
17. Dry
dimethylamine from Fluka Chemical Corporation or MC and B Manufacturing Chemists was used as delivered.
18. A
12 × 55-mm heavy magnetic stirring bar is used for good stirring.
19. The monochloroamidate distills at 123°C (9 mm) and is identified in the
1H NMR by its
3JPH = 13.5.
Distill slowly in the beginning! The purity of the product is ≥99%. Redistill if a dark-yellow color develops; however, this color does not precluded successful lithiation.
20. The distilled diamide is a pale-yellow oil at room temperature; it freezes in the refrigerator (+4°C) if seeded within some hours. The first spontaneous crystalization took several weeks. It can also be obtained as snow-white crystals from
diisopropyl ether/hexane, mp
15–16°C. Spectroscopic data for
furyl tetramethyldiamidophosphate are as follows:
1H NMR (400 MHz, CDCl
3 TMS) δ: 2.71 (d, 12 H,
3JPH = 10, two N(CH
3)
2), 5.62 (m, 1 H, furan-H3), 6.28 (m, 1 H, furan-H4), 6.95 (m, 1 H, furan-H5);
13C NMR (15.03 MHz, CDCl
3, TMS) δ: 151.9 (d,
2JPC = furan-C2), 134.5 (s, furan-C5), 111.3 (s, furan-C4), 88.8 (d,
3JPC = 4, furan-C3), 36.6 (d,
2JPC = 4, N(CH
3)
2). Note that multiplicities s and d refer to C-P coupling. MS
m/
e (rel. int.): 218 (6), 136 (6), 135 (100), 127 (2), 111 (2), 92 (7), 90 (2), 83 (4), 69 (3). M
+ at 218.0822: calcd. 218.0820 for C
8H
12N
2O
3P; IR cm
−1: 2900, 2800, 1610, 1300, 990, 960.
23.
Methyl iodide should be added carefully in the beginning when the reaction mixture is mostly solid.
24. The phosphate can be crystallized from
diisopropyl ether/
hexane at −20°C in
80–85% yield; mp
42–44°C. Spectroscopic data for
2-(3-methylfuryl) tetramethyldiamidophosphate are as follows:
1H NMR (400 MHz, CDCl
3, TMS) δ: 1.95 (dxt, 3 H,
J = 0.4 and 2.2 CH
3), 2.73 (d, 12 H,
3JPH = 10.2, two N(CH
3)
2), 6.16 (dxdxq, 1 H,
J = 0.4 and 2.2, furan-H4), 6.91 (dxdxq, 1 H,
J = 0.4 and 2.2, furan-H5);
13C NMR δ: 8.4 (sxq, CH
3), 36.6 (dsq,
2JPC = 4, N(CH
3)
2), 98.7 (dxs,
3JPC = 5, furan-C3), 113.8 (dxs,
4JPC = 2, furan-C4), 133.9 (dxd,
4JPC = 2 furan-C5), 147.8 (dxs,
3JPC = 8, furan-C2); multiplicities underlined in the
13C spectrum refer to C-P coupling, the other to C-H coupling; MS
m/
e (rel. int.): 232 (7), 135 (100), 97 (3), 92 (5). M
+ at 232.0980: calcd. 232.0977 for C
9H
17N
2O
3P: Calcd. for C
9H
17N
2O
3P: C, 46.55, H, 7.33, N, 12.07. Found: C, 46.5, H, 7.6, N, 12.0.
25. The water bath can be removed after 5 min. The reaction is vigorous in the beginning, and chilling is necessary to avoid formation of
dimethylformamide (DMF), which is formed at elevated temperatures.
26.
Formic acid (98–100%), obtain from Merck & Company, Inc., was used.
3. Discussion
The reagent must be added to the electrophile when the leaving group is an alkoxide. For example, quenching with MeOD on larger scales yields products labelled also in the 5-position, whereas reverse addition with good stirring does not.
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
petroleum ether
amine
benzophenone ketyl
brine
dimethylformamide (DMF)
butenolide
2-(3-methylfuryl) tetramethyldiamidophosphate
Perhydrol
bromolactone
2-(3-Lithio)furyl tetramethyldiamidophosphate
calcium chloride (10043-52-4)
sulfuric acid (7664-93-9)
hydrochloride (7647-01-0)
Benzene (71-43-2)
ethyl acetate (141-78-6)
ether,
diethyl ether (60-29-7)
sodium chloride (7647-14-5)
hydrogen bromide (10035-10-6)
sodium carbonate (497-19-8)
sodium sulfate (7757-82-6)
formic acid (64-18-6)
acetone (67-64-1)
pyridine (110-86-1)
potassium hydroxide (1310-58-3)
toluene (108-88-3)
sodium (13966-32-0)
benzyl chloride (100-44-7)
hydrogen peroxide,
peroxide (7722-84-1)
Methyl iodide (74-88-4)
potassium thiocyanate (333-20-0)
Furan (110-00-9)
Furfural (98-01-1)
Pentane (109-66-0)
methylene chloride (75-09-2)
magnesium sulfate (7487-88-9)
Ethyl iodide (75-03-6)
dimethylamine (124-40-3)
benzyl bromide (100-39-0)
butyllithium (109-72-8)
Tetrahydrofuran (109-99-9)
diisopropyl ether (108-20-3)
ferrous ammonium sulfate (10045-89-3)
dimethylformamide (68-12-2)
hexane (110-54-3)
oxazoline
triethylamine (121-44-8)
N,N-dimethylethanolamine,
N,N-dimethylaminoethanol (108-01-0)
phenanthroline
2(5H)-Furanone (497-23-4)
phosphoryl chloride (10025-87-3)
diisopropylethylamine,
ethyldiisopropylamine (7087-68-5)
phosphorus pentoxide (1314-56-3)
sodium disulfite
Furyl phosphorodichloridate (105262-70-2)
furyl tetramethyldiamidophosphate,
Furyl N,N,N',N'-tetramethyldiamidophosphate,
furyl N,N,N',N'-tetramethylamidophosphate (105262-58-6)
2-chlorofuran (3187-94-8)
2(3H)-Furanone
3-Methyl-2(5H)-furanone,
2(5H)-Furanone, 3-methyl- (22122-36-7)
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