Organic Syntheses, Coll. Vol. 8, p.396 (1993); Vol. 68, p.162 (1990).
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 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
, 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
) of pure butenolide
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)
(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
) 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
) of pure material (Note 20)
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)
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.
is used to salt out the water phase; brine
is not effective. The yield without the sulfate is 5–10% lower.
Formic acid (98–100%), obtained from Merck & Company, Inc.
, was used.
"Perhydrol" (30%), obtained from Merck & Company, Inc.
, gave reproducible results without efforts to determine the activity of the peroxide
. An excess is used.
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.
Sodium disulfite, Na2S2O5, from Merck & Company, Inc.
was used. The saturated solution of disulfite should be the lower phase.
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.
The use of more pentane
or petroleum ether
gave a product of better stability and purity.
Once-distilled product was usually not color-stable for prolonged periods.
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: 1
H NMR (60 MHz, CDCl3
, TMS) δ: 5.85 (m, 1 H, furan-H
3), 6.30 (m, 1 H, furan-H4), 7.05 (m, 1 H, furan-H5); 13
C NMR (CDCl3
, 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
[relative intensity (rel. int.)]: 202 (16), 200 (26), 119 (4), 117 (6), 83 (100), 55 (31). M+
201.9160: calcd. 201.9167 for C4
P; observed 199.9195. calcd. 199.9197. IR cm−1
: 1610 (s), 1300 (s), 980 (s), 890, 870. Anal. calcd. for C4
P: C, 23.9, H, 1.5. Found: C, 23.8, H, 1.5.
Pure, pale-yellow dichloridate is stable for months without extensive change of color if stored in well-stoppered bottles
in the refrigerator.
The purity of this product is 97–98%
. It contains some butenolide
; therefore an excess of dimethylamine
is used in the subsequent step.
Dry dimethylamine from Fluka Chemical Corporation or MC and B Manufacturing Chemists
was used as delivered.
A 12 × 55-mm heavy magnetic stirring bar
is used for good stirring.
The monochloroamidate distills at 123°C (9 mm) and is identified in the 1
H 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.
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: 1
H NMR (400 MHz, CDCl3
TMS) δ: 2.71 (d, 12 H, 3JPH
= 10, two N(CH3
), 5.62 (m, 1 H, furan-H3), 6.28 (m, 1 H, furan-H4), 6.95 (m, 1 H, furan-H5); 13
C NMR (15.03 MHz, CDCl3
, 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(CH3
). Note that multiplicities s and d refer to C-P coupling. MS m
(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 C8
P; IR cm−1
: 2900, 2800, 1610, 1300, 990, 960.
should be added carefully in the beginning when the reaction mixture is mostly solid.
The phosphate can be crystallized from diisopropyl ether
at −20°C in 80–85%
yield; mp 42–44°C
. Spectroscopic data for 2-(3-methylfuryl) tetramethyldiamidophosphate
are as follows: 1
H NMR (400 MHz, CDCl3
, TMS) δ: 1.95 (dxt, 3 H, J
= 0.4 and 2.2 CH3
), 2.73 (d, 12 H, 3JPH
= 10.2, two N(CH3
), 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); 13
C NMR δ: 8.4 (sxq, CH3
), 36.6 (dsq, 2JPC
= 4, N(CH3
), 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 13
C spectrum refer to C-P coupling, the other to C-H coupling; MS m
(rel. int.): 232 (7), 135 (100), 97 (3), 92 (5). M+
at 232.0980: calcd. 232.0977 for C9
P: Calcd. for C9
P: C, 46.55, H, 7.33, N, 12.07. Found: C, 46.5, H, 7.6, N, 12.0.
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.
Formic acid (98–100%), obtain from Merck & Company, Inc.
, was used.
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.
Chemical Abstracts Nomenclature (Collective Index Number);
calcium chloride (10043-52-4)
sulfuric acid (7664-93-9)
ethyl acetate (141-78-6)
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)
potassium hydroxide (1310-58-3)
benzyl chloride (100-44-7)
Methyl iodide (74-88-4)
potassium thiocyanate (333-20-0)
methylene chloride (75-09-2)
magnesium sulfate (7487-88-9)
Ethyl iodide (75-03-6)
benzyl bromide (100-39-0)
diisopropyl ether (108-20-3)
ferrous ammonium sulfate (10045-89-3)
phosphoryl chloride (10025-87-3)
phosphorus pentoxide (1314-56-3)
Furyl phosphorodichloridate (105262-70-2)
furyl N,N,N',N'-tetramethylamidophosphate (105262-58-6)
2(5H)-Furanone, 3-methyl- (22122-36-7)
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