Organic Syntheses, Coll. Vol. 6, p.520 (1988); Vol. 58, p.56 (1978).
has been identified as a carcinogen; OSHA has issued emergency standards on its use. All procedures involving benzene
should be carried out in a well-ventilated hood
, and glove protection is required. The reaction in Part C should be carried out in a well-ventilated hood because iron carbonyls are highly toxic.
A. 2,4-Dibromo-3-pentanone (1)
. A 300-ml., three-necked, round-bottomed flask
equipped with a magnetic stirrer
, a thermometer
, and a 125-ml., pressure-equalizing dropping funnel
, connected to a trap
for absorbing hydrogen bromide
evolved during the reaction (Note 1)
, is charged with 43.0 g. (0.500 mole) of diethyl ketone
and 100 ml. of 47% hydrobromic acid
. The dropping funnel is charged with 160 g. (1.00 mole) of bromine
, which is added with stirring over a 1-hour period, causing the temperature of the reaction mixture to increase to 50–60°. After addition is complete, stirring is continued for an additional 10 minutes, before 100 ml. of water is added to the reaction mixture. The separated heavy organic layer is washed with 30 ml. of saturated aqueous sodium bisulfite
. The brownish organic solution is dried over calcium chloride
and distilled under reduced pressure through a 15-cm. vacuum-jacketed Vigreux column
, yielding 85.2–92.5 g.
) of 2,4-dibromo-3-pentanone (1) (Note 2)
, b.p. 51–57° (3 mm.)
, as a slightly yellow liquid.
B. α-Morpholinostyrene (2)
. A mixture of 75.0 g. (0.625 mole) of acetophenone
, 81.0 g. (0.930 mole) of morpholine (Note 3)
, 200 mg. of p-toluenesulfonic acid
, and 250 ml. of benzene
is placed in a 500-ml., round-bottomed flask equipped with a water separator (Note 4)
, under a reflux condenser
protected by a calcium chloride drying tube
. Separation of water begins with reflux and is complete after 180 hours. After the mixture is cooled to room temperature, 200 mg. of sodium ethoxide
is added to remove p-toluenesulfonic acid
, and the mixture is concentrated with a vacuum rotary evaporator
(50°, 80–100 mm.). The crude oily product is distilled under reduced pressure through a 15-cm. vacuum-jacketed Vigreux column. After 40–50 ml. of a mixture of morpholine
is recovered as a forerun at 40–90° (20 mm.), 67.5–75.4 g.
) of α-morpholinostyrene
is collected as a pale yellow liquid, b.p. 85–90° (0.03 mm.) (Note 5)
C. 2,5-Dimethyl-3-phenyl-2-cyclopenten-1-one (3)
. A 1-l., three-necked, round-bottomed flask
equipped with a sealed mechanical stirrer
, a rubber septum
, and a bubbler filled with liquid paraffin is charged with 40.0 g. (0.110 mole) of diiron nonacarbonyl (Note 6)
and 250 ml. of dry benzene (Note 7)
. The system is flushed with nitrogen
, and 56.8 g. (0.300 mole) of α-morpholinostyrene (Note 8)
and 24.4 g. (0.100 mole) of 2,4-dibromo-3-pentanone (1)
are injected by syringe through the rubber septum. The flask is immersed in a 32° bath, and the reaction mixture is stirred under a nitrogen
atmosphere (Note 9)
. After 20 hours 230 g. of silica gel (Note 10)
and 100 ml. of benzene
are added. The resulting slurry is stirred at 32° for an additional 2.5 hours (Note 11)
. The whole mixture is poured onto a silica gel pad (Note 10)
and (Note 12)
with the aid of 200 ml. of diethyl ether
, and the pad is washed with 1 l. of ether (Note 13)
and (Note 14)
. The combined organic solutions are concentrated on a vacuum rotary evaporator (Note 13)
, giving 35–45 g.
of the desired cyclopentenone 3
, a brown oil contaminated by acetophenone
formed by decomposition of the excess enamine. The oil is distilled under reduced pressure with a short-path distillation apparatus (Note 15)
. The forerun of 20–25 g.
, b.p. 35–50° (0.1 mm.)
, is recovered acetophenone
. At 100–105° (0.02 mm.)
, 12.0–12.4 g.
yield (Note 14)
] of cyclopentenone 3
is obtained as a pale yellow oil, which crystallizes on cooling with ice water. Recrystallization from hexane
gives an analytical sample as colorless needles, m.p. 57–59° (Note 16)
The submitter reported a yield of 116 g.
). Care should be taken to prevent the dibromoketone from coming into contact with the skin; allergic reactions have been observed in several cases. Also, the checkers found the crude product to have lachrymatory properties. Immediate use after distillation is recommended if high yield is to be obtained in the next step.
An excess of morpholine
is required because a considerable amount is lost with the water that separates during the reaction.
The distilled product is 97% pure and contaminated with 3% acetophenone
(NMR analysis). Since the enamine is easily hydrolyzed and deteriorates on long standing, use of a freshly-distilled material is recommended. The checkers found that α-morpholinostyrene
contaminated with 20% acetophenone
could be used for the next step without any significant reduction in yield.
Diiron nonacarbonyl is available from Alpha Inorganics, Inc., or Strem Chemicals, Inc.
The submitters made the complex through photolysis of iron pentacarbonyl
by the method of King.2
Procedures for preparation are also given by Braye and Hübel,3
who use the name diiron enneacarbonyl.
The submitters obtained a markedly lower yield of product when an excess of the enamine was not used.
Evolution of carbon monoxide
begins a few minutes after mixing the starting materials, continuing for ca.
3 hours. Cessation of gas evolution does not necessarily mean completion of the cyclocoupling reaction.
The submitters used Merck Kieselgel 60 (70–230 mesh ASTM).
The 150 g. of silica gel
is packed in a 13 (diameter) × 12-cm. (length) glass filter.
The filter cake and the distillate must be treated with nitric acid
to decompose the contaminates of iron carbonyl complexes. This treatment should be done very carefully in a well-ventilated hood, because carbon monoxide
is evolved vigorously.
The submitters reported a yield of 14.8–15.6 g.
) based on the starting dibromide. The submitters report that the cyclopentenone product seems to absorb on silica gel
, and 1 l. of ether
is required to attain complete extraction. A smaller quantity of ether
wash was used by the checkers. 1
H NMR analysis of the crude mixture before distillation indicated the formation of the cyclopentenone 3
The spectral properties of pure product are as follows: IR (CCl4
: 1696 (conjugated C=O) and 1626 (conjugated C=C); UV (C2
OH) nm. max. (ε): 220 (5220) and 279 (11,200); 1
H NMR (CCl4
), δ (multiplicity, coupling constant J
in Hz., number of protons, assignment): 1.22 (d, J
= 7.0, 3H, CHCH3
), 1.91 (t, J
= 2.0, 3H, vinyl CH3
), 2.1–2.7 (m, 2H, CH
and a methylene H cis
), 3.14 (d of d of q, J
= 18, 7.5, and 2.0, 1H, methylene H trans
), and 7.38 (m, 5H, C6H5
The starting materials, 2,4-dibromo-3-pentanone4
have been prepared in satisfactory yields by modifying known procedures. The procedure for the 3 + 2
5 cyclocoupling reaction is essentially that described originally by the submitters.6
The main advantages of this procedure are the directness, the availability of starting materials, and the wide generality for preparation of 2,5-dialkyl-2-cyclopenten-1-ones, as shown in Table I. Enamines derived from aldehydes, open-chain ketones, and cyclic ketones can be employed. The method has been extended to the synthesis of spiro[4.n
]alkenones and certain azulene derivatives.6
A reaction mechanism for the cyclocoupling reaction has been advanced.7
The reactive oxyallyl intermediates generated from dibromoketones and iron carbonyls can be trapped efficiently by enamines,6
and alkyl 1H
Intramolecular trapping of the reactive species by olefin or furan
has also been achieved.14
At present, dibromides of methyl ketones cannot be used as starting materials except in intramolecular cyclocoupling reactions. However, polybromoketones, including α,α,α',α'-tetrabromoacetone
, serve as a precursors of the reactive species in certain cases, and the coupling reactions have been applied to various naturally occurring products.14,15,16,17,18,19
IRON CARBONYL-PROMOTED CYCLOPENTENONE SYNTHESISa
bA mixture of epimers, when possible, is obtained.
cIsolated yield based on starting dibromide.
Chemical Abstracts Nomenclature (Collective Index Number);
calcium chloride (10043-52-4)
diethyl ether (60-29-7)
carbon monoxide (630-08-0)
nitric acid (7697-37-2)
hydrogen bromide (10035-10-6)
sodium bisulfite (7631-90-5)
sodium ethoxide (141-52-6)
diethyl ketone (96-22-0)
lithium aluminum hydride (16853-85-3)
p-toluenesulfonic acid (104-15-4)
2-Cyclopenten-1-one, 2,5-dimethyl-3-phenyl- (36461-43-5)
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