Organic Syntheses, CV 7, 411
Submitted by Rajendra K. Singh and Samuel Danishefsky
1.
Checked by M. R. Czarny and M. F. Semmelhack.
1. Procedure
A.
Preparation of cyclopropane 1,l-dicarboxylic acid (1). To a
1-L solution of aqueous 50% sodium hydroxide (Note
1), mechanically stirred in a
2-L, three-necked flask, was added, at 25°C,
114.0 g (0.5 mol) of triethylbenzylammonium chloride (Note
2). To this vigorously stirred suspension was added a mixture of
80.0 g (0.5 mol) of diethyl malonate and
141.0 g (0.75 mol) of 1,2-dibromoethane all at once. The reaction mixture was vigorously stirred for 2 hr (Note
3). The contents of the flask were transferred to a
4-L Erlenmeyer flask by rinsing the flask with three 75-mL portions of water. The mixture was magnetically stirred and cooled with an
ice bath to 15°C, and then carefully acidified by dropwise addition of
1 L of concentrated hydrochloric acid. The temperature of the flask was maintained between 15 and 25°C during acidification. The aqueous layer was poured into a
4-L separatory funnel and extracted three times with
900 mL of ether. The aqueous layer was saturated with
sodium chloride and extracted three times with
500 mL of ether. The
ether layers were combined, washed with
1 L of brine, dried
(MgSO4), and decolorized with activated
carbon. Removal of the solvent by rotary evaporation gave
55.2 g of a semisolid residue. The residue was triturated with
100 mL of benzene. Filtration of this mixture gave
43.1–47.9 g (
66–73%) of
1 as white crystals, mp
137–140°C.
B.
6,6-Dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (2). A suspension of
39.0 g (0.30 mol) of 1 and
33.0 g (0.33 mol) of freshly distilled isopropenyl acetate was stirred vigorously (
magnetic stirrer). To this suspension was added dropwise over a period of 30 min,
0.5 mL of concentrated sulfuric acid. While being stirred for an additional 30 min, the solution became clear yellow, and then partly solidified after being kept at 5°C for 24 hr. After addition of 50 mL of cold water, the precipitated solid was filtered, washed with 10 mL of cold water, and air-dried to give
30.9 g of crude spiroacylal
2. The filtrate was extracted three times with
50-mL portions of ether. The combined organic layers were carefully washed with
50 mL of brine, dried (MgSO
4), and decolorized with activated
carbon. Evaporation of the solvent gave an additional
7.8 g of spiroacylal
2 as a yellow solid. The combined samples of crude spiroacylal (
38.7 g) were recrystallized from
110 mL of hexane and 25 mL of benzene to give
28.7–31.5 g (
55–61%) of
2 as colorless needles, mp
65–67°C. Concentration of the above mother liquor to ca. 40 mL gave
0.80 g of a second crop of spiroacylal
2 as slightly yellow crystals, mp
58–60°C.
C.
2-Oxo-1-phenyl-3-pyrrolidinecarboxylic acid (3). To
1.70 g (10 mmol) of spiroacylal 2 was added
2.79 g (3 mmol) of aniline. The mixture became a homogeneous orange solution after 15 min and was allowed to stir at room temperature for 12 hr. The resulting crystalline mass was diluted with
150 mL of chloroform, washed three times with
10 mL of aqueous 10% hydrochloric acid, washed once with
20 mL of brine, dried (MgSO
4), and decolorized with a small amount of activated
carbon. Concentration of the organic layer by rotary evaporation gave
5.27 g of a brown residue, which was recrystallized from
chloroform-hexane to afford
4.86–5.07 g (
79–82%) of the pyrrolidinone
3 as white crystals, mp
146–148°C (dec) (Note
4).
2. Notes
2. This compound is commercially available from Aldrich Chemical Company, Inc. Alternatively, it can be made very cheaply and simply by mixing
benzyl chloride (1 equiv) with
triethylamine (2.5 equiv). The mixture is allowed to stand for 4–7 days at room temperature. Filtration of the solid and drying in vacuum give
triethylbenzylammonium chloride suitable for use in nearly quantitative yield.
3. Some exothermicity results on mixing, causing the temperature to rise to ca. 65°C.
3. Discussion
Previously
cyclopropane-1,1-dicarboxylic acid had been prepared
2,3,4 by hydrolysis of the corresponding diester. The preparation of 1,1-dicarboalkoxycyclopropanes by a conventional double alkylation of
diethyl malonate with
1,2-dibromoethane was severely complicated by the recovery of unreacted
diethylmalonate. This required a rather difficult distillation to separate starting material and product. In fact, many commercially offered lots of cyclopropane diester contain extensive amounts of
diethyl malonate. Furthermore, preparation of the diacid required a separate and relatively slow saponification of the diester.
5
The procedure described here for compound
1 is a scale-up of a published method.
6 Phase-transfer catalysis
7 and concentrated alkali are used to effect a one-pot conversion of
diethyl malonate to the cyclopropane diacid, which is easily obtained by crystallization. Apparently alkylation of the malonate system occurs either at the diester or monocarboxylate, monoester stage since the method fails when
malonic acid itself is used as the starting material. This method of synthesizing doubly activated cyclopropanes has been extended to the preparation of
1-cyanocyclopropanecarboxylic acid (
86%) by the use of
ethyl cyanoacetate and
1-acetylcyclopropanecarboxylic acid (
69%) by use of
ethyl acetoacetate.
6
The spiroacylal
2 is potentially a valuable agent in organic synthesis.
8 It is readily attacked by a variety of nucleophiles, including
pyridine, to give ring-opened products bearing a stabilized carbanion. It is thus seen to be a synthetic equivalent of

CH
2-CH
2-CH(CO
2H)
2 and

CH
2(CH
2)
2-CO
2H, i.e., a homo-Michael acceptor. The general reaction is
where Y =
aniline,
piperidine,
pyridine,
mercaptide, enolate, etc. Spiroacylal
2 was designed under the rationale that the constraint of the carbonyl groups into a conformation in which overlap of their π-orbitals with the "bent bonds" of the
cyclopropane is assured should dramatically increase the vulnerability of the
cyclopropane toward nucleophilic attack.
8 Experimental support for this notion is abundant.
8 Spiroacylal
2 is considerably more reactive than
1,1-dicarbethoxycyclopropane in such reactions. For instance, reaction of
2 with
piperidine occurs at room temperature. The corresponding reaction in the case of the diester is conducted at 110°C.
5 Reactions with enolates also occur under mild conditions.
8 Compound
2 reacts with the weak nucleophile
pyridine at room temperature to give a
betaine.
8 An illustrative mechanism for the reaction of the acylal
2 with
aniline to afford
2-oxo-1-phenyl-3-pyrrolidinecarboxylic acid (
3) is
The synthesis of the spiroacylal
2 from the diacid
1 follows a procedure used by Scheuer in a different context.
9
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