Cyclobutanedicarboxylate

DIETHYL 1,1-CYCLOBUTANEDICARBOXYLATE (1,1-Cyclobutanedicarboxylic acid, diethyl ester) 

Checked by William S. Johnson, William DeAcetis, and Herbert Title. 

It is important to maintain strictly anhydrous conditions throughout this reaction. The equipment should be carefully predried and the absolute ethanol freshly prepared (preferably by the magnesium ethoxide methods) and distilled directly into the reaction flask. If the volume of ethanol is less than 2.5 1. the sodium ethoxide may not remain in solution. It is convenient to employ a three-necked flask carrying two condensers for this operation and to add the sodium through the third neck, which is otherwise kept stoppered. 

Trimethylene chlorobromide can be obtained commercially. Material boiling at 141-142°/755 mm., d 1.4843, was used. 

The stirring must be continued during this operation otherwise the mixture will bump badly. 

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In the case of enamines derived from aldehydes a cycloaddition to give a cyclobutane occurs (48-50). Thus the enamine (16) reacted with methyl acrylate in acetonitrile to give a 91 % yield of methyl 2-dimethylamino-3,3-dimethylcyclobutane carboxylate (56). Similarly, treatment of (16) with diethylmaleate at 170° gave a 70% yield of diethyl 4-dimethylamino-3,3-dimethyl-l,2-cyclobutanedicarboxylate (57), and 16 and acrylonitrile gave a 65% yield of 2-dimethylamino-3,3-dimethylcyclobutanecarbonitrile (58). 

Draw all possible stereoisomers of L,2-cyclobutanedicarboxvlic acid, and incli cate the interrelationships. Which, if any, are optically active Do the same fo 1,3-cyclobutanedicarboxylic acid. 

Some examples of alkylation reactions involving relatively acidic carbon acids are shown in Scheme 1.3. Entries 1 to 4 are typical examples using sodium ethoxide as the base. Entry 5 is similar, but employs sodium hydride as the base. The synthesis of diethyl cyclobutanedicarboxylate in Entry 6 illustrates ring formation by intramolecular alkylation reactions. Additional examples of intramolecular alkylation are considered in Section 1.2.5. Note also the stereoselectivity in Entry 7, where the existing branched substituent leads to a trans orientation of the methyl group. 

Diethyl 1,1-cyclobutanedicarboxylate has been prepared by the alkylation of diethyl sodiomalonate with trimethylene dibromide 8i4>6 7 or with trimethylene chlorobromide 6-8 and by the peroxide-catalyzed addition of hydrogen bromide to diethyl allylmalonate followed by intramolecular alkylation.9 The procedure described here is that of Mariella and Raube.6... 

The steam distillation separates ethyl malonate and ethyl 1,1-cyclobutanedicarboxylate from ethyl pentane-1,1,5,5-tetra-carboxylate, formed in a side reaction between malonic ester (2... 

If this extraction with ether is omitted the yield of 1,1-cyclobutanedicarboxylic acid is 3-4 g. less. 

The submitters used 55 cc. of hydrochloric acid at this point the checkers stated that this amount was insufficient to neutralize the mixture. The purpose of acidification at this point is not to liberate the cyclobutanedicarboxylic acid, but merely to remove carbonates and excess potassium hydroxide. After the carbon dioxide has been expelled, the solution is made alkaline with ammonia hence a great excess of hydrochloric acid should be avoided. The submitters used only enough hydrochloric acid to make the solution acid to litmus. After the solution has been made basic with ammonia, barium chloride solution is added until there is no further precipitation of barium malonate. 

Cyclobutanedicarboxylic acid has been prepared by hydrolysis of the ethyl ester,1 or of the half nitrile, 1-cyano-l-car-boxycyclobutane.2 The ethyl ester has been prepared by condensation of ethyl malonate with trimethylene bromide1 or chloro-bromide.3 The half nitrile has been prepared by condensation of trimethylene bromide with ethyl cyanoacetate followed by hydrolysis of the ester to the acid.2... 

Pt Carboplatin [Pt(NH3)2(CBDCA)] CBDCA= cyclobutanedicarboxylic acid Anticancer agent... 

Sulfonium, cyclopropyldiphenyl tetrafluoroborate, 54, 28 Sulfonium salts, acetylenic, furans from, 53, 3 Sulfonium ylides, 54, 32 Sulfur, reaction with organo-lithium compounds, 50, 105 Sulfuryl chloride, with 1,1-cyclobutanedicarboxylic acid to give 3-chloro-l,1-cyclobutanedicarboxylic acid, 51, 73... 

CHLORO-,51, 73 1,1-Cyclobutanedicarboxylic acid, with sulfuryl chloride to give 3-chloro-1,1-cyclobutanedicarboxylic acid, 51,73... 

Dicarboxylic acids give very poor yields of the cyclopropane under Kolbe reaction conditions. ITie cyclobutanedicarboxylic acid 25 affords a bicyclobutane [132], 2,2-DiraethyIglutaric acid gives low yields of a hydrocarbon, which is not... 

Methylene groups can be dialkylated if sufficient base and alkylating agent are used. Dialkylation can be an undesirable side reaction if the monoalkyl derivative is the desired product. Use of dihaloalkanes as the alkylating reagent leads to ring formation, as illustrated by the diethyl cyclobutanedicarboxylate synthesis (entry 7) shown in Scheme... 

Diethyl 1,1-cyclobutanedicarboxylate is prepared by the method of Mariella and Raube.2 The diester is isolated in 55% yield, b.p. 111-114° (16 mm.). The diester can be saponified by the method of Heisig and Stodola,3 but omitting the barium chloride step, to give the diacid. This material upon recrystallization from ethyl acetate gives the diacid in high purity. The diacid may also be purchased from Aldrich Chemical Company, Inc. 

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