Phenylcyclopropanecarboxylic Acid

Submitted by Caul Kaiser, Joseph Weinstock, and M. P. Olmstead1 

Cheeked by William E. Parham, Wayland E. Noland, Paul Cahill, and Thomas S. Straub 

cis-2-Phenylcyclopropanecarboxylic acid. In a 1-1. threenecked flask equipped with a dropping funnel, stirrer, and a 

The checkers used xylene purified by distillation from sodium. 

Ethyl diazoacetate is available from Aldrich Chemical Co., 2371 North 30th Street, Milwaukee, Wisconsin. Diazoacetic esters are potentially explosive and therefore must be handled with caution.2 

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A solution of 4.62 grams of 2-phenylcyclopropanecarboxylic acid in 15 cc of dry benzene is refluxed with 4 cc of thionyl chloride for 5 hours, the volatile liquids are removed and the residue once more distilled with benzene. Fractionation of the residue yields the carbonyl chloride of 2-phenylcyclopropane. 

Since (Z)- and ( )-stereoisomers of unsaturated oxazolones can be obtained using appropriate isomerization procedures, cis and trans isomers of cyclopropane derivatives can be obtained in a stereoselective manner, although special care must be taken with experimental conditions to obtain the best stereoselectivity. Both racemic cis- and fraui-l-amino-2-phenylcyclopropanecarboxylic acid 641 and 644 have been obtained from the corresponding (Z)- or ( )-4-benzylidene-2-phenyl-5(4//)-oxazolone 621 and 642 using diazomethane. Care was taken to affect the... 

A solution of the above ester (207.8 grams) and 64.5 grams of sodium hydroxide in 80 cc of water and 600 cc of ethanol is refluxed for 9 hours. The carboxylic acid of 2-phenylcyclopropane is liberated with 200 cc of concentrated hydrochloric acid. The 2-phenylcyclopropanecarboxylic acid contains 3 to 4 parts of the trans isomer to 1 part of the cis isomer. The acid is recrystallized from hot water. The pure trans isomer comes out as crystalline material (solid) while the cis isomer stays in solution. 

Burger and Yost4 reported m.p. 106-107° for pure cis-2-phenylcyclopropanecarboxylic acid and m.p. 93° for pure [Pg.97]

The present method offers a convenient preparation of cis-2-phenylcyclopropanecarboxylic acid that is amenable to large-scale work. The process above has been carried out in the laboratories of the submitters on a twentyfold scale with essentially the same results. The method also provides an example of the separation of two isomers based on differences in reaction rate. 

The checkers note that in the paper by Inouye, et al. the diacid was prepared by ozonolysis of (+)-trans-2-phenylcyclopropanecarboxylic acid having 96.3% optical purity. The product diacid was purified by sublimation and recrystallization from water to obtain material giving the cited physical properties. Although the original publication claims an optical purity of 96.3% for this diacid, it is probably optically pure because of the recrystallization step. 

Cleavage of acetates. DePuy used methyllithium in the first and last step of a general method for the synthesis of cyclopropanols from cyclopropanecarboxylic acids, for example traus-2-phenylcyclopropanecarboxylic acid (1). Reaction with 2... 

Curtius reaction. The overall process of converting an acid through the azide and isocyanate into an amine is known as the Curtius reaction. For application of the Curtius reaction to Cii-2-phenylcyclopropanecarboxylic acid, J. Weinstock found the route to the azide through the acid chloride unsatisfactory because of ready isomerization to the trans acid chloride. An efficient alternative method utilizes a mixed anhydride intermediate of a type found serviceable in the synthesis of peptides. A solution of the acid in aqueous acetone was treated with triethylamine to... 

Oxidative decarboxylation of cis- and tra .v-2-phenylcyclopropanecarboxylic acid (19) by lead tetraacetate in anhydrous benzene containing copper(II) acetate and pyridine as catalyst affords a mixture of 7 products in a total yield of 55-58% among which phenylcyclopropane (20) and, 2-diphenylcyclopropane (21) were present in only 1.2% and 15% yield, respect-... 

Both trans- and c/j-2-phenylcyclopropanecarboxylic acid (6) can also be decarboxylated with lead tetraacetate in benzene at 80 C in the presence of a catalytic amount of pyridine and copper(II) acetate to give rran. -l,2-diphenylcyclopropane (8) in low yield (18-22%). When the oxidative decarboxylation of these carboxylic acids is carried out with lead tetraacetate in the presenee of iodine under irradiation ra ,v-l-iodo-2-phenylcyclopropane (9) is obtained as the sole product in 43% yield. Under identical conditions 2,2-diphenylcyclopropanecarboxylic acid leads to 2-iodo-l,l-diphenylcyclopropane (mp 45.5 C) in 57% yield. 

Similarly, A.A-dialkylamides of 2-hydroxy-2-phenylcyclopropanecarboxylic acids 2 were obtained in good yield from A/A-dialkylamides of 3-benzoylpropanoic acid in diethyl ether.2... 

There are few examples of the reactions of alkenes with diazoesters of chiral alcohols which give high face discrimination in rhodium-catalyzed reactions [936, 1497). However, Davies and coworkers [192, 193, 1503] have performed the reactions of alkenes with vinyldiazoesters of chiral alcohols under Rh2(OAc)4 or better yet Rh2(OCOC7H j 5)4 catalysis. The ester of (K)-pantolactone 1.16 is the most efficient substrate, and ftum-cyclopropanecarboxylates are obtained highly selectively. Starting from 7.141 (R = Ph), the enantioenriched plant hormone l-amino-2-phenylcyclopropanecarboxylic acid has been prepared (Figure 7.88). 

The L-proline derived diketopiperazine 27 and diazomethane afford a 1-pyrazoline diastereo-mer which is photolyzed to give the cyclopropane derivative 28 in high yield. Acid hydrolysis then provides (+)-1-amino-2-phenylcyclopropanecarboxylic acid (29) [a] 5 +105 (c = 0.69, water) 81. The optical purity of this amino acid is not reported. Similarly the (—)-enantiomer of l-amino-2-phenylcyclopropanecarboxylic acid is available from a dehydroamino acid using (-)-Ar-methylephedrine as auxiliary81. 

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