Synthesis of cis- and trans-2-Phenoxycyclopropylamines and Related Compounds

Abstract

A ' 4, 4 included in an exhaustive study by Kaiser and co-workers6' and by Zirkle and co-workers6b on the effect of chemical structure upon RIA0 inhibition. Nevertheless, we wish to describe our chemical work and pharmacological findings in this field.The synthesis of 2-phenoxycyclopropylamine was accomplished by the series of reactions shown in Scheme I. The reaction between phenyl vinyl ether (1) and ethyl diazoacetate (2) in the presence of copper was employed by Julia' to obtain ethyl 2-phenoxycyclopropanecarboxylate (3) ; he hydrolyzed the ester to the corresponding acid, n1.p. 112". Since he described the one acid rather than the two possible diastereorneric acids, one might assume that the synthesis produced only one ester. Later, Looker and BraunE employed the same reactants but without copper and under slightly different experimental conditions, to prepare the ester 3. They stated that no attempt was made to obtain the pure diastereomeric ethyl esters. However, upon hydrolysis they were able to demonstrate the presence of the two acids, ie., trans-2-phenoxycyclopropanecarboxylic acid, m.p. 113-113.7', and the cis isomer, m.p. 135-137'. They therefore concluded that the latter acid was not obtained by Julia, and that the trans acid was his sole reaction product. In our hands, the reaction between 1 and 2 in the presence of copper produced the ester 3, which proved to be a mixture of the cis and trans esters of 3. The isomers were separated by redistillation through a spinning-band column and characterized. Thus, we were able to obtain a fraction which contained 87.3y0 of one ester and 99.4% of the other, based upon V.P.C. analyses. The interrelationship of the two ester forms was established when it was found that the 99.4y0 ester, which had a longer retention time could be epimerized by refluxing with sodium ethoxide in absolute ethanol into 95.1% of the other ester with the shorter retention time. We designated the ester with the shorter retention time as trans and the ester with the longer retention time as cis.Additional evidence to confirm these designations was obtained by hydrolyzing each ester separately to its (6) (a) (7) M. Julia, Bull. soc chzm. France, 181 (1956). (8) J. H. Looker and L. L. Braun, J . Org. Chem., 23, 933 (1958).corresponding acid. Thus, the cis ester yielded the cis acid 9, m.p. 13fj-138". The trans ester gave the trans acid 10, m.p. 111-113". These respective melting points are in good agreement with those previously reported.8It will be noted that the synthesis favored the formation of the thermodynamically more stable trans form by a ratio of approximately 3 : 1 over the cis form. A study of the Dreiding models indicated that phenyl vinyl ether and carbethoxycarbene, during reaction, develop a considerable crowding effert in an attcinpt to form the cis isoiner. In the formation of the tmns product, the two bulky groups do not interfere with each other. In retrospect, this relationship in yield of the cis and trans isomers, can be detected by careful comparison of the i...

Synthesis and Characterization of 2(2-Tetrahydropyranylthio) methyl cyclopropylamine

“…methyl-1carboethoxycyclopropane 4 and a sulfonium ylide rearrangement product namelyethyl-α-allyl-α (2-tetrahydropyranylthio) acetate 5 in 81.4% and 18.6% yield at 150-155C° respectively 8 . Ethyldiazoacetate reacts with allymercaptan to generate trans-and ciscyclopropane derivative 4 through carbene addition to the double bond 9 and with thioether group to form sulfonium ylide 10 . Such sulfonium ylide is known to undergo Steven's rearrangement, which depends on the structure of the ylide, may either involve an antrafacial 1,3-sigmatropic rearrangement or suprafacial 1,5-sigmatropic rearrangement 11 .…”

Some Relationships Between Chemical Structure and Pharmacological Activities

“…For example, cis-2-phenoxycyclopropylamines, which had been reported to be appreciably more active than the trans (165). were later indicated to show no consistent differences among other tests (166) .…”

Ring-opening reactions of 2-benzoylcyclopropane isocyanate

“…The regiochemistry and overall structure of 3 was subsequently confirmed by a hydrolysis experiment. When a chloroform solution of 3 was extracted with water, methyl 3-(2-ethoxy-3-hydroxyindoleninyl)acetate (4) was isolated in 40% yield. The indoleninylacetate (4) was identified from OH, 0=0, and C=N stretching bands at 3480, 1720, and 1625 cm-1, respectively, in the ir spectrum, the nmr data reported in the Experimental Section, and a strong mass spectral parent ion at mfe 249.…”