Umyehsify of I$I201A

Synthesis of compounds related to aminocyclopentanecarboxylic acid by ring closures

Item Type text; Thesis-Reproduction (electronic)

Authors Wolgemuth, Larry Gene, 1933-

Publisher The University of Arizona.

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Link to Item http://hdl.handle.net/10150/319271 UMYEHSIfY OF i$I2 0 1 A ■ i' . / 0 3

StATEMfflT BY AUfHOE T W s .. thesis;, has beeB ■ SBbiiii'tt.'eS- ia partial f ulflllmettS,: ©f reqmremesatsf®ss as- advapeed degre© at the 'Uaiversiiy- ©f Arlwma- smd is. deposited 'ia the Baiyersity Eibrary t© foe made arailalbl® t© borrowers BPder rml©# ©f th® Libraryo are special, p@nlii3©S.@p9. ppovided that: a®earate- aekpe^rledgmept o.t seuap©® is, «ad©«: ..Requests- f®s? permissiom. .for ©sstepded qrnetatiom- fp©m ©r rep3K@;dB&tioB ©f■ this, maapseript ia wheie or ip -part .may b© graBted by the head ©f. the majer departmemt sr the BeaP: @f the Grpadmt® Ssilege wh®p ia 'their jiadgmept- the ppop@sed as© @f the. material. i@: ip the .interests ©£ ■ sehoiarsMpo la all. ether ©■srer, permlssiea mast b© ©fotaiaed frbm the,.. author <

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IFFROfAL BY THESIS BIBECTOE

thesis has b@ea appreved ©a the ACKNOWLEDGMENT

. TKe writeB' wishes: to express: his sin.eere:- appreeiatioH tjo Drc, Alee Kelley for his advice, assistance as# eaeoaragemeBt ■throttgh the eowse ^ ©f this worko : ; • TABLE-OF CONTENTS

IOW o o o b O b 9 O O b C 0 ,0 O O O b O O O O O O O O O O O b O » S b O » O o b » o o o o o o o o1 ©XSGUfSiSXCXM o o o o o o o o-o^ o o o o o o o b o o o o b o- o e 6 o oo b o o o o^o oooooooooooooe3

O O O O O O O O O O O O o O 0 6 0 O e. o O O O OOOO 6006 6. oo-ooooad. 00000-0 0: H o o O O O O O © O 0.0 O o o o o b o POO O O 0 6 0 0 0 6 0 O O'© 0 o © o o o o o o 2.2, A^P^’SlX6 ,:0. o O O 0 O 0 0 6 -O' 6 0 6- © 6 O 6 O O O O O O 0 6 6 © 6 © 0 6 0 0 0 6 0 0 6 0 0 0 0 X2, ; ' Pr^paratieB of Tetraethyl- 1 91 9 4 9 4»Biatanetetraearbox- yls.te. 0 0 0.0 0 OO O O 06 0 0 00 0 0 .6 0 OO 00 60 0 6 0 6 6 ©OOOOQ0OO 60 00 11 Attempted Preparation, ef: Bimethyl 2-0%o^lg3-cyelo=

© O O O 6 0 O b o 0,0 0.00 0 0 6 0 6 O O O 6 © OO OO 14 Preparation of Diethyl: 2-G%o=l, 3=>byelopeB.tanediear-=' hozKylate o o o @ o o o o.o-»o o.o o o » » »» 0 0.000000 @ o 000 0 0 000000 14 Attempted Reduction of Diethyl D-Oxo-l, g-eyelopem^ . 01 o-o 0 0 o o o 0 o o 0 o o o o o o 0 .0 o o o o 000 O 0 o © ID Preparation of l>,3"Cye2.o'pentanediearboxylie Acid 000 15 Preparation of beta^Iodoprbpionic Acid 000000.0000000 17

Preparation, of Ethyl beta-lodopropionate 0 0 0 00000000 . 17 Preparation of Triethyl Igl^S^Ethanetriearboxylate. .«,• 17 Prep.aratibE: of , Tetraethyl ! ,2,2,4-Bntametetracarbox= ylate 0 0 o»6 o o 0 0 * o 000 © © 0 o 0, o © o o © © © © © © & ©; © © © o © © © © © © © © IS Preparation., of Tetraethyl i s3 93 95=Pentahetetracar-- boxylate 0 0 © © © © © © © © o © © © © © © © © © © © © © © © © © © ■© © © © © © © © © © © IS of 3-0xocyelopentaneearbo3£ylie Acid. ©©©© . 19 Preparation of 4-0xoeyelohexanecarboxylie Acid ©o © © © 20 ; ■ Attempted Preparation, of 1 -Hydroxy-1 g 3=eyelopemtane= ' : di.carbossylie Acrd © ©. © © © © © © © © © © © © © © © © © © © © © © © © © © © © © 20 Attempted Preparation.of Diethyl 1-Amino-l93-cyclo- ■ pentanedicarbosyi at©•© © © © © © © © © © © © © © © © ©©©©©©©©©©© © 21 COjNCLDS I ON © © © © © © © © © © © © © © © © © © © © © © © © © © © © © © © © © © © © © © © © © © © © © © © ©-© - 23 LI&T■0F DEFEDEtNCES ©©©©©©©©©©©©©oo©©©©©©©©©©©©©©©©©©©©©©©©©© 24

xv INTRODUCTION

It was reported that the compound 1-aminocyclopentanecarboxylic acid (I) shows an effectiveness against tumors but also possesses the disadvantage of being highly toxic toward healthy cells. It was therefore proposed to synthesize similar compounds for investigation as chemotherapeutic agents for cancer. The compound, 1-amino-1,3-cyclopentanedicarboxylic acid (II), is related not only to compound (I) but also to glutamic acid (III), and therefore may be nontoxic and may act as a folic acid (IV) antagonist as well as an amino acid antagonist. The

,CH CH ?°2H \“ (CVI ) CH2 \ c /NH2 CH2 X c/NH2 I 22 CH2 y COgH HOgC-CH / COgH ^HNH2 c h 2 c h 2 c o 2h

(I) (II) (III)

NH-CH-CH„-CH„-CO„H

(IV) preparation of this compound (II) was approached through the cyclization of polyfunctional aliphatic compounds. This cyclic compound (II) possesses two asymmetric carbon atoms, i.e., a carbon atom having attached to it four different atoms or groups. As a result of these asymmetric carbon atoms, the preparation of this compound could lead to a final product 2

. eontainiB'g a' mixture of foiar sterebisdmerst a dl pair (eaaatia- miprphs) ®£ both, the cis amd trams isomerso . Since biological ■ systemB. would be -used iiav testing these compounds,. it would be desirable to isolate individual isomers from such a mixture, for physiological effectiveness and toxicity, may vary widely for-- 'stereoisomers -o This variation in physiological effectiveness ..is! described by Mol.ler^, who says that MThe differences in behavior of enantiomorphs in livihg, matter are catalysed largely by opti cally active ensymes," two,, examples ' being that ( -)-tartaric, acid is more toxic than (+)-tartaric acid, .and that (-}-adrenaline has twelve, times the activity @fi C +.) -adrenaline in raising blood . . pressures : : _ V;' '. ' : /, r.) DISCUSSION

In a synthetic problem of this type various methods are tried in an attempt to find a procedure which gives the desired product in the largest yield through the most practicable proce dure. Since this problem was approached through the cyclization of polyfunctional aliphatic compounds, the following methods were attempted. 1. A two-step condensation of malonic ester with 1,2- dibromoethane leads to intermediate (V).

C2H50-Mg-0C2H5 CH CH-CH2-CH2-CH 2 Br-CH2-CH2-Br

(V)

(a) If intermediate (V) is subjected to a second dialkylation with diiodomethane, followed by hydrolysis and de carboxylation, 1,3-cyclopentanedicarboxylic acid (VI) results.

20# HCl^ reflux

co2H

(VI)

If the acid halide of this acid (VI) is treated with one half molar amount of bromine, and the product (VII) of this bromination left standing in an ammoniacal solution for several days,

1-amino-1,3-cyclopentanedicarboxylic acid (VIII) should be ob-

3 tained. C0C1 Br C0C1 H.N C0oH CH C 2 C 2

CH \ Br CH \ NH CH \

c h 2 / CH2 ^ c h 2 y 0”2 hydrolyze> c h 2 y " 2

COC1 C02C1 C02H

(VII) (VIII)

This method of bromination, however, has the disadvantage that compound (VI) has two hydrogen atoms which cam be replaced by bromine with equal ease. These hydrogen atoms are the two at tached to the two carbons alpha to the carboxylic acid groups. This then, may lead to dibromination instead of monobromination. Even if the molar concentration of bromine is controlled, a mix ture of the dibromo and the monobromo compound would probably result. Since only the monobromo compound is desired, the expected yield of this compound might be low. (b) Another possible means to the desired product starting with intermediate (V) would be to close this compound into a five membered ring by means of a Dieckmann ring closure. The product of such a reaction would be diethyl 2-oxo-l,3-cyclo- pentanedicarboxylate (IX), which followed by reduction and

X\ CH \ i n l r y > ^ /C=0 hy W e > benzene decarboxylate CH C02C2H5 (IX) hydrolysis gives compound (VI). This then would be treated as in (a) • These methods failed to yield the desired product because in repeated attempts to prepare compound (VI), only once was the desired product obtained, and this was in a yield of less than a gram. Also, from intermediate (V), it was found that compound (IX) could readily be obtained in fair yield, but the method used to reduce compound (IX) failed to lead to compound (VI). The reduction method which was used was the Huang-Minion modification of the Wolff-Kishner reduction— that is, using hydra zine and potassium hydroxide in a high boiling solvent such as diethylene glycol. This method was favored over the Clemmensen reduction for it was felt that the conditions of the Clemmensen reduction would hydrolyze the ester, thus giving a beta ketoacid which would decarboxylate readily to give cyclopentanone, which then could be reduced to cyclopentane by these conditions. The failure of the Huang-Minion reduction could possibly be caused by the existence of the compound (IX) primarily in the enolic form. Also it is quite possible that the ethoxy group of the ester is replaced by hydrazine to form a hydrazide or other undesirable products. 2. Compound (IX) could also be prepared by an aceto- acetic ester type of condensation of 1 ,2-dibromoethane with a di ester of 1 ,3-acetonedicarboxylic acid. In two experiments this procedure failed to give the desired product, and further efforts to prepare compound (IX) by this method were dropped, since all attempts to reduce compound (IX) had met with failure. 6

3* Another means to compound (VI) would be to condense diethyl oxalate with diethyl glutarate. The resulting compound (X) could then be reduced to yield compound (VI). However, it seemed likely that reduction of compound (X) to compound (VI)

CO C H / CO C H | Na-OC H 0=C

> o i s / C " 2 < « > C02C2H5 V 2C2H5 (X)

would meet with the same difficulties as had reduction of compound (IX). 4. A different approach to the problem is a Dieckraann ring closure of tetraethyl 1,2,2,4-butanetetracarboxylate (XI) followed by hydrolysis and decarboxylation to give 3-oxocyclo- pentanecarboxylic acid (XII). This compound would then be treated with sodium cyanide in an ammoniacal solution to obtain 1-amino- l-cyano-3-cyclopentanecarboxylic acid (XIII). Compound (XIII) is then either hydrolyzed by dilute aqueous acid or esterified by

9°2C2H5 „(C02C2H5)2 W 5* C ------CH ?H2 Na . ?H2 \ / „ / ?H2

(IH , benzenf CH2 / 2 2 3 \ / C(C02C2H5)2

T 2 2 9 C02C2H5 0

(XI) 7

20% HCl^ / ?H2 NaCN ?H2 \ ^ NH2

(XII) (XIII)

CH, CH. dry HC1 ^ .,NH 2 absolute ethanol C2H502C -CH C02C2H5 2

(XXV) passing dry hydrogen chloride through a solution of compound (XIII) in absolute alcohol• This should give the desired product, 1-amino-1,3-cyclopentanedicarboxylic acid or the diester (XIV) of this aminoacid, depending on the solvent used. The starting material for the above procedure is not com mercially available, but it is readily obtained in good yield by a two step condensation of diethyl malonate with either ethyl bromoacetate or ethyl chloroacetate. This gives triethyl 1,1,2- ethanetricarboxylate, which is then alkylated with ethyl 2-iodopropionate to yield the desired starting product— tetraethyl 1 ,2,2,4-butanetetracarboxylate.

<'02C2H5 COCH Na-OC2H | azeotrope method. Here again the yield is very good. The steps in this reaction sequence, up to the Dieckmann ring closure, give easily purified compounds in good yield and have the additional advantages of simplicity and of requiring no special equipment. The yield in the Dieckmann reaction is suffi cient to be practicable. Following the Dieckmann ring closure, the steps in the reaction are easily carried out, but the product isolated from this reaction has not been positively identified. 5. Again making use of the Dieckmann reaction, a possible method would be ring closure of tetraethyl 1,3,3,5-cyclohexane- tetracarboxylate into a six membered ring, followed by hydrolysis and decarboxylation to yield 4-oxocyclohexanecarboxylate (XV),

CHo-CH-C0oCoH

benzenebenzene 9 ,CH_—CH, 2 2 X HOgC-CH c=o X CH2-CH2 (XV) which would then be treated with bromine. The resulting dibromo- ketone, upon being shaken with an aqueoue solution of potassium hydroxide (the Wallach degradation) should lead to 1-hydroxy-1,3- cyclopentanedicarboxylic acid (XVI). If the hydroxyl group in compound (XVI) is replaced by bromine, then the bromine with an

Br, 2 (XV)

CH2-CH-Br

(XVI) amino group as described in preparing compound (VIII), the product obtained should be compound (VIII)• The starting material for this reaction sequence was not commercially available and had to be prepared. This was readily accomplished by the alkylation of diethyl malonate with ethyl 2- iodopropionate in a one to two molar ratio. l?p through; the Bieekmanm'-ring ©Ipsure:, this reaction' sequence> like .the one preceding it 3. is. made up only of simple to. run: reactions^.; and.:with: such yields., as to make the entire reaction sequence practicable.» - HoweTer^ following' the Dieckmaaa reaction, 'the procedure followed failed. to yield the desired product <, -v "'. ■ ■ ; . V ; E3CPEEIMEMTAL

Material© c, ==01 ethyl malonate was obtained from the Fisher Seientifie Company or'from Fluka AG. The latter was also the sowree of the diiodomethane and the diethyl 1,S^aeetonediear” bosylateo Baker0© sodium■ sulfate, sodium cyanide, and hypophos«= phorous aeid..were used, while the m a g n e s i u m sulfate was a Malline=> krodt Chemical Works. product> From the Metal Hydrides, Inc.-, was- obtained the sodium.hydride, and from Celanese Corporation was . obtained the beta-propiolactome. The l,2>=dibrom©ethane-, ethyl ehloroacetateand- ethyl: foromoaeetat© were- Eastman Kodak White Label productso- . The hydroiodic acid.was -freshly, generated from oxidised solutions of hydroiodic acid using- essentially the proeedure and apparatus * described,, by • Foster and Eahas 2 »• ■ Apparatus o-.— A mumber of the various reactions -were run in :the. same type- of apparatus^ which .consisted of a one lifer round- bottom, three-neck, flask with ground glass joints, to which was attacked a.Friedrich- condenser .with a calcium chloride drying tube. The three-neck- flask .was also.fitted with- a Hirshberg stir rer powered by an electrical motor. This apparatus shall.-, through out the rest- of the experimental section, be referred! to as Appara tus (A). Also- used were a continuous liquid-liquid extractor and a continuous esterificatiom apparatus 3 . A Coca-Cola bottle wrapped with chicken -wire and fitted with a rubber stopper which was wired in place was- used as the reaction vessel-for all closed reactions. A Carl 21ess refraetometer was used, and the infrared spectrophotometer was a Beckman- IE-4. The cells used in the Beck man IR-4 were of - sodium -chloride . -

In the preparation of tetraethyl 1,1,4., 4-butanetetracarhoxylate, three procedures have been attempted. Two of these three proce dures yielded the desired product; however, neither of those were 12

©©mpleiely satisfactory» Of the three 9 the third gave the best resBltso '■ Ao l?r©eedur© (I) o Ôeasideriag the cwpling. of ^1,2* dibromoethane with diethyl maloaate as essentially the same type of reaction as coupling 1 g2=dibroraoethane with, dimethyl 1 93«= t ■ 4 acetoBediearbosylate■as described by (3uha and Seshadriengar 9 the following prooedwe was tried: To 40© mlo of dry beMeae; la .Apparatus (A), tvas added 47 go Cl m©l©9 of sodium, hydride) of. a 51 o2^ sodium hydride-iaineral oil suspension 0 A . mixture Of 16© §<, (JL mole) of' diethyl malonat© and 94 go (Oo5 mole) of 1 92-"dibromoethane was added dropwiseo The mixture was refItaed with stirring for 12 . hours o The bensene was then distilled.off and the .solid residue remaining was treated with dilute hydrochloric acid*. The - non-=aqueous layer was sepa^ rated9 and the aqueous layer was extracted with ether several times 9 the ethereal solution being added .to the nonâqueous layero This .non-aqueous-=ethereal solution was then dried over sodium sul fate and fractionally.distilled under reduced- pressure' to give the. following fractions, collected at 1 mmo pressures Cl) 54<=59°, unidenti.£ied| ' (2) - 59-62° 9 diethyl raalonate| ■ (3) 82-145°, mineral oil., (4) undisf 11 labl e r es i due * A second attempt was. made using the above procedure and similar results were' -obtained*. Bo -Procedure- (II)■ o--This procedure, which • is described by Noyes and Eyriakides , uses magnesium.ethexlde as the base* . Glean magnesium ribbon (20 go, or Oo823 mole) was- put in Apparatus (A) and 800 go (4 moles) of mercury was added* This mixture was heated until, amalgamation was complete, them allowed; to eoolo After cooling, 200 mlo of absolute ethanol.was added to this amalgamate, and the mixture heated at 100° for. three- hours* The flask was then cooled and 200. go of diethylmalonate was added and the resulting mixture, heated for three.hours, at 100°0 The flask was cooled, and 1 ,2-dibromoethane (116 go, or 0o62 mole) was added over a short period of time? the mixture was heated for 12 hours at 100°o As .m.ueh’ as possible of the alcohol was distilled off under reduced pressure and-the mixture was treated with dilute hydro™ ehloric acid until, the liquid separated into two layers» Bther ;■ extractions were made, the ethereal solution dried over magnesium sulfate, and then the ether was'removed by distillation. 1 The remaining liquid was.them fractionally distilled under- reduced pressureI the following fractions were collected a t 3 mm. pres sures (l) up to : 165°§ (2 ) 167-182.0? (3) undistillable residue. Fraction (2) consisted of 35 ml. of a heavy oily material .with = 1 0.4435 o; This fraction .was refractionated - under - reduced pressure yielding the following fractions at 3 mm. pressures- ' ; - - - ' ' ' '. V - '. -■ <’ 25 Fraction Boiling Range ■ : ' ' Volume-- 1 n„ C°c» .,at 3 mifflo ) . (ml . ) 1 ' 167-172 9 . 1 = 4430: 2 172^175 17 ' 1=4430 3,: ; : :175-177: ■' 8 1=4428. /4-:. ;:V - - 177-179 , ■ ; . ■ V 1 _■ / 1=4437. Fractions # I -, 2 .9. and 3 were ' combined; . on standing, there crystallised out -a compound which had a melting point of 77° after recrystallization from 95% ethanol= Later this compound was: • proved to be tetraethyl 1 91 g4$,4=>cyelohexanetetracarboxylate0 The oil remaining after filtering out the crystals. had sx^ = : • l.=4425o ‘ ’ ' ' ' r .'v. : . ." The reaction was run three-more times using the same procedure= The results, after fractionation under reduced pres- sure9 .were similar* The yield pf. product averaged 12% of the . thepretieal:.yielidix'. . .■ '-. ' t - : :; -. • ' . .'C=;: Procedure (lIl)o--TMs procedure involved - the - modi - fi cat ion as described by Mein eke, Cox, and MeBlvain „ that is, the preparation of magnesium ethoxide (the Lund and Bjerrum method) by refluxing magnesium turnings with absolute ethanol using 'iodiae- as-. a catalyst to, start.the ethoxide formation. After - format ion of'the magnesium- .ethoxide, the procedure was the same as that of procedure (II)= . Using ih£@' modificationg the reaction was rira six timeso The yield and- parity were inconsistent9 ranging from a 52% yield of prodnet having n^ = l o4400 to a 17% yield of product having hu® = l-04448» The literature values® are a boiling point of 193»1950/15 mao and n" = I*4470& Attempted Preparation of Bimethyl 2 dicarboxylate o.°°The procedure as outlined by Guha and Sesha= driengar was used with some modification^ Instead of using the diethyl ester of 193=aeetonediearboxylic acid9 the dimethyl ester was usedo The sodium derivative of this dimethyl ester was pre~ pared by adding dropwise into Apparatus/(A)9 which contained'2©•go (0o55 mole) of a'5 1 sodium hydride^mineral oil suspension in • 250 ml, of dry bensene, a mixture- consisting of 48 go (0o29 mole) of dimethyl 1 ,3=aeetonediearboxylaie and 5109 go (0<>28 mole) of l 92“dibromoethaneo After the reaction was allowed to run for 100 hours 9 the bensene was.distilled off and the solid residue was acidified, then extracted with ethero The ethereal solution was dried with magnesium sulfate and the ether was removed by dis<= tillationo Upon standing, a compound crystallised out from the remaining residue» This compound, after recrystallisation from- ligroin, gave a melting point of 140=141°0 This.compound has not been farther characterised, but is considered to - be -the methyl. analog of the compound referred to by Csuha and Seshadriengar as a 60phenolic lactone." Other attempts to prepare the desired com* pound by this method gave similar results:o of =cyclopemtanedicar= fooxylate-o ==Thls reaction was runas described, by. Meineke, Cox, and .ScEivain 6 , that is , a mixture consisting of 52.g. (0,15 mole) of tetraethyl 1,1,494=butanetetracarboxylate and 1 0 .5 go (OdS mole) of freshly prepared sodium ethoxide was introduced into a flask provided with a condenser for distillation and a mechanical .stirrer. The flask was heated at 85° for five hours and then at 120° for another five hours under a pressure, of 200 mm.. At the end of the ten hours of heating, the remaining residue was treated 1 5 with 90 mlo ©f water, and, aeetie aeid ©quilixralent to the sodima ethoxide esedo The aqueous layer was extracted twice with eth@f and the "ether reiaoêd ''by- distillation after drying - over ma#iesimm sulfateo ©a fractionating the remaining.residue.under reduced. pres.sure9 6 g.« of the desired ketoacid ester was. obtained = This © 25 ketoacid ester had a boiling range of 152-164 /8 imio 9 = 1 o4521» and gave a dianiiide derivative melting at 19205=195°o The lit erature values^ are a boiling range, of. 154-162°/8 mm o, and a melt ing.-, point of the:, diamilide derivative, of 195° o . Attempted. Reduction of. Biethyl 2-0xo-l,3-eyclopentane- diearboxylateo— Since■hydrazine replaces the ethoxy group of esters - readily , the reduction was tried on the dianiiide deriva- tivso Using an apparatus similar to that described by Huang- .Minion , 2-oxo.-l,5=eyclopentanedicarbani 11 de (3 g«» or 0 o116 mole) was added to 85% hydrasine (16»3 go, or 0<>431 mole) in 42 mlo of diethylene glycolo The mixture was refluxed for three hours at 14©°, then four hours at 20©°» The mixture was cooled and poured into water, but nothing separated outo An ether extraction was made of the diethylene' glycol-water solution, but this failed to extract a compound* The reaction vessel was noticed to have a transparent film on the'inside? neither water nor ether would dis solve it* An.aqueous ethanol-potassium, hydroxide'solution was refluxed in the reaction flask for three hours*: JEhe solution, when ■ poured into water, formed, a paraffin-like- film covering, the water* The water layer was extracted with, ether and benzene, but nothing was obtained* The water layer was acidified and extracted with ether , and.again no compound, was obtained from the ethereal solution* @n filtering the aqueous" solution to remove the paraf = • fin-like film, no material could be recovered from the filter paper* procedure described by Perkins and' Scarborough^ was followed, using 1QQ g* (0*29 mole) of tetraethyl 1,1,4,4-butanetetraear- 16 foosqriatej) 13 o3 g» (0 56 mol®) of metal lie - sodium, and 7?05 go (0o29 mole) of methylene iodide8 to the point where the ether extraction was made = After making am ether extraction at this point,- the ethereal solmtion was dried using magnesium sulfate0 The ether was removed hy distillation, and the residue remaining in the distilling flask was.fractionated at 3 amo pressure to give the following fractionss . Boiling Range Anount Fraction 4 5 (0, 3 mm®) (go) 1 110=130 26 1 o 4464 2 130=150 1®4460 3 150=17© 13 ®,1 lc4464 4 190=220 ' 4 1=4546 5 Umdistillable residme Fractions # 1 and 2 were combinedo This combined fraction and fractions # 3 and 4 were each heated separately with alcoholic potassium hydroxide solutiono After refluxing for two hours, the solutions were acidified with nitric acid and the desired diear« boxylie acid separated, as described by Pospischill J t O o ' Only from fraction four could any of the desired acid (0 02 g*) be isolated? it melted at 80=90° and thus consisted of a mixture of els and trams isomers o Two other attempts, both using the above procedure except for one reaction being: run in Apparatus (A) rather than a closed bottle, only yielded starting material« . A fourth attempt was made to prepare this compound using the same quantities as before, but using magnesium ethpxide as the base and Apparatus (A) as the reaction vessel» This procedure, when worked up in the usual manner and distilled under reduced pressure, yielded 12 mlo fraction with a boiling range of 185=200°/ 25 2mm^ and having * l 04531o This fraction, upon refluxing with 100 mlo of 20% hydrochloric acid them removing the aqueous hydro= chloric acid by distilling under reduced pressure, gave, on standing, an orange crystalline compound => This orange crystalline . . . ■ ^ 17 eompo$md'9 when r@erystall-ia@'d from absolute-, .ethanol, became' white and melted between 76=78° c % e - literature. ••*alue ■ for the eis. isomer i s .121° and for the trans isomer- is 88° o On the chance that the. crsrstalline material consisted'" of. a mixture of" isomers 9 an -attempt' was made.to separate isomers through their-difference "in.- solubility in carbon- tetrachloride^ /The result was. ©o 9 go ©f a compound melting at 75=78°» Wo farther".attempt has been mad® toward identifying this ■ compound <> Preparation of beta=lodopropionie A®ido=°To 1200 g« of freshly generated constant boiling hydroiodic acid in a three neck9 ground: glassy round bottom flask was added dropwise 10© go. of beta=propiolaet©ne or its polymer» which is a solid and may be added all at once. This mixture was. then refluxed for six - hours, after which the volume was decreased to half by distilling.. off the water formed by - the reaction and also some of the excess constant, boiling hydroiodic acid. The remaining material was. then poured, while still hot, into a - beaker <> ©n cooling, large leaf crystals precipitated.out; on recrystallisation from water they had . a melting point of- 82°o The yield amounted to- 87 05% of . 11 the theoretical yieldo The literature■value for the melting point is 82°o Preparation of Ethyl. beta=Iodopropionateo— The esterifi= cation of .the beta=iodopropionic acid was brought about by the ' 1 ■ . sulfuric acid=ethanol^benaene. aaeotrope method* • < The ester was; then obtained from this azeotropic mixture by distilling off the ethanol “benzene, then, washing the" remaining ester with sodium: bisulfite solution, sodium bicarbonate solution, and finally with small portions of distilled water„ The ester was fractionated 25 under reduced pressure, to - give a 72=80% yield| n^ between lo4915 and 1 o4922, boiling■point, 57=590/3 mmo The literature values^^ are- B^® « lo4@6l , boiling point. §3“5@°/lol - to lo2, mtoo. Preparation of Triethyi 1 „ 1 ,2=&thanetrlcarboxylate.o ==The procedure, used to prepare this compound was as described by Kay and Perkins 13 « '■ " ' \ V ' ' i s ■:; To 350 mlo of absolute alcohol ia Apparatus (A) was added 23 go (1 mole) of metallic sodium and the mixture left standiag until all the soditam had reacted * The reaction flask was them placed-in. an ice bath, and to this /.stirred sodium ethoxide solu- , tioa: was. added dropwise :160. go. .Cl mole) ©f diethyl malornatee Fcl- lowing the addition of all the diethyl malonate, ethyl bromoaee-= tate (lOO go s or 0 066 mole) was added dropwise<. After the ethyl bromoaeetate had been added, the reaction was allowed to gradually .. - . - ' o come to room temperature, heated for one hour at 100 , and them cooled® A large excess' of water was.then added, the solution separating into two layers® The organic layer, (top layer) was■ \ : removed, and the aqueous layer was then ■extracted several times: with ether., the . ethere:al solution: being added to the . original . ■ Organic layero This ethereal solution was then dried using mag nesium sulfate , and the ether was removed by distillation0 A reduced pressure fractionation gave the desired product in 05% -yieldg .boiling range 115-130^/3 mm®, and n2^ - 1®4290® The lit- > JL S ^ y * ' V ' eratur©: :vala®■ tor. the boiling- range is 160-170. /15 mm® . ' ... ' - In; one .preparation ethyl chloroacetate was used ..in place of.ethyl bromoacetate with the heating time changed from one hour - to eight hours® The yield stayed the same® Preparation of ^Tetraethyl 1,2,2,4-°Butanete.fracarboxylate® •; ■ - . . . ■ .,e ■ 13 • Again following the procedure of Kay and Perkins 5 sodium (8 ®9 g®, or 9=39 mole) was added to 135 ml® of absolute ethanol® After ■the formation of the sodium ethoxidewas complete, the solution was cooled and to it was added dropwise 95 g® (0=39 mole) of the triethyl 1 ,1 ,2 -ethanetricarboxylate prepared above ® The rest of the procedure, is identical to that described above in the prepara tion of triethyl 1 ,1,2 -ethanetricarboxylate after the addition of the ethyl bromoacetate® This procedure gave the desired product ■: ,:-in 85-88% yield, boilihg range, 185-167^/3 mm®, and = 1=4415® ,■ ' The literature, value-'. , is. 29.0-293 /12,. mm® ■■ :■;. Preparation of Tetraethyl 1,3,3,5-Pentanetetracarbox- ylate®--This compound was prepared in a similar manner tb that described above in the preparation of triethyl 1 ,1 v2-ethanetri" earboi’sylate, tout with two moles ethyl beta-=iodopropionate being coupled to the diethyl malonateo The eompoumd was prepared,toy • . ' o g ' this means in 63o5==7€>o5% yield and had n^ =■ 1 o4442=lo4433 when.; eelleeted at 168^182e/5 mm0 The literature values^1* are boiling range 138=149^/0o3 maoo and n ^ = lo444o Preparation of 3=0%o@yelopentaaecartoo%ylic Aeido°-=In the first attempts to, prepare this compound, the procedure of. Kay; and 13 - Perkins was used with some modifications» Instead of convert■= lag the tetraethyl l92 92q4'=butanetetracartooxylate into the tri= ethyl l,92 »4 =butaBefricartoo3cylate-9 the tetra=-ester (57 g P, or Gel85 mole) in twice its volume of dry bensene was added dropwise to 8 go (0o35 mole) of sodium sand, which was at a temperature of 100®o This reaction was carried out in Apparatus (A) with rapid stirring. After all the sodium sand had reacted, the excess to@n= sene- was:removed by distillation'and the reaction mixture was Allowed to cool. This material, which was very viscous, was poured into a mixture of dilute hydrochloric acid and ice, ©n standing, am organic layer separated (top phase). This organic layer was removed and the aqueous solution was extracted a number of times with bensene, the.bensene solutions being added to the original organic phase. This benzene solution was then dried using magnesium sulfate and the benzene was removed toy.distilla=- tion. The remaining residue was•refluxed'with ten times■itos- volume of 8% sulfuric acid until the organic.phase had all■dis~ appeared into■the aqueous phase. This aqueous phase was. saturated with ammonium., sulfate and continuously extracted with ether. The ether solution obtained from this extraction was dried over mag= nesium sulfate and the ether- removed by distillation. On stand ing, the desired acid .crystallized out in 2 2 ,6% yield with a melting point of SS^Gl® when recrystallized from benzene, iater th©' procedure.was modified to correspond with that given by 3,5 Shemyakin,'et al, ' This modification consisted of fractionating the organic layer obtained from the Dieekmamn ring closure and ' . ' ... ■ : ' 20 taking the fraction coming over hetween nmio and reflux^ lag it with ten times its volumeof 20%'hydrochloric acid: until '..all the organic phase had gone into solution 0 $he aqueous acid . was removed ::hy-,- distillation ..under reduced pressure.» The. residue . remaining. was refractionated under reduced pressure-,: and, almost all of it came over b.etwe.en,: 130-150 ,/3 mmo. This material: crystallized almost immediately, giving a white solid which'melts at 59=61° when reerystallis@d from,benzene» . This procedure gave the pro duct in 27% yieldo. 'Literature values for the melting point are 64-65° 13 and 61=5-62° 15 (from diethyl, ether).' ' ' ;/ Preparation.of 4-@xdcyelohexanecarhoxylie Acid.— This compound.was prepared by the cyclization of tetraethyl 1,3,3,5- pentanetetracarbo^ylate by the means described ahove for the .. preparation, of 3=©xoeyelopentan.ecarboxylie .aeidb • .The' product „ ' reci^ystalllzedî'from - water ^ y melt ed at - 55=66:. i,-xeiBdir ©presented -a .21 o5% .yieldo The literature value^3 for the' melting point 'is 67—68°o ' : Attempted Preparation of l-8ydrox.y-l ,3-eyclopentanedicar- ; boxyiic Acid o — The procedure described by Wallaeh, ...Q-erhardt, and JeSsen for the conversion of cyclohexanones into eyelopentanes was followed with some modification. The dibromo derivative was prepared by dissolving 8 »5 g 0 (0o056 mole) of 4-oxocyclohexane- carboxyiic acid in 24 ml. of glacial acetic acid and adding dropwise 6o5 go (OoOSl. toole) of bromineo Sulfur dioxide gas was then . passed through thesolution to destroy any unreacted bromine and ' the' solut-ion 'was- poured into: twice its volume' of: water. The . aqueous.solution;was continuously extracted with ethero The ether eal solution from this extraction was dried with.magnesium sulfate, and then the ether was removed by distillation. The residue re maining after removal of the ether was neutralized and poured into a solution consisting of 12 g. of potassium hydroxide in 540 ml. of water. ,This solution was shaken on a mechanical shaker for four hours and then processed as described by Waflach, Ger hard t, and Jessen. Only from the continuous ether extraction was 21 aa.organic compound isolated, and this in very small amount0 This compound is insoluble in acid and hot carbon tetrachloride, but soluble in five. per. cent sodium hydroxide solution, water, dioxane, and hot. absolute ©fhanolc It has. a melting point of 178-184°o, A sodium fusion followed by .subsequent tests gave a ■ negative test for bromine,.thus indicating that it was not the dibromo derivativeo The infrared spectrum of this compound showed that it was neither the original starting material nor the desired product© When the potassium hydroxide solution was evap- . ©rated to dryness, attempts to isolate a compound from the resi= due .remaining met. with, failure« .Attempted Preparation■of Diethyl l°&mino-l,g°cyclopen° tanedicarboxylate6 — The procedure used in.preparing diethyl l~amin©=J.93-cyel0.pentanediearboxylate, starting with S-oxocycIo- pentanecarboxy1ic acid,.followed closely that described by Eepdall and Mellensi® 17 for the preparation of alanine, To 25 go (0o195;mole) of. 3=bxo©yel©pentanecarboxyli©.acid in .a 25© mlo. bottle were added 13o© go.(®o25 mole) of ammonium chloride , 11 b,5 , gc C©o 195 mole), of 29% ammonia solution , and 33halo. of watero The mixture.was then cooled in an ice bath, and to it was added a solution, containing llo9 go (0<34 mole) of sodium cyanide in 33 ml* of water* After the addition of the. sodium cyanide solution, the bottle was stoppered- securely, placed in a mechanical shaker ,, and shaken for. eight hours- at room temperature o At the end of. this'time 15 ml».of concentrated'hydrochloric acid (0ol95 mole) was .added o. The solution was then concentrated by means of reduced pressure, and low heato The residue remaining after the removal of the water was taken up in 250 m l » of absolute ethanol through which, anhydrous hydrogen chloride was -then bubbled for six-hoursi The- alcohol was removed under reduced pressure, and.the residue..was-dissolved in the smallest amount of water possible s.. This aqueous, solution was. them neutralised and ex== ■ tracted several times with ether» The ethereal solution was dried by magnesium sulfate and the ether removed by distillation* The ■ residue remaining at .this point was a dark brown to black tar=> 1 ike material.». soluble in most organic solvents; it gives a posi= ;tive. test for nitrogen when., qualitative ■ tests are run following.a' : sodium- fusion o This compound s- whem.'.taken' ,up in '.carbon' tetraehler” id©- settles:, out on the .walls of. the .containera still a dark- brown" fb: black tar=like material', when-:'anhydrous, hydrogen chloride is' ■ ; bubbled through the carbon tetrachloride solutioBo Although the . /infrared •spectrum of. this ' compound: is- hot. inconslstent with the . ' spectrum expected ..of - di.ethyl 1 = amino =1,3 <=cyclopentanedi carbo3Eyl= ’ • atej it is.also/not, ihcbnsistent-with the- spectrum expected of -/the. ethyl,. ester/ of Sôxoeycl.G.pentanecarfooxylie acid (esterified starting.. pr.odmet).o : Theref ore the identity of this compound is . still - uncertaino ' ■ . ■ • . " CONCLUSJOM

: VarieHS.- synthetie proeedures for th© preparation of eom= pounds related to. i-=aminoeyelopeBtaBeearboxylie-. acid ■ have beem * attemptedo, A. proeedure-v inwoiwing a Dieckmama ring closer© fol= lowed byv ainination and addition of cyanide has yielded a compound. . which gives an infrared- speetrmn and other data which is not. in™

tanediearfooxylatec. . Eeitherhowever, is this spectrum and data inconsistent for '.that expected for. ethyl- 3 =.oxocy el op ent aneear - boxylate: (esterified :starting, material of this reaction)„ There fore the identity of ' this compound is still ah'cerfaim^ : V' " . Various aspects of this work are felt to, .merit.further ■ • inrestigati.on.o. A " procedure'.-to:' isolate, the more water-soluble, com-.. Vponents' frow the; Wdl-l.aeh:, reaction-.might . lead ' to rewarding:-resmltSs 'since-the-one material isolated by the ether extraction eorre=> sponded;. to ■ only- #"small- -fraction, of .'the: -weight 'of - the starting" materials Also a procedure, for. the,purification- of the compound . obtained inaminatich-.and': ■addition. o.f leyanide^'t©;' 3“.oxocy©lop©n-..; tahecarteoxylie. acid will, be necessary- before a positive identi- ■ ; .fication. ..of n-the ' product; Can be made = - Only af ter - this- : idehtif i-■ •: . cation', will -itt -be.;.possibl.e to decide; whether.:-,the procedures .. herein developed., are leading to the 'desiredvresultso. • ' L&ST OF EEPSEEMCES

2® ^ So;'Foster-: and E. ■:G. i!Jalias, Jr. in "Inorganic Syntheses,’6 . ; Yolo I, McGraw-Hill Book Coo, Irieo, Sew York,' H, . Z» , 1946, , po 21O 0 . ' : - - . • ; ■ ■■ ■ 3o Ho To.Clark and A» W® Davis in ,!Orgaaic ,Syntheses,M Colli> Yol® I, '2d'edo-,.. John Wiley and Sons 9 Inco, New York, No To, T941, ■

vV' :p° 2 6 1 0 ■ ■'/ ; : ' ' , : . :4o Po Co Guha and N® ICo Seshadriengar, Current Science, 4, 158 ' - (1935)? Co A,, 20, 1032 (1936)o So Wo -Ao Moyes. and Lo Po Eyriakides, Jo Am, Chemo Soe., 32, 1057 ' (1910). '' ' ‘ ; . ■. ■ ; : r '

6 o So So Meineke',- Be.- F» B, Cox, and Sv M « . MdElvaiii j. Jo. Am.' Chemo ; : SoCo, 57,--ll33 (1935) o ^ 7 o' ,Ho Lund and J.o Bjerrum, Bero, 64, 210 . (1931) o . ■

8 * Huang°Minlen, J « Am® Chemo Soe., 6 8 , 2487 (1946)« 9®' Wo Ho Perkins, .and Ho A o'-Scarborough, Jo Chern = Soc«, 119, ■ 1400 (1921) o •

.10. Ko To Pospischill, Bero,.'.3.1, :1950 (1898)o - .11. . .’'Handbook of ' Chemistry and Physics39th ed,, Chemical Bub- . her Publishing Co., Cleveland, 1958, p. 1132=

12. Co Go ..Overberger, Pao-Tung Huang, T« :B„ .Gibh, J 0 Am. Chemo Soe. 75, 2G78-82 (1953) ? Co Ao ^ , 5120' .(1954) o

13o Fo Wo Kay and W. Ho Perkins, J.® Chemo SoCo, 89, 1643-49 ' V(id0 6 ),< : . y ; :■ r'. 14. To iio Gresham, J. E.« Jasen, F= #.. Shaver, M® Ro Frederick, ■ ; arid.Wo’ljo'.BeearsV.'Jo Am. Chemo Soe. , 73, 2345-7 (1951) ,

15.■ ||.o M o . Shemyakin,. Bo A. Shehukima, E= I. Vinogradova, M. N 0 Kolosov, R-o Go Vdovina, M. Go .Karapetyan., V. Ya. Rodionov, Go.- A.: lavdel, Yu. B= Shvetsov, E„ M. Bamdas, 32= S. Charman, jCo' Mo Evmolaev,. and E. Po-'-Semkin, 2hur= ©bshehei Khim», 27, : . 742-8 (1957).?'Co/-A..51, 16313 (1957). 5. ; - ■ • - : ' \ ■ ; • ■ ■ ' •' , ■ " . ■ ■ - ' ■ ■ :: ■ 25 : " 16* •©*: Wallach-, Mo Gerhardt, and W*. Jessens 1 Cheaio Zentro 1».- , o 365«9''tl916) Co A.- 2210 (1916).„ ' :'v

-I?*' , G *^ Eemdall; amd:. % F« McKenaie ■ ini' "Organic Synthesis 9" . . , . Coll*' Folo I', -2d edoV'"'lohn Wiley and Sons,' Inco, New York, 'jjo y.: , 1941fl:;p» ilo1; .. . : " ; V - V.' ; ;18o Po Co Gttha and S* Ko Ranganathan, Ber*, 69, 1199 .(1936) *

. ; - 20* Co Ko Ingold and Jo F® Thorp®, Jo Ch®m0 r:So®* '119* 501 .(.1921) e

2 1 0 Wo No Haworth and'Ao T* King, J * Chem* Soc*, 105, 1350 (.1,914) O . .'1 '■ r'; "V'' ..:V' '