United States Patent (15) 3,682,970 Henricket al. - (45) Aug. 8, 1972

(54) PRODUCTION OF UNSATURATED (56) References Cited CARBOCYCLIC 72) Inventors: Clive A. Henrick, Palo Alto; John A. UNITED STATES PATENTS Edwards, Los Altos; John H. Fried, 3,472,885 10/1969 Bucourt et al...... 260/.397.45 Palo Alto, all of Calif. (73) Assignee: Syntex Corporation, Panama, Pana Primary Examiner-Henry R. Jiles a Assistant Examiner-Cecilia M. Shurko 22) Filed: March 27, 1969 Attorney-Evelyn K. Merker and William B. Walker 21 ) Appl. No.: 811,237 57 ABSTRACT 52) U.S. Cl...... 260/327 M, 260/247, 260/293.51, Preparation of ag-unsaturated carbocyclic ketones by 260/340.9, 260/345.7, 260/345.8, 260/345.9, reacting a methylene or methine phosphonium ylid 260/347.2, 260/347.3, 260/347.4, 260/347.8, with a 8-keto , anhydride or acyl 260/.397.5, 260/469, 260/514 R, 260/526 S, halide. The reaction is useful for producing inter 260/544 L, 260/546, 260/586 R, 424/238, mediates for synthesis of known steroids having es 424/241, 260/606.5 P trogenic, progestational, or anabolic activity, for ex 51 Int. Cl...... C07d 73/00, C07d 13/04, C07d 7/04 ample. 58 Field of Search...... 260/340.9, 586 R, 327 M,514 R, 260/340.9,345.9, 7 Claims, No Drawings 345.7,347.3 3,682,970 1. 2 PRODUCTION OF UNSATURATED The phosphonium ylids which are useful in the CARBOCYCLICKETONES production of ag-unsaturated carbocyclic ketones by This invention relates to the production of unsatu the process of this invention are the methylene rated carbocyclic ketones. More particularly, this in phosphonium ylids which can be represented by the vention relates to a novel process for converting 8-keto following formula carboxylic acid , anhydrides or acyl halides into o,6-unsaturated carbocyclic ketones. The expression "8-keto carbocyclic acid," as used herein, refers to cyclopentyl propionic acid compounds 10 having a keto group and the propionic acid group at (I) tached to adjacent carbon atoms of a cyclopentyl ring. The expression "ag-unsaturated carbocyclic wherein R, R, R and Rs are as defined above. The ketones,' as used herein, refers to carbocyclic ketones phosphonium ylids of the above formula can also be having ag-ethylenic unsaturation with respect to the 15 represented as follows keto group. Ri Prior to this invention, o,3-unsaturated carbocyclic ketones were produced from keto carboxylic acids by a RSF-GHR multi-step process which involved converting the keto R3 carboxylic acid to the corresponding enol lactone by 20 (I) treatment with acetic anhydride-sodium acetate, react ing the enol lactone with a Grignard reagent, for exam wherein R,R,R, and Rs are as defined above. ple, methyl magnesium chloride, to open the lactone Phosphonium ylids of Formulas I and I' can be ring, and thereafter cyclizing the thus-obtained prepared, for example by reacting the phosphonium diketonic intermediate product by treatment with acid 25 halide or alkali to obtain the carbocyclic . See, for ex ample U.S. Pat. Nos. 3,057,907 and 3,321,489 and R1 French Pat. No. 1,359,675. The principle object of this invention, therefore, is to / provide an improved process for producingo,6-unsatu 30 LRsE-ouk rated carbocyclic ketones from keto carboxylic acid esters, anhydrides, or acyl halides which overcomes the e.g., the bromide or chloride, with a base which is capa aforementioned disadvantages. Another object of this ble of removing hydrogen halide. These phosphonium invention is to provide a process for producing a?s-un halides can be prepared by known methods such as by saturated carbocyclic ketones which is economical and 35 reacting a tertiary phosphine with an organic halide. simple to operate. Suitable bases which can remove hydrogen halide are Another object of this invention is to provide a sin organometallic compounds such as or aryllithium gle-step process for producing ag-unsaturated carbo or alkali metal . The ylid can be formed in an cyclic ketones. Still another object of this invention is 40 inert solvent such as , tetrahydrofuran or dioxane to provide a processfor producing ag-unsaturated car and preferably in an inert, oxygen-free atmosphere. bocyclic ketones which is useful in the total synthesis of The method of preparing the phosphonium ylid is not steroids and to novel intermediates therefor. part of the present invention. Procedures for forming In general, the process of this invention is a method methylene phosphonium ylids useful in the present in for producing a 6-unsaturated carbocyclic ketones 45 vention and examples of suchylids are described by A. which comprises reacting, under anhydrous conditions Johnson, W. Johnson (Ylid ) Academic in an inert organic solvent, a methylene phosphonium Press Inc., New York (1966); S. Trippett, Quarterly ylid represented by the formula Reviews, 16, pages 406-440 (1962); S. Trippett, Ad vances in Organic Chemistry, Vol. I, Interscience, New R1 50 York pages 83-102 (1960); and A. Maercker, (Or RNP=CHR ganic Reactions), Vol. 14, John Wiley & Sons, New York, pages 270-490 (1965) and in U.S. Pat. Nos. (I) 2,905,717; 2,197.523; 2,917,524; 2,950,321; 2,957,933; 3,078,256 3,130,219; 3,152,152 and with a lower alkyl ester, aryl ester having up to 10 car 55 3,347,932. bons, lower alkylthioester, lower alkylcarboxylic acid Methylene phosphonium ylids are sometimes unsta anhydride, or acyl halide of a 2-oxo-1-cyclopentyl ble compounds which react easily with oxygen and propionic acid, wherein R is selected from the group decompose on standing for any appreciable period of consisting of hydrogen and substituted and unsub time. Thus, in the practice of the process of the present stituted, saturated and unsaturated, aliphatic, carbo 60 invention, it is preferable to use tricarbocyclic cyclic and carbocyclic-aliphatic radicals, and each of phosphonium ylids wherein each of R, R and Rs of R, R and R is selected from the group consisting of Formula I is a saturated carbocyclic group, e.g., substituted and unsubstituted, saturated and unsatu cyclohexyl or an unsaturated carbocyclic group, e.g., rated, aliphatic and carbocyclic radicals and lower al monoaryl such as phenyl, tolyl, anisyl, chlorophenyl, koxy radicals, about two molar equivalents of saidylid 65 and the like. It is also preferable to avoid isolating the being present for each mole of said 2-oxo-l-cyclopen phosphonium ylid; the ylid can be prepared in situ in tylpropioific acid ester, anhydride or acyl halide. the reaction medium subsequently used for reacting the 3,682,970 3 4. ylid with the keto carboxylic acid esters, anhydrides or acyl halides. / While the methylene phosphonium ylids which can Rs Rs be used in the process of this invention are too nu merous to list here, they can be exemplified by the fol- 5 lowing: CH2OH -) CEX RO &H RO &H methylenetrimethylphosphorane, cí, k, Yo?1, (V) (VI) methylenetricyclohexylphosphorane, 10 methylenetriphenylphosphorane, / methylenetri-N-piperidylphosphorane, Rs R f4-R. methylenetri-N-morpholinophosphorane, 15 p?, Y, X-> methylenetri-(p-tolyl)phosphorane, R4O CH methylenetri-(p-anisyl)phosphorane, Ye?, (VII) methylenetri-(n-butyl)phosphorane, 20 Rs Ri methylenedimethylphenylphosphorane, CH-P%r, methylenedimethyl-p-methoxyphenylphosphorane, R40 N &H Yr, methylenediphenyltolylphosphorane, 25 cí?k, - . (II) methylmethylenetriphenylphosphorane, " -- . ------(ethylidenetriphenylphosphorane), The (III) is reacted with methyl ox bromoacetate or methyl a-bromopropionate in an inert 3-cycloethylenedioxybutylmethylenetriph 30 anhydrous solvent such as in the presence of enylphosphorane, zinc dust and then refluxed in the presence of p-toluene to yield the ester (IV). The ester is then 3,3-dimethoxypropylmethylenetriphenylphosphorane, hydrogenated, for example using a five percent palladi ethylmethylenetriphenylphosphorane, 35 um-on-carbon catalyst in ethanol to yield the cor responding saturated ester. Reduction of the saturated n-propylmethylenetriphenylphosphorane, and the like. ester, for example with lithium aluminum hydride in tetrahydrofuran, yields the corresponding (V). Preferred phosphonium ylids for use in the process of Reaction of the alcohol (V) with phosphorus this invention are substituted 1-propanyl-3- trichloride or tribromide in an inert solvent such as ylidenetriphenylphosphoranes which can be 40 benzene yields the corresponding halide (VI) which, represented by Formula II: upon reaction with a phosphine Rs R (H=P(R. 45 RO N un R3 C2 R. R1, R2 and Rs being as defined above, e.g., triphen ylphosphine, yields the corresponding phosphonium ------slat (VII). Treatment of the salt with a base capable of O 50 removing hydrogen halide such as sodium methylsul wherein R is lower alkyl or other similar alkaline sta finylmethide, phenyl lithium or butyl lithium yields the ble, acid labile protecting group, Rs is hydrogen or corresponding phosphonium ylid (II), for example, 1 lower alkoxy, R is hydrogen or methyl and R1,R2 and methoxy-3-phenylpropylidenetriphenylphosphorane, Rs are as defined above. 1,5-dimethoxy-3-phenylpropylidenetriphen These preferred phosphoniumylids and a method for 55 ylphosphorane, 1-methoxy-3-phenyl-(2-methylpropy their preparation have been described in U.S. Pat, ap lidene)triphenylphosphorane, 1,5-dimethoxy-3-phen plication Ser. No. 747,466 filed July 25, 1968 now yl-(2-methylpropylidene)triphenylphosphorane, and abandoned. The method can be generally illustrated by the like. the following representative procedure wherein X is Other phosphoniumylids useful in the process of this bromo or chloro and R, R2, Ra, R, Rs and Rs are as 60 invention can be represented as follows: defined above. O R Rs Rs HO botch-oh-rée, R3 O 65 (VIII)

&-och, R Yo O N CH c^ / H Y. CH3 on Sc/CHCH-OH-KR, (III) (IV) 3,682,970 6 In the above formulas R, R and X are as defined R hereinabove. / CH CHCHCH-P-R The 8-keto carboxylic acid esters, anhydrides and O N CH3 R3 5 acyl halides useful in the process of this invention in (X) clude 2-oxo-1-cyclopentylpropionic acid esters, an hydrides and acyl halides represented by Formula XIV Cl 6 ) R. R. R.

CH-C-OHCHCHSo?oH,CECH-KR,R - - - - - (XI) 10

Q 9 Q R. (XIV) - CH-C-CH2CH2CH-C-CH2CHCH-P-R 15 wherein R is a suitably protected oxo group (pro R3 tected with an alkaline-stable, acid-labile protect (XII) ing group) such as lower alkylenedioxy, e.g., ethylenedioxy or ? 2O Q 9 Ri R. CH-C-CitiCHCH-C-CICHCH-PR, wherein -ORs is an ether group such as lower alkoxy, R3 e.g., methoxy, ethoxy, t-butoxy, or tetrahydropyran-2- yloxy, tetrahydrofuran-2-yloxy, or 4-methox (XIII) . . . . ------25 ytetrahydropyran-4-yloxy and the like; in the above formulas R, R and Rs are as defined. R is lower alkyl; and above. These phosphonium ylids can be prepared by Rio is lower alkoxy, aryloxy (including phenylal reaction of the following respective phosphonium ha kyleneoxy and alkylphenyleneoxy) having up to 10 lides with a strong base as described hereinabove. carbons, lower alkylthio, lower alkanoyloxy, - 30 bromo or chloro, e.g., methoxy, ethoxy, butoxy, O R1 hexoxy, phenoxy, benzyloxy, tolyloxy, phen ylethylene-oxy, methylthio, ethylthio, butylthio, Y, acetyloxy, propionyloxy, valleryloxy, and the like. y annoukk In general, the process of this invention can be (VIII) 35 represented by the following schematic diagram: wherein R, R, R2, R, R, R and Rio are as defined above. R R R. R. R. R. CHCH, Sc4CHCHCHF4R, X- 40 N CH2 R2-P=cCEIR -- ? 's Ye, / CH. ' (IX) R3 mran R Out O 10 NY R 45 R C3 CHCH-CHF4R, X (I) (XIV) (XV) Oc CH Y, In the process of the present invention, the reaction (X) is carried out with from 1.2 to 2.5 and preferably about 50 2.1 moles of the phosphoniumylid per mole of the keto carboxylic acid compound of Formula XIV. More than 2.5 equivalents of the phosphonium ylid can be used Q 9 but it is generally disadvantageous to do so because in CH-C=CHCHCH-C-CHCHCH.P.R. X some cases the excess reagent may react further with R3 55 the of the desired carbocyclic ketone. (XI) Any organic solvent can be used for the reaction medi um so long as it is inert to the reaction and reagents. Suitable organic solvents are set forth in the references Q 9 9 -R 60 listed hereinabove and include hydrocarbons such as CH-C-CHCHCH-C-CHCHCH.P.R. X benzene, toluene, and the like; such as R3 tetrahydrofuran, dioxane, monoglyme, diglyme, and the like; dialkylsulfoxides such as dimethylsulfoxide, ---. (XII)' ...... -- - -- ww and the like; and mixtures thereof. When the 65 phosphonium ylid is prepared in situ, the keto carbox ylic acid compound can be introduced as a solution M l R. using the same solvent as that used for the preparation on céchschich e4.ch.ch.chi(r, X of the ylid. The reaction generally goes to completion (XIII) R 3 in from about 0.5 hours to about 48 hours depending 3,682,970 7 upon such factors as temperature and the relative reac preferred reaction solvent is diglyme in that the process tivity of the ylid and keto carboxylic acid compound. is very efficient in terms of time and yield. In the The reaction temperature can vary from about -40°C foregoing methods, when it is not desired to isolate the to the reflux temperature of the reaction mixture de ylid, the efficiency of the reaction is generally in pending upon such factors as the stability of the ylid, creased by increasing the reaction temperature to the relative reactivity of the ylid and keto carboxylic above room temperature, such as reflux temperature. acid compound being reacted, and the time in which it For optimum results, it is important that the reaction is desired to complete the reaction. In the case of the be conducted under as near anhydrous conditions as more stable ylids derived from, for example, tri possible and preferably under an inert oxygen-free at arylphosphonium halides such as methylenetriphen 10 mosphere such as nitrogen, argon, and the like. While ylphosphorane, it is best to employ reaction tempera the concentration of the keto carboxylic acid com tures of about room temperature to elevated tempera pound and ylid does not appear to be critical, it is tures such as the reflux temperature of the reaction preferred to operate at low concentrations of about two mixture, in order to complete the reaction within a 15 to about twenty-five percent by weight of the reaction shorter period of time. medium. The aforegoing reaction conditions are large There is formed an intermediate ylid which in some ly dependent upon the particular phosphoniumylid and cases can be isolated, if desired, or the reaction con keto carboxylic acid compound employed and are tinued without interruption to form the or,3-unsatu present as a guide. Provided with the foregoing and the rated carbocyclic ketone. Whether an intermediate ylid 20 examples hereinafter, the most advantageous or op is formed that can be isolated is dependent upon the timum conditions and proportions of the keto carboxyl reactivity of the particular phosphonium ylid and keto ic acid compound and phosphonium ylid for a particu carboxylic acid compound being reacted, the solvent lara,3-unsaturated carbocyclic ketone are easily deter medium and the reaction temperature. If it is desired to minable by one of ordinary skill in the art using routine isolate the intermediate phosphonium ylid, the keto 25 experimentation. carboxylic acid compound and phosphonium ylid are The term "lower alkyl' and derivations thereof such preferably mixed together at room temperature or as "lower alkoxy," "lower alkylthio,' 'lower al below, preferably about 0°C to 15° C. If it is desired kanoyloxy' and the like, as used herein, refer to satu not to isolate the intermediate ylid, the reaction can be rated aliphatic hydrocarbon groups (or derivations continued without interruption or it can be continued 30 thereof), branched or straight chain, containing one to more efficiently by the addition of a lower monohydric six carbon atoms. The term "aryl" refers to phenyl and aliphatic alcohol, such as methanol, ethanol, substituted phenyl, such as tolyl, chlorophenyl, isopropanol, t-butanol, and the like, with or without the methoxyphenyl, benzyl and the like. addition of a base such as an alkali metal alkoxide, such Use of the process of this invention in the synthesis of as sodium methoxide, sodium ethoxide, potassium 35 estradiol and related estrogenic compounds is illus methoxide, sodium t-butoxide, and the like. The lower trated by the following procedures wherein R,R,R, alcohol or an alcohol containing a base should be R. Rs, Re, R, Re and Rio are as defined above, R's is added after the initial reaction of the keto carboxylic hydrogen or hydroxy, and R', is keto or 17,3-hydroxy. acid compound and phosphonium ylid is substantially complete, that is, after substantial disappearance of the 40 Rs R initial phosphonium ylid from the reaction mixture. HC-P1, cg: Conventional analytical techniques such as thin layer yer Y, -- 2 chromatography can be used to determine when these -CH2 R8 o conditions have been obtained. A part or all of the Rio original solvent can first be removed, if desired, and the 45 (II) alcohol, with or without base, added thereafter. The amount of lower alcohol added should generally be / R such as to provide at least about 10 percent by volume R of the total amount of solvent in the reaction mixture, 50 preferably from about 25 to 80 percent. The amount of Rs base included in the alcohol should be sufficient to pro | O vide at least about 0.1 molar equivalents of base per HC mole of intermediate ylid after reacting with any base -3 labile groups which might be present, e.g., ester groups. 55 RO -off, Y. RO The amount of base is otherwise not critical. The most advantageous amount of base is easily determinable by (XVI) routine experimentation giving consideration to the particular keto carboxylic acid compound, phosphoni umylid and solvent being employed. In the case of sol 60 vents such as diglyme, monoglyme, dialkylsulfoxide, and the like, if it is not desired to isolate the ylid inter mediate, it has been found to be advantageous to in clude or add after mixing the keto carboxylic acid com pound and ylid, from about 10 to 75 percent, 65 preferably 25 to 50 percent by volume of the total sol RO -CH2: R8 vent of a dipolar aprotic solvent, such as hex amethylphosphoramide, dimethylformamide, (XVII) dimethylacetamide, and the like. A particularly 3,682,970 9 10 R’ yethylmalonic acid diethyl ester. A mixture of 5 g. of / R9 this ester in 100 ml. of ethanol containing 5 g. of sodi R5 um hydroxide is heated under reflux until evolution of carbon dioxide ceases. The reaction mixture is then 5 saturated with carbon dioxide and evaporated to dry -9 ness under vacuum. The residue is suspended in 50 ml. HO- aR6 of dry dimethylformamide to which is added a large ex cess of methyl iodide. The reaction mixture is stirred at (XVIII) (XX) room temperature for about 24 hours and then poured In the procedures shown by the above schematic dia 10 into water. The resulting mixture is extracted with gram, the phosphonium ylid of Formula II is reacted ether and the ether extracts combined, washed with with the keto carboxylic acid compound of Formula water and evaporated to give y-dimethoxybutyric acid XIV as described above. For example, the ylid can be methyl ester which is purified by distillation. A mixture prepared in a mixture of monoglyme and hexane to 15 of 4 g. of this methyl ester, 50 ml. of dry tetrahydrofu which the keto carboxylic acid compound is added in ran and 1.1 equivalents of lithium aluminum hydride is cold monoglyme. After the initial reaction is substan refluxed overnight. The reaction mixture is allowed to tially complete, that is, the reaction of the ylid is sub cool and then diluted with water. This mixture is ex stantially complete, a quantity of hex tracted with ether and the ether extracts are combined, amethylphosphoramide can be added, and the mixture 20 washed, dried and evaporated to dryness to afford 4,4- can be refluxed for several hours to yield the 4-phen dimethoxybutanol (CHO)2-CH-CH-CH2-CH2 ylethylene-5,6,7,7a-tetrahydroindan-5-ones (9,10 OH). secoestra-1,3,5(10),8(14)-tetraen-9-ones) of Formula A solution of 0.1 moles of 4,4-dimethoxybutanol in XVI. Hydrogenation of this a 6-unsaturated ketone us 50 ml. of dimethylformamide containing 0.1 moles of ing, for example, a five percent palladium-on-carbon 25 triphenylphosphine is allowed to react for 18 hours catalyst in an inert organic solvent such as benzene with 0.1 moles of carbon tetrabromide. The mixture is yields the corresponding 4-phenylethyleneperhydro diluted with water and extracted with ether. The ether indan-5-ones (9,10-secoestra-1,3,5(10)-trien-9-ones) extracts are combined, washed with water, dried and of Formula XVII. The latter compounds can be evaporated to a crude product which is purified by cyclodehydrated at the reflux temperature of a solvent 30 distillation to yield 4,4-dimethoxybutylbromide. This such as benzene in the presence of a dehydrating acid bromide on treatment with triphenylphosphine in such as p-toluenesulfonic acid according to conven toluene furnishes 4,4-dimethoxybutyltriphen tional procedures to yield the estra-1,3,5(10),9( 11)- ylphosphoniumbromide. tetraenes of Formula XVIII. Reduction of the latter compounds, for example, using five percent palladium 35 A mixture of 1 g of 4,4-dimethoxybutylbromide, 25 on-carbon catalyst in benzene yields the estra ml. of dioxane and 1 ml. of five percent aqueous HCl is 1,3,5 (10)-trienes of Formula XX. Alternatively, the heated at reflux for 15 minutes. The mixture is allowed a,6-unsaturated ketones of Formula XVI can first be to cool and then is poured into water and separated. cyclodehydrated using p-toluenesulfonic acid in The organic phase is evaporated to dryness to furnish benzene as described above or preferably with 40 the corresponding 3-formylpropylbromide. To a stirred polyphosphoric acid at 80°C to yield the estra solution of 1 g of the aldehyde in 10 ml. of acetone, 1,3,5(10),br8, 14-pentaenes of Formula XIX. The latter cooled to 0°C is added under nitrogen a solution of 8 N compounds when hydrogenated in the presence of a chromic acid (prepared by mixing 26 g. of chromium metal catalyst such as a 10 percent palladium-on-car trioxide with 23 ml. of concentrated sulfuric acid and bon catalyst in benzene yields the estra-1,3,5(10)- 45 diluting with water) until the color of the reagent per triene of Formula XX. Removal of the protecting group sists in the mixture. The mixture is then stirred for five at the 17-position (R) by conventional acid hydrolysis minutes at 0°-5° C and diluted with water. The solid yields the corresponding 3p3-hydroxyestra-1,3,5(10)- which forms is collected by filtration, washed with triene-17-ones or the estra-1,3,5(10)-triene-3,6,166, 50 water and dried under vacuum to yield 3-carboxypro 17gdepending upon what protected group was present pylbromide. This bromide on treatment with triphen at the 17-position. The compounds of Formula XX are ylphosphine in toluene yields 3-carboxypropyltriphen known in the art and are useful for their estrogenic ac ylphosphonium bromide. tivity. By repeating this procedure using carbon Phosphonium halides useful in the process of this in 55 tetrachloride in place of carbon tetrabromide, there is vention can be prepared as follows: obtained 4,4-dimethoxybutyltriphenylphosphonium PREPARATION A chloride and 3-carboxypropyltriphenyl-phosphonium chloride. 4,4-dimethoxybutyltriphenylphosphonium bromide Also, by using other tri-substituted phosphines in and 3-carboxy-propyltriphenylphosphonium bromide 60 place of triphenylphosphine in the above procedure, To 0.5 moles of diethylmalonate in 0.5 liters of dry e.g. tri(p-tolyl)phosphine, trichlorophenylphosphine, benzene is added 0.5 moles of sodium hydride cau diphenyltolylphosphine, the corresponding tri-sub tiously and the mixture stirred until hydrogen evolution stituted phosphonium bromide and chloride are ob ceases. Then 0.5 moles of bromoacetal tained. dehydedimethylacetal (CHO)2-CH-CH2-Br) in 65 100 ml. of benzene is added and the mixture stirred PREPARATION B overnight followed by refluxing for two hours. The 4,4-ethylenedioxyhexyltriphenylphosphonium bromide reaction mixture is cooled, washed with water and pu A solution of 20.9 g of the ketal of ethyl 3 rified by vacuum distillation to give B,6-di-methox bromopropyl ketone (obtained by treating the ketone 3,682,970 12 with ethylene glycol in benzene in the presence of p containing 0.5 g. of mercuric chloride. The mixture is toluenesulfonic acid) in 100 ml. of benzene is refluxed allowed to stand overnight and then heated to 60° for with 20 g. of triphenylphosphine for two hours. The five hours. After cooling, water is added and the tosy mixture is cooled, filtered and the solid material thus late of the ketal 8-(t-butoxy)-4,4-ethylenediox collected washed and dried to yield 4,4-ethylenediox ynonanol, yhexyltriphenylphosphonium bromide, CH3 C CH-CH2-CH-C-(CH2)-CH-OH OC(CH3)3 Y) L -- License. X 10 isolated by extraction with ether. This is cyclized by treatment in methanol containing hydrogen chloride at wherein R is phenyl and X is bromo. This is converted 25 for about 12 hours to give the tosylate of 3-(2- to the respective ylid by treatment with butyl lithium, methoxy-6-methyl-tetrahydropyran-2-yl)propanol, for example, as described above. The 1-halo-4-alkanone compounds can be prepared, 15 CH-OH for example, by procedures described in German Pat. / CH CH-CH No. 801,276 (Dec. 1950) or Jager et al., Arch. Pharm. o/ 2 - 12 293,896 (1960). OCH PREPARATION C 20 This is converted into the corresponding bromide by 3-(2-methoxy-6-methyltetrahydropyran-2-yl)-propyl treatment with lithium bromide in isopropanol as described above. The bromide is treated with triphen triphenyl-phosphonium bromide ylphosphine in benzene to afford the phosphonium bro A suspension of 0.5 g. of 1-chloropentan-4-ol in 40 mide 3-(2-methoxy-6-methyltetrahydropyran-2-yl)pro ml. of methylene chloride is cooled to -70 and then 40 pyltriphenylphosphonium bromide ml. of isobutylene and 0.6 ml. of 93 percent sulfuric 25 acid are added. The mixture is shaken for 17 hours in a pressure vessel. The vessel is then recooled to -70, opened and the solution poured into aqueous sodium R. P. CH-CH-CH, CH3 bicarbonate with stirring. Isolation with methylene O chloride yields the t-butyl ether of 1-chloropentan-4-ol. CH3 A mixture of 0.5 moles of 1,3-dithiane and 300 ml. of wherein R is phenyl and X is bromo. tetrahydrofuran cooled to -30° is treated with 0.5 Treatment with butyl lithium or phenyl lithium thus molar equivalents of 1.5 molar n-butyl lithium in hex gives the corresponding ylid. The other phosphonium ane under nitrogen and stirred for 15 hours at -20. halides of this can be prepared similarly by using lithi Then 0.5 moles of the tetrahydropyranyl ether of 3 35 um chloride, lithium iodide or sodium iodide in place of bromopropanol in 200 ml. of tetrahydrofuran is added lithium bromide and using other tri-substituted phos slowly with stirring at -5° and then left for 14 hours at phines in place of triphenylphosphine. O under nitrogen. The resulting mixture is cooled to -30° and treated with an additional 0.5 molar PREPARATION D equivalents of 1.5 molar n-butyl lithium in hexane. 40 8-chloro-4,4-ethylenedioxy-7-nonenyltriphen After 1.5 hours, 0.5 moles of the t-butyl ether of 1 ylphosphonium bromide chloropentan-4-one in 200 ml. of tetrahydrofuran is A mixture of 0.5 moles of 1,3-dithiane and 300 ml. of added. The reaction mixture is left standing for 18 tetrahydrofuran cooled to -30° is treated with 0.5 hours at 0° and then allowed to warm to room tempera molar equivalents of 1.5 molar n-butyl lithium in hex ture for four hours. Water is added and the resulting 45 ane under nitrogen and stirred for 15 hours at -20. mixture extracted with ether. The ether extracts are Then 0.5 moles of the tetrahydropyranyl ether of 3 combined, washed with water, dried and concentrated. bromopropanol in 200 ml. of tetrahydrofuran is added The resulting dialkylated thiane 2-8-(t-butoxy)-4,4- slowly with stirring at -5° and then left for 14 hours at trimethylenedithiononyloxyl-tetrahydropyran, 0 under nitrogen. The resulting mixture is cooled to -30 and treated with an additional 0.5 molar CH-C-CH-CH2-CH-C-(CH2)2-C-O-/ N C. ) equivalents of 1.5 molar n-butyl lithium in hexane. OC(CH3)3 S S mem After 1.5 hours, 0.5 moles of 4-chloro-1-bromopent-3- ene in 200 ml. of tetrahydrofuran is added. The reac N/ 55 tion mixture is left standing for 18 hours at 0' and then is dissolved in methanol and stirred for 0.5 hour with 20 allowed to warm to room temperature for four hours. ml. of one percent oxalic acid solution. The reaction Water is added and the resulting mixture extracted with mixture is poured into water containing an excess of ether. The ether extracts are combined, washed with sodium carbonate solution and then extracted with water, dried and concentrated. The resulting dialky ether to afford the corresponding free hydroxy con 60 lated thiane 2-(8-chloro-4,4-trimethylenedithio-7- pound. A mixture of 2 g of the free hydroxy compound nonenyloxy)-tetrahydropyran and 30 ml. of methylene chloride: (2:1) is cooled to -70 and then treated with one equivalent of tosyl chloride in methylene chloride. The mixture is left standing at 0° for 18 hours and then allowed to warm to 65 CH-C=CH-CHS c/CH)-o-( X room temperature. The mixture is then diluted with O water and the resulting tosylate isolated by extraction is dissolved in methanol and stirred for two hours with with methylene chloride and purified by chromatog 20 ml. of one percent oxalic acid solution. The reaction raphy. The tosylate is dissolved in dry ethylene glycol mixture is poured into water containing an excess of 3,682,970 13 14 sodium carbonate solution and then extracted with wherein R is phenyl and X is bromo. This 1-bromo ether to afford the corresponding free hydroxy com compound is dissolved in dry ethylene glycol contain pound. A mixture of 2 g of the free hydroxy compound ing 0.5 g. of mercuric chloride. The mixture is allowed and 30 ml. of methylene chloride:pyridine (2:1) is to stand overnight and then heated to 60° for five cooled to -70 and then treated with one equivalent of 5 hours. After cooling, water is added and the cor tosyl chloride in methylene chloride. The mixture is left responding diketal 4,4;8,8-di(ethylenedioxy)-nonyl standing at 0 for 18 hours and then allowed to warm to bromide room temperature. The mixture is then diluted with water and the resulting tosylate isolated by extraction 6 O () with methylene chloride and purified by chromatog O X-CH2-(CH2) No4(CH), Scécil, raphy. The thus-obtained tosylate is dissolved in dry wherein R is phenyl and X is bromo is isolated by ex ethylene glycol containing 0.5 g. of mercuric chloride. traction with ether. The diketal is treated with triphen This reaction mixture is allowed to stand overnight and ylphosphine in benzene to afford 4,4:8,8- then heated to 60° for five hours. After cooling, water is di(ethylenedioxy)-nonyltriphenyl-phosphonium bro added and the corresponding ketal isolated by extrac 5 mide tion with ether. The ketal (0.5 g.) in 25 ml. of dry isopropanol and 0.5g of lithium bromide is refluxed 6 for 12 hours. After cooling, the reaction mixture is diluted with water and extracted with ether. The result ing 8-chloro-4,4-ethylenedioxy-7-nonenyl bromide 20 wherein R is phenyl and X is bromo. On treatment with - butyl or phenyl lithium this gives the corresponding Cl O O ylid. CH-C=CH-CHNc/ch)-Br The trimethylenedithio compound can be similarly is treated with triphenylphosphine in benzene to yield treated with triphenylphosphine to yield 4,4- 8-chloro-4,4-ethylenedioxy-7-nonenyl-triphen 25 ethylenedioxy-8,8-trimethylenedithiononyltriphen ylphosphonium bromide ylphosphonium bromide

, , Cl ^ - O 30 -- N / Ra P-CH2-(CH2)4-C-(CH2)4-C-CH3 ------wherein R is phenyl and X is bromo. On treatment with wherein R is phenyl and X is bromo. This can be con butyl lithium this gives the correspondingylid. verted into the corresponding ylid as described above. By using lithium chloride or lithium iodide in the Similarly, other tri-substituted phosphines can be above process, the respective phosphonium chloride or 35 used in place of triphenylphosphine to prepare other phosphonium iodide are obtained. By using other tri compounds of formulas. substituted phosphines, e.g. tricyclohexyl, tribenzyl, This invention is further illustrated by the following tritolyl, trimethyl, tributyl, and the like in place of specific but non-limiting examples. triphenylphosphine, the corresponding tri-substituted phosphonium compounds are obtained. 40 EXAMPLE 1. PREPARATIONE 1-(lower)alkyl-5-oxo-cyclopent-1-ylpropionates A mixture of 0.3 g of 2-methylcyclopentane-1,3- 8,8-ethylenedioxy-4,4-trimethylenedithiononyltriphen dione, 0.33 ml. of methyl acrylate and a catalytic ylphosphonium bromide and 4,4;8,8-di(ethylenediox amount of sodium methoxide in 10 ml. of dimethylfor y)nonyltriphenylphosphonium bromide 45 mamide is refluxed for two hours. The reaction mixture A mixture of 0.5 moles of 1,3-dithiane and 300 ml. of is evaporated to a small volume, diluted with aqueous tetrahydrofuran cooled to -30° is treated with 0.5 sodium hydroxide, nd extracted with ether. The extract molar equivalents of 1.5 molar n-butyl lithium in hex is washed until neutral with water, dried and ane under nitrogen and stirred for 15 hours at -20. evaporated to yield methyl 1-methyl-2,5-dioxo Then 0.5 moles of the ethylene ketal of methyl-3- SO cyclopent-1-ylpropionate which is purified by distilla bromopropyl ketone in 200 ml. of tetrahydrofuran is tion. A mixture of 1 g of the latter compound, 25 ml. of added slowly with stirring at -5° and then left for 14 dry benzene, 1 molar equivalent of ethylene glycol and hours at 0° under nitrogen. The resulting mixture is 50 mg. of p-toluenesulfonic acid monohydrate is cooled to -30° and treated with an additional 0.5 molar 55 refluxed for 16 hours using a water separater. The reac equivalents of 1.5 molar n-butyl lithium in hexane. tion mixture is then washed with water, dried and After 15 hours, 0.5 moles of 1-bromo-3-iodopropane in evaporated to dryness to yield methyl 2,2- 200 ml. of tetrahydrofuran is added. The resulting mix ethylenedioxy-1-methyl-5-oxo-cyclopent-1-yl ture is left standing for 18 hours at 0°C and then al propionate which is purified by chromatography on sil lowed to warm to room temperature and stand for four 60 ica gel, eluting with benzene-ether. hours. Water is added and the resulting mixture ex Repeating the above procedure with ethyl acrylate, tracted with ether. The ether extracts are combined, propyl acrylate, n-butyl acrylate, n-pentyl acrylate, n washed with water, dried and evaporated to yield 4,4- hexyl acrylate, benzyl acrylate, phenyl acrylate, tolyl ethylenedioxy-8,8-trimethylene dried and evaporated acrylate, p-propylphenyl acrylate yields the cor to yield 44-ethylenedioxy-8,8-trimethylenedithiononyl 65 responding, respective ethyl, propyl, n-butyl, n-pentyl, bromide n-hexyl, benzyl, phenyl, tolyl and p-propyl-phenyl 2,2- ethylenedioxy-1-methyl-5-oxocyclopent-1-yl ^ - propionates. S S () () Repeating the above procedures with methyl acry late and the other enumerated acrylates but replacing

213 0.048 o200 3,682,970 15 16 2-methylcyclopentan-1,3-dione with 2-ethylcyclopen 2,2-ethylenedioxy-5-oxo-1-(n-pentyl)cyclopent-1-yl tan-1,3-dione, 2-propylcyclopentan-1,3-dione, 2-(n- propionyl chloride, and butyl)cyclopentan-1,3-dione, 2-(n-pentyl)cyclopen 2,2-ethylenedioxy-1-(n-hexyl)-5-oxocyclopent-1-yl tan-1,3-dione, and 2-(n-hexyl)cyclopentan-1,3-dione propionyl chloride, respectively. yields the corresponding methyl, ethyl, propyl, n-butyl, n-penty, n-hexyl, benzyl, phenyl, tolyl and p EXAMPLE 4 propylphenyl esters of 2,2-ethylenedioxy-1-(lower)alkyl-5-oxocyclopent-1-yl 2,2-ethylenedioxy-1-ethyl-5-oxocyclopent-1-yl propionic acid, propionyl bromide O Repeating the procedure of Example 3 but replacing 2,2-ethylenedioxy-5-oxo-1-propylcyclopent-1-yl carbon tetrachloride with a solution of 10 g. of carbon propionic acid, tetrabromide in 50 ml. of hexane yields the correspond 1-(n-butyl)-2,2-ethylenedioxy-5-oxocyclopent-1-yl 1ng propionic acid, 2,2-ethylenedioxy-1-ethyl-5-oxocyclopent-1-yl 2,2-ethylenedioxy-5-oxo-1-(n-pentyl)cyclopent-1-yl 15 propionyl bromide, propionic acid, and 2,2-ethylenedioxy-5-oxo-1-propylcyclopent-1-yl 2,2-ethylenedioxy-1-(n-hexyl)-5-oxocyclopent-1-yl propionyl bromide, propionic acid, respectively. 1-(n-butyl)-2,2-ethylenedioxy-5-oxocyclopent-1-yl The 1-alkyl-5-oxocyclopent-1-ylpropionates can also propionyl bromide, be prepared according to the procedure described in 20 2,2-ethylenedioxy-5-oxo-1-(n-pentyl)cyclopent-1-yl French Pat. No. 1496,817. propionyl bromide, and EXAMPLE 2 2,2-ethylenedioxy-1-(n-hexyl)-5-oxocyclopent-1-yl 2,2-ethylenedioxy-1-(lower)alkyl-5-oxocyclopent-1-yl propionyl bromide, respectively. propionic acid 25 EXAMPLE 5 One gram of methyl 2,2-ethylenedioxy-1-methyl-5- oxocyclopent-1-ylpropionate is hydrolyzed in a 2,2-ethylenedioxy-1-(lower)alkyl-5-oxocyclopent-1-yl methanolic KOH solution at room temperature for 24 propionic acid anhydrides of lower aliphatic carboxylic hours, and the reaction mixture is then carefully acids neutralized with 0.1 N hydrochloric acid to a pH of 30 A methanol solution of 1 g. mole of 2,2- 2-3. The solvent is then evaporated, the residue ex ethylenedioxy-1-methyl-5-oxocyclopent-1-ylpropionic tracted with ether, and the ether solution washed with acid is titrated to neutrality with methanolic potassium aqueous sodium bicarbonate, aqueous sodium chloride hydroxide and evaporated to yield the corresponding solution, and then dried to yield 2,2-ethylenedioxy-1- potassium salt. To a suspension of this salt in benzene is methyl-5-oxocyclopent-1-ylpropionic acid. 35 added 1 g. mole of acetic anhydride, and the mixture is Repeating the above procedure with the other esters maintained at room temperature for one hour. The sol produced in Example 1 yields the corresponding vent is then filtered and evaporated to yield 2,2- 2,2-ethylenedioxy-1-ethyl-5-oxocyclopent-1-yl ethylenedioxy-1-methyl-5-oxocyclopent-1-ylpropionic propionic acid, acid acetic acid anhydride. This is immediately 2,2-ethylenedioxy-5-oxo-1-propylcyclopent-1-yl 40 dispersed in tetrahydrofuran and used since it is rela propionic acid, tively unstable. 1-(n-butyl)-2,2-ethylenedioxy-5-oxocyclopent-1-yl Repeating the above procedure with the other acids propionic acid, produced in Example 2 yields the corresponding 2,2-ethylenedioxy-5-oxo-1-(n-pentyl)cyclopent-1-yl 2,2-ethylenedioxy-1-ethyl-5-oxocyclopent-1-yl propionic acid, and 45 propionic acid acetic acid anhydride, 2,2-ethylenedioxy-1-(n-hexyl)-5-oxocyclopent-1-yl 2,2-ethylenedioxy-5-oxo-1-propylcyclopent-1-yl propionic acid, respectively. propionic acid acetic acid anhydride, 1-(n-butyl)-2,2-ethylenedioxy-5-oxocyclopent-1-yl EXAMPLE 3 50 propionic acid acetic acid anhydride, 2,2-ethylenedioxy-1-(lower)alkyl-5-oxocyclopent-1-yl 2,2-ethylenedioxy-5-oxo-1-(n-pentyl)cyclopent-1-yl propionyl chloride propionic acid acetic acid anhydride, and One molar equivalent of 2,2-ethylenedioxy-1- 2,2-ethylenedioxy-1-(n-hexyl)-5-oxocyclopent-1-yl methyl-5-oxocyclopent-1-ylpropionic acid is added to a propionic acid acetic acid anhydride, respectively. solution of one molar equivalent of triphenylphosphine 55 Repeating the above procedure with acyl chlorides and one molar equivalent of carbon tetrachloride, and of other lower aliphatic carboxylic acids such as the mixture is maintained at room temperature for one propionyl chloride, butyryl chloride, valleryl chloride hour. The reaction product is evaporated to dryness to and the like yields the corresponding 2,2-ethylenediox yield 2,2-ethylenedioxy-1-methyl-5-oxocyclopent-1-yl y-l-(lower)alkyl-5-oxocyclopent-1-ylpropionic acid propionyl chloride. This is immediately dissolved in. 60 anhydrides of the respective lower aliphatic carboxylic tetrahydrofuran and used since it is relatively unstable. acids. Repeating the above procedure with the products of Example 2 yields the corresponding EXAMPLE 6 2,2-ethylenedioxy-1-ethyl-5-oxocyclopent-1-yl S-(lower)alkyl 2,2-ethylenedioxy-1-(lower)alkyl-5-ox propionyl chloride, 65 ocyclopent-1-ylpropanethioates 2,2-ethylenedioxy-5-oxo-1-propylcyclopent-1-yl One gram mole of 2,2-ethylenedioxy-1-methyl-5-ox propionyl chloride, ocyclopent-1-ylpropionyl chloride in 25 ml. of a 1:1 pu 1-(n-butyl)-2,2-ethylenedioxy-5-oxocyclopent-1-yl ridine-benzene solution is mixed with 1 g. mole of propionyl chloride, methylmercaptan in 25 ml. of a 1:1 pyridine-benzene 3,682,970 17 18 solution, the reaction mixture is maintained at room water and evaporated to yield 1,1-ethylenedioxy-7a temperature for one hour. The solvent is evaporated, methyl-5,6,7,7a-tetrahydroindan-5-one which is pu and the residue is extracted with ether. The ether phase rified by chromatography on silica gel, eluting with is washed with aqueous sodium bicarbonate, then aque benzene-ether. ous sodium chloride, and then dried to yield S-methyl 5 2,2-ethylene dioxy-1-methyl-5-oxocyclopent-1-yl EXAMPLE 9 propanethioate. Repeating the procedure of Example 8 but replacing Repeating the above procedure with other lower methyl 2,2-ethylenedioxy-1-methyl-5-oxocyclopent-1- alkyl mercaptans such as ethyl mercaptan, propyl mer ylpropionate with captan, n-butyl mercaptan, n-pentyl mercaptan, and n 10 hexyl mercaptain yields the corresponding S-ethyl, S ethyl 2,2-ethylenedioxy-1-methyl-5-oxocyclopent-1- propyl, S-(n-butyl), S-(n-pentyl) and S-(n-hexyl) 2,2- ylpropionate, ethylenedioxy-1-methyl-5-oxocyclopent-1-yl phenyl 2,2-ethylenedioxy-1-methyl-5-oxocyclopent propanethioates. 1-ylpropionate, 15 tolyl 2,2-ethylenedioxy-1-methyl-5-oxocyclopent-l- Repeating the above procedures with the other ylpropionate, propionyl chlorides produced in Example 3 yields the benzyl 2,2-ethylenedioxy-1-methyl-5-oxocyclopent corresponding S-methyl, S-propyl, S-(n-butyl), S-ethyl, 1-ylpropionate, S-(n-pentyl) and S-(n-hexyl) thioates of the respective S-methyl 2,2-ethylenedioxy-1-methyl-5-oxo 2,2-ethylenedioxy-1-(lower)alkyl-5-oxocyclopent-1-yl 20 cyclopent-1-ylpropanethioate, propanes. S-propyl 2,2-ethylenedioxy-1-methyl-5-oxo EXAMPLE 7 cyclopent-1-ylpropanethioate, 2,2-ethylenedioxy-1-methyl-5-oxocyclopent-1-yl In a tetrahydrofuran solution (50 ml.) under a propionyl bromide, and nitrogen atmosphere, 7 g of methyltriphen 25 ylphosphonium bromide was suspended. To this 2,2-ethylenedioxy-1-methyl-5-oxocyclopent-1-yl suspension was added with stirring 1 1.4 ml. of a 1.6 M propionyl chloride, yields 1,1-ethylenedioxy-7a solution of butyl lithium in hexane. The mixture was methyl-5,6,7,7a-tetrahydroindan-5-one. stirred for 17 minutes at room temperature, and a solu Repeating this procedure with other propionates, tion of 2.1 g of methyl 2,2-ethylenedioxy-1-methyl-5- 30 propanethioates and propionyl halides, e.g., oxocyclopent-1-ylpropionate in 15 ml. of tetrahydrofu methyl 1-(n-butyl)-2,2-ethylenedioxy-5-oxo ran was added. The mixture was held at room tempera cyclopent-1-ylpropionate, ture for 24 hours, concentrated in vacuo, diluted with phenyl 2,2-ethylenedioxy-1-ethyl-5-oxocyclopent-1- water, and extracted with ether to isolate the inter ylpropionate, and mediate ylid. 1.6 Grams of the intermediate ylid was 35 S-propyl 2,2-ethylenedioxy-5-oxo-1-propyl dissolved in dry ethanol, and 1.0 g. of dry sodium cyclopent-1-ylpropanethioate yields the corresponding ethoxide was added thereto. The mixture was refluxed 5,6,7,7a-tetrahydroindan-g5-ones, that is, for seven hours under a nitrogen atmosphere, the sol 7a-(n-butyl)-1,1-ethylenedioxy-5,6,7,7a vent was removed in vacuo, and the product was ex tetrahydroindan-5-one, tracted with ether and purified by chromatography on 40 1,1-ethylenedioxy-7a-ethyl-5,6,7,7a-tetrahydroin silica gel, eluting with benzene-ether to yield 1,1- dan-5-one, and ethylene-dioxy-7a-methyl-5,6,7,7a-tetrahydroindan-5- 1,1-ethylenedioxy-7a-propyl-5,6,7,7a-tetrahydroin OC. dan-5-one. The above-prepared or,6-unsaturated bicarbocyclic ketone is a valuable intermediate for the synthesis of 45 EXAMPLE 10 steroids using the method of Whitehurst et al., U.S. Pat. Repeating the procedure of Example 8 but replacing No. 3,317,566, for example. methylenetriphenylphosphorane with substituted methylenetriphenylphosphoranes such as, for example, EXAMPLE 8 50 methylmethylenetriphenylphosphorane, 3 A solution of 1.6 ml. of methylenetriphen cycloethylenedioxybutylmethylenetriph ylphosphorane in 25 ml. of monoglyme (1,2-dimethox enylphosphorane, 3,3-dimethoxypropyl yethane) is prepared under nitrogen by adding 2.4 methylenetriphenylphosphorane, equivalents of phenyl lithium to a dry monoglyme ethylemthylenetriphenylphosphorane, n-propyl suspension of 1.2 equivalents of methyltriphen 55 methylenetriphenylphosphorane, and the like, the cor ylphosphonium bromide with stirring followed by stir responding 1,1-ethylenedioxy-7a-methyl-5,6,7,7a ring the mixture for 30 minutes. A solution of 7.2 ml. of tetrahydroindan-5-one is obtained having at the 4-posi a 1.6 M solution of butyl lithium in hexane is added, tion the respective methyl, 3-cycloethylenedioxy-butyl, and the solution is stirred for 17 minutes at room tem 3,3-dimethoxypropyl, ethyl and n-. perature. Then, 2.1 g of methyl 2,2-ethylenedioxy-1- 60 methyl-5-oxocyclopent-1-ylpropionate in 15 ml. of EXAMPLE 1 monoglyme is added, and the reaction mixture is left at To 3 g of 3-(3,5-dimethoxyphen-1-yl)prop-1- room temperature for 24 hours. Then 12 ml. of hex ylidenetriphenylphosphorane in 50 ml. of dry amethylphosphoramide is added to the reaction mix monoglyme under nitrogen, there is added two molar ture, and it is refluxed for six hours under nitrogen. The 65 equivalents of methyl 2,2-ethylenedioxy-l-methyl-5- reaction mixture is cooled, poured into an ether oxocyclopent-1-ylpropionate in 75 ml. of dry benzene solution, and the organic layer is washed with monoglyme. The reaction mixture is allowed to stand 3,682,970 19 20 for seven hours at room temperature, 150 ml. of 5,6,7,7a-tetrahydroindan-5-one. A mixture of 1 g. of diglyme and 50 ml. of hexamethylphosphoramide are the latter ketone, 25 ml. of methanol and 1 ml. of con added, and then the mixture is heated at reflux for 20 centrated HCl is boiled for 15 minutes. The reaction hours. After cooling, water is added, and the product mixture is allowed to cool, poured into water, and the isolated by extraction with chloroform and purified by 5 resulting mixture separated. The organic phase is chromatography on alumina to yield 1,1-ethylenediox evaporated to dryness to furnish 4-(2-formylethyl)-7a y-7a-methyl-4-(3,5-dimethoxy-1-phenylethylene)- methyl-5,6,7,7a-tetrahydroindan-1,5-dione which is 5,6,7,7a-tetrahydroindan-5-one. taken up in 20 ml. of acetone, cooled to 0 C, and a Repeating this procedure with other 3-(phen-1- slight molar excess of Jones reagent (prepared by mix yl)prop-1-ylidenetriphenylphosphoranes and cyclopen O ing 26 g. of chromium trioxide with 23 ml. of concen tylpyopionic acid compounds of Formulas II and XIV trated sulfuric acid and diluting with water to 100 ml.) above yields the corresponding compounds of Formula is added. Upon completion of the oxidation as followed XVI, e.g. by thin layer chromatography, the reaction mixture is 1,1-ethylenedioxy-7a-methyl-4-(3-methoxyphen-1- 15 diluted with water and then combined with ethyl ylethyl)-5,6,7,7a-tetrahydroindan-5-one, acetate. The ethyl acetate extracts are combined, 1,1-ethylenedioxy-7a-ethyl-4-(3,5-dimethoxyphen washed with water, dried and evaporated under 1-ylethyl)-5,6,7,7a-tetrahydroindan-5-one, reduced pressure to yield 4-(2-carboxyethyl)-7a 1,1-ethylenedioxy-7a-ethyl-4-(3-methoxyphen-1- methyl-5,6,7,7a-tetrahydroindan-1,5-dione. This ylethyl)-5,6,7,7a-tetrahydroindan-5-one, 2O product is a valuable intermediate for the synthesis of 1,1-ethylenedioxy-7a-propyl-4-(3,5-dimethoxyphen known 19 -nor-A and A steroids useful as 1-ylethyl)-5,6,7,7a-tetrahydroindan-5-one, therapeutic agents using the procedure of, for example, 1,1-ethylenedioxy-7a-propyl-4-(3-methoxyphen-1- Belgium Pat. No. 629,251 (1963); French Pat. No. ylethyl)-5,6,7,7a-tetrahydroindan-5-one, 1,465,400 (1965); Netherlands Pat. No. 6,414,702; or 1,1-ethylenedioxy-7a-ethyl-4-3-(3,5-dimethox- 25 Velluz et al., Tetrahedrin, Suppl. 8 Part II, pp. 495-505 yphen-1-yl)-propyl-5,6,7,7a-tetrahydroindan-5-one, (1966). 1,1-ethylenedioxy-7a-methyl-4-3-(3,5-dimethox Repeating the procedure with the other correspond yphen-1-yl)-propyl-5,6,7,7a-tetrahydroindan-5-one, ing 2,2-ethylenedioxy-1-(lower)alkyl-5-oxocyclopent and the like. 1-ylpropionates produced in Example 1 yields the cor 3O responding 7a-(lower)alkyl compounds. EXAMPLE 12 As an alternate procedure, sufficient phenyl lithium To a suspension of 7 g. of methyltriphenylphosphoni in hexane is added with stirring to a suspension of 4 g. um bromide in 50 ml. of tetrahydrofuran was added of 3-carboxypropyltriphenylphosphonium bromide in with stirring, 11.4 ml. of a 1.6M solution of butyl lithi 50 ml. of dry monoglyme under nitrogen to provide 2.4 um in hexane. The mixture was stirred for 17 minutes 35 molar equivalents of phenyl lithium after neutralization at room temperature, and a solution of 2.1 g of methyl of the acid. This mixture is stirred for 30 minutes, and 2,2-ethylenedioxy-1-methyl-5-oxo-cyclopent-1-yl then 1.1 molar equivalents of methyl 2,2-ethylenediox propionate in 15 ml. of tetrahydrofuran was added. The y-1-methyl-5-oxocyclopent-1-ylpropionate in 50 ml. of mixture was held at room temperature for 24 hours, 40 dry monoglyme is added. The reaction mixture is and a solution of 1 g. sodium methoxide in 50 ml. of dry heated at reflux for about three hours and is allowed to ethanol was added thereto. cool to room temperature. The reaction mixture is then The mixture was refluxed for seven hours under a diluted with water and acidified with hydrochloric acid, nitrogen atmosphere, the solvent was removed in and extracted with ethyl acetate. The ethyl acetate ex vacuo, and the product was extracted with ether and 45 tract is washed with water, dried and evaporated under purified by chromatography on silica gel to yield 1,1- reduced pressure. The residue is chromatographed on ethylenedioxy-7a-methyl-5,6,7,7a-tetrahydroindan-5- silica to yield 4-(2-carboxyethyl)-7a-methyl-5,6,7,7a Oe tetrahydroindan-1,5-dione. EXAMPLE 1.3 Repeating this alternate procedure with the other SO corresponding 2,2-ethylenedioxy-1-(lower)alkyl-5-ox 4-(2-carboxyethyl)-7a-methyl-5,6,7,7a-tetrahydroin ocyclopent-1-yl-propionates produced in Example 1 dan-1,5-dione yields the corresponding 7a-(lower)alkyl compounds. To a suspension of 4 g. of 4,4-dimethoxybutyl triphenylphosphonium bromide in 50 ml. of dry EXAMPLE 1.4 monoglyme under nitrogen, there is added 2.4 55 2,5-dimethyl-1,2-(3'-oxocyclopentano)- equivalents of phenyl lithium in hexane with stirring. 1,2,3,4,6,7,8,8a-octa-hydronaphthylene-6-one This mixture is stirred for about 30 minutes, and then Repeating the procedure of Example 8 but replacing 1.1 equivalents of methyl 2,2-ethylenedioxy-1-methyl methyltriphenylphosphonium bromide with 44 5-oxocyclopent-1-ylpropionate in 50 ml. of dry ethylenedioxyhexyltriphenylphosphonium bromide monoglyme is added. The reaction mixture is heated at 60 yields the corresponding 1,1-ethylenedioxy-4-(3,3- reflux for about three hours and then is allowed to cool ethylenedioxypentyl)-7a-methyl-5,6,7,7a-tetrahydroin to room temperature. The reaction mixture is then dan-5-one. One gram of this compound in 100 ml. of 80 diluted with water and extracted with ether. The ether percent acetic acid is refluxed under nitrogen for seven extracts are combined, washed, dried over magnesium 65 hours. The mixture is concentrated under vacuum and sulfate, and evaporated under reduced pressure. The poured into water. The solid formed is separated by fil residue is chromatographed on silica to provide 1,1- tration, washed with water and dried. Two grams of this ethylenedioxy-4-(3,3-dimethoxypropyl)-7a-methyl compound in 25 ml. of 0.2 percent triethylamine and 3,682,970 2. 22 100 ml. of 95 percent aqueous ethanol is hydrogenated This compound is a useful intermediate for the at room temperature and room pressure over five per preparation of steroids according to procedures cent palladium-on-charcoal until one equivalent of described in French Pat. No. 1,465,400 and U. S. Pat. hydrogen is absorbed. The mixture is filtered and the No. 3,413,314 (1968). filtrate evaporated to yield 2,5-dimethyl-1,2-(3'-oxo 5 Repeating this procedure with the other correspond cyclopentano)-1,2,3,4,6,7,8,8a-oc ing 2,2-ethylenedioxy-1-(lower)alkyl-5-oxocyclopent tahydronaphthylene-6-one which can be represented as 1-ylpropionate produced in Example 1 yields the cor follows: responding 7a-(lower)alkyl compounds. OII CH3 10 EXAMPLE 16 5-(3-chloro-2-buten-1-yl)-2-methyl-1,2-(3'-oxo CH3 cyclopentano)-1,2,3,4,6,7,8,8a-octahydronaphthylen 6-one 15 Repeating the procedure of Example 8 but replacing O methyltriphenylphosphonium bromide with 8-chloro 4,4-ethylenedioxy-7-nonen-1-yltriphenylphosphonium This compound is an intermediate for A-androstenes bromide yields the corresponding 4-(7-chloro-3,3- or retrosteroids using the procedure of, for example, ethylenedioxy-6-octen-1-yl)-1,1-ethylenedioxy-7a Netherlands Pat. No. 6,707,919 (1967). 20 methyl-5,6,7,7a-tetrahydroindan-5-one. This com Repeating the above procedure with the other 2,2- pound is then hydrolyzed, hydrogenated, and then cycl ethylenedioxy-1-(lower)alkyl-5-oxocyclopent-1-yl ized with aqueous hydrochloric acid by the procedure propionates produced in Example 1 yields the cor described in Example 15 to yield 5-(3-chloro-2-buten responding 7a-(lower)alkyl compounds. 1-yl)-2-methyl-1,2-(3'-oxocyclopentano)- 25 1,2,3,4,6,7,8,8a-octahydronaphthylen-6-one which can EXAMPLE 1.5 be represented as follows: 2-methyl-5-(3-oxobutyl)-1,2-(3'-oxocyclopen O tano)perhydronaphthylen-6-one Repeating the procedure of Example 8 but replacing methyltriphenylphosphonium bromide with 3-(2- 30 methoxy-6-methyltetrahydropyran-2-yl)propyltriphen ylphosphonium bromide yields the corresponding 1,1- ethylenedioxy-4-(2-methoxy-6-methyltetrahydro pyran-2-ylethyl)-7a-methyl-5,6,7,7a-tetrahydroindan 35 5-one. This compound is hydrolyzed with sulfuric acid The above tricarbocyclic ketone is a useful inter in aqueous dioxane. Two grams of the product in 25 ml. mediate for the synthesis of aromatic steroids using the of 0.2 percent triethylamine and 100 ml. of 95 percent procedure of U. S. Pat. Nos. 3,050,550 and 3,150,152. aqueous ethanol is hydrogenated at room temperature Repeating this procedure with the other correspond and room pressure over five percent palladium-on 40 ing 2,2-ethylenedioxy-1-(lower)alkyl-5-oxocyclopent charcoal until one equivalent of hydrogen is absorbed. 1-ylpropionates produced in Example 1 yields the cor The mixture is filtered, and the filtrate evaporated to responding 7a-(lower)alkyl compounds. yield a solid residue. EXAMPLE 1.7 A mixture of 1 g of the residue, 100 ml. of methanol, 45 10 ml. of ether, and 20 ml. of 37 percent hydrochloric 2-methyl-5-(3-oxobutyl)-1,2-(3'-oxocyclopen acid is heated at reflux for two hours under nitrogen. tano)perhydronaphthylen-6-one The solvent is removed under reduced pressure, and Repeating the procedure of Example 8 but replacing isolation with ether yields the unsaturated tricarbo methyltriphenylphosphonium bromide with 44;8,8- cyclic diketone 5-(3-hydroxybutyl)-2-methyl-1,2-(3'- 50 di(ethylenedioxy)-non-1-yltriphenylphosphonium bro oxocyclopentano)-1,2,3,4,6,7,8,8a-oc mide yields the corresponding 1,1-ethylenedioxy-4- tahydronaphthylen-6-one. This is hydrogenated using 3,3:7,7-dicethylenedioxy)octyl)-7a-methyl-5,6,7,7a the procedure described above to yield the correspond tetrahydroindan-5-one. This compound is then ing saturated tricarbocyclic diketone which is oxidized hydrolyzed, hydrogenated, cyclized with aqueous using chromium trioxide in pyridine or Jones reagent as 55 hydrochloric acid, and then hydrogenated by the described in Example 13 to yield the saturated procedure described in Example 15 to yield 2-methyl triketone 2-methyl-5-(3-oxobutyl)-1,2-(3'-oxo 5-(3-oxobutyl)-1,2-(3'-oxocyclopentano)per cyclopentano)perhydronaphthylen-6-one. hydronaphthylen-6-one. Repeating the procedure of Example 8 but replacing 60 methyltriphenylphosphonium bromide with 8,8- ethylenedioxy-4,4-tri-methylenedithionon-1-yltriphen ylphosphonium bromide yields the corresponding 1,1- r ethylenedioxy-4-(7,7-ethylenedioxy-3,3- trimethylenedithiooct-1-yl)-7a-methyl-5,6,7,7a 65 tetrahydroindan-5-one. This compound is then hydrolyzed, hydrogenated, cyclized with aqueous - H O hydrochloric acid and then hydrogenated by the 3,682,970 23 24. procedure5-(3-oxobutyl)-1,2-(3'-oxocyclopentano)per described in Example 15 to yield 2-methyl 0.4 g of p-toluenesulfonyl chloride is added to the hydronaphthylen-6-one. cooled solution. This mixture is allowed to stand at room temperature for four days, and is then washed Repeating this procedure with the other correspond with aqueous sodium carbonate solution and water, ing 2,2-ethylenedioxy-1-(lower)alkyl-5-oxocyclopent dried and evaporated. The residue is chromatographed 1-ylpropionates produced in Example 1 yields the cor on neutral alumina, eluting with hexane, to yield responding 7a-(lower)alkyl compounds. methyl 1-methyl-5-oxo-2-(tetrahydropyran-2-yloxy)- EXAMPLE 1.8 cyclopentylpropionate which is recrystallized from pentane. Repeating the procedure of Example 8 but replacing O Repeating the above procedure but replacing methyl 2,2-ethylenedioxy-1-methyl-5-oxocyclopent-1- dihydropyran with 4-methoxy-5,6-dihydro-2H-pyran ylpropionate with yields methyl 1-(4-methoxytetrahydropyran-4-yloxy)- methyl 2-methoxy-1-methyl-5-oxocyclopent-1-yl 1-methyl-5-oxocyclopentylpropionate. propionate, To a solution of 1 g of methyl 2-hydroxy-1-methyl-5- methyl 2-ethoxy-1-methyl-5-oxocyclopent-1-yl 15 oxocyclopent-1-ylpropionate in 25 ml. of methylene propionate, dichloride is added liquid isobutylene. A catalytic methyl 1-methyl-5-oxo-2-(tetrahydropyran-2-ylox amount of concentrated sulfuric acid is added, and the y)cyclopent-1-ylpropionate, mixture is agitated in a sealed bomb overnight at room methyl 2-(t-butoxy)-1-methyl-5-oxocyclopent-1-yl 20 temperature. The reaction mixture is then washed with propionate, and aqueous sodium bicarbonate solution, evaporated, and methyl 2-(4-methoxytetrahydropyran-4-yloxy)-1- recrystallized from chloroform:methanol to yield methyl-5-oxo-cyclopent-1-ylpropionate, methyl 2-(t-butoxy)1-methyl-5-oxocyclopent-1-yl yields the corresponding propionate. 1-methoxy-7a-methyl-5,6,7,7a-tetrahydroindan-5- 25 The invention claimed is: One, 1. A process for producing 4-substituted-4,6,7,7a 1-ethoxy-7a-methyl-5,6,7,7a-tetrahydroindan-5-one, tetrahydroindan-5-ones comprising reacting, under an 7a-methyl-1-(tetrahydropyran-2-yloxy)-5,6,7,7a hydrous conditions in an organic solvent inert to the tetrahydroindan-5-one, reaction, a methylene phosphoniumylid with a 20xo-1- 1-(t-butoxy)-7a-methyl-5,6,7,7a-tetrahydroindan-5- 30 cyclopentylpropionic acid derivative, at least two one, and molar equivalents of said ylid being present for each 1-(4-methoxytetrahydropyran-4-yloxy)-7a-methyl mole of said 2-oxo-1-cyclopentylpropionic acid deriva 5,6,7,7a-tetrahydroindan-5-one, respectively. tive, said methylene phosphonium ylid being selected The 2-ethers used in this procedure are prepared as from the group represented by the formulas: follows: A solution of 200 mg. of sodium 1-methyl-2,5- 35 dioxocyclopent-1-yl-propionate in 32 ml. of anhydrous R5 isopropanol and 25 mg. of sodium borohydride is CH=P-R2R. stirred at room temperature for 15 hours. 100 Mil N liliters of water is added, and the resulting suspension 40 RO -CH=H R3 extracted several times with ether. The ether phase is R6 dried over sodium sulfate and evaporated to dryness under reduced pressure to yield sodium 2-hydroxy-1- HoccH.CHCH-P%r,R. methyl-5-oxocyclopent-1-ylpropionate, which may be N R3 further purified by recrystallization from ether. 45 To a solution of 0.1 g. moles of sodium 2-hydroxy-1- - methyl-5-oxocyclopent-1-ylpropionate in 200 ml. of 6 o R. methanol, 15.5 g. of methyl iodide and 14 g. of potassi CICI2-C. -CH2CH2=P-R2 um carbonate is added. The mixture is stirred over R3 night, diluted with water and extracted with ether. The 50 ether phase is dried over sodium sulfate and evaporated R to dryness under reduced pressure to yield methyl 2 CH-Q CH2CHCH-P-R2/ hydroxy-1-methyl-5-oxocyclopent-1-ylpropionate. O N To a solution of 1 g of methyl 2-hydroxy-1-methyl-5- CH3 R3 oxocyclopent-1-ylpropionate in 25 ml. of DMF is 55 added three molar equivalents of methyl iodide and 2 g o o R; molar equivalents of silver oxide. The mixture is main CH-C-CHCHCII-C-CHCH-CH=PR: tained at room temperature for 12 hours, filtered, R3 evaporated under reduced pressure to yield methyl 2 -- methoxy-1-methyl-5-oxocyclopent-1-ylpropionate 60 & ) o, to R. which is recrystallized from chloroform:methanol. Re cII-C-CHCHCH-C-CHCH-CH=PR,R3 peating2-ethoxy-1-methyl-5-oxocyclopent-1-yl-propionate. this procedure with ethyl iodide yields methyl Two milliliters of dihydropyran are added to a solu tion of 1 g of methyl 2-hydroxy-1-methyl-5-oxo 65 cyclopent-1-ylpropionate in 15 ml. of benzene. About N / s is R. 1 ml. is removed by distillation to remove moisture, and cHo?ch.ch.ch, So?ch.ch.ch-PCR, R3 3,682,970 25 wherein R is an alkaline-stable, acid-labile protecting O R group, Rs is hydrogen or lower alkoxy, Rs is hydrogen HOCCH2CH2CH=P-R/ or methyl, and each of R, R and R is selected from N the group consisting of substituted and unsubstituted, R3 saturated and unsaturated, aliphatic and carbocyclic radicals and lower alkoxy radicals, and said 20xo-1- 6 / R. cyclopentylpropionic acid derivative being selected CHCH-C-CHCHCH-rr, from the group represented by the formula: R3 R 10 / CH. R. R. CH3-l. CICH2CH=P-R2 O N CH3 R3 R10 Os- ? g o, o R. wherein R is a lower alkylenedioxy or 15 CH-C=CHCHCH-C-CHCH-CH=PR, R. R3 w H, O O 6, o R. wherein R is a lower alkoxy, tetrahydropyran-2-yloxy, CHNc4CHCHCNc/CHCHCH-Pér, 20 tetrahydrofuran-2-yloxy or 4-methoxytetrahydropyran R3 4-yloxy; R is lower alkyl; and Rio is lower alkoxy, aryloxy having up to 10 carbons, lower alkylthio, lower alkanoyloxy, bromo or chloro. 5N/ s R. 2. The process of claim 9 wherein the methylene 25 phosphonium ylid has the formula CH-C-CHCHCH-C-CHCH-CH=r.R3 4. The process of claim 1 including the step of adding a lower monohydric aliphatic alcohol and an alkali metal alkoxide or alkaline earth metal alkoxide base to R. 30 the reaction mixture subsequent to the substantial dis CElseF-RR. appearance of said ylid, and thereafter the reaction N mixture is maintained at a temperature of from room RO CH-CH R3 temperature to reflux temperature. 5. The process of claim 1 including the step of adding 35 a dipolar aprotic solvent to the reaction mixture sub sequent to the substantial disappearance of said ylid, and thereafter the reaction mixture is maintained at a wherein R4 is lower alkyl, tetrahydropyran-2'-yl, temperature of from room temperature to reflux tem tetrahydrofuran-2'-yl or 4'-methoxytetrahydropyran-4 perature. '-yl group, R is hydrogen or lower alkoxy, R is 40 6. The process of claim 5 wherein the dipolar aprotic hydrogen or methyl, and each of R, R2 and R3 is solvent is hexamethylphosphoramide, and thereafter selected from the group consisting of substituted and the reaction mixture is maintained at reflux tempera unsubstituted, saturated and unsaturated, aliphatic and ture. carbocyclic radicals and lower alkoxy radicals. 7. The process of claim 3 wherein said organic sol 3. The process of claim 1 wherein the methylene 45 vent is diglyme, and the reaction mixture is maintained phosphonium ylid is selected from the group of com at reflux temperature. pounds having the formulas

50

55

60

65