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The reaction of 22,42-Dibromocholestan-3-one with N,N-imethylaniline

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The reaction of 22,42-Dibromocholestan-3-one with N,N-imethylaniline

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Content THE REACTION OF 2*, 4<t-DIBR0M0CH0LESTAN-3-0NE WITH N fN-DIMETHYLANILINE by Paetong Na Nonggai A Thesis Presented to- the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree MASTER OF SCIENCE (Chemistry) January 1962 UMI Number: EP41630 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. UMI EP41630 Published by ProQuest LLC (2014). Copyright in the Dissertation held by the Author. Dissertation Publishing UMI Microform Edition © ProQuest LLC. Ail rights reserved. This work is protected against unauthorized copying under Title 17, United States Code ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 4 8 1 0 6 -1 3 4 6 UNIVERSITY OF SOUTHERN CALIFORNIA G R A D U A TE SCHOOL. U N IV E R S IT Y PARK LO S A N G E LE S 7 , C A LI FO R N IA C . f c i N8>x This thesis, w ritte n by F-ae.lang-.Ea.-llanggaJ.................. under the direction o f hex. Thesis Comm ittee, and approved by a ll its members, has been p re sented to and accepted by the Dean of the Graduate School, in p a rtia l fu lfillm e n t of re quirements fo r the degree of .............. Mias.tLer...Qf...Scjteiice................ ,........... Dean Date Jartu ary 196 2 THESIS COMMITTEE M Chairy To My Boss. \ I ACKNOWLEDGEMENT The author wishes to express her appreciation to Professor Edgar W. Warnhoff for his warm guidance in i 'writing this thesis as well, as in performing the experiments• LIST OP FIGURES Figure Page I* Ultraviolet. Spectra of Schwenk*s Compound) Bihydro Sehwenk's Compound and N-Methylindole from A*-Cholest©n-3-one 22 II* Infrared Spectrum of Schwenk's Compound . . 23 III. Infrared Spectrum of Bihydro Schwenk's Compound • * .................. 24 IV. Infrared Spectrum of N-Methylindole from Cholestan-3-one .............. . 25 V. Infrared Spectrum of N-Methylindole from Coprostan-3-one . . . . . . . . . . . . 26 VI. Infrared Spectrum of Non-crystalline Bihydro Schwenk's Compound . ............. 27 VII. Infrared Spectrum of N-Methylindole from Al-Cholesten-3-one .............. 28 VIII. Infrared Spectrum of N-Methylindole from Cholestan-2-one . . . . . . . . . . . . 29 IX. Infrared Spectrum of Synthetic Schwenk's Compound 30 TABLE OF CONTENTS Page ACKNOWLEDGEMENT . . .... ii i LIST OF FIGURES . . . . . . . . . . . . . . . . . iii INTRODUCTION .......... 1 DISCUSSION . . . . . . . ......... . . . . . . . 4 EXPERIMENTAL . . . . . . . . . . . . ....... 31 A^-Cholesten-3-one • • • • • • • • • • • 32 Cholestan-3/3-ol ......... 32 Cholestan-3-one • . . • • • . . . . . . . 33 2 *,4*-Dibromocholestan-3-one ...... 33 Dehydrobromination of 2 *,4*-Dibromo- cholestan-3-one with N,N-Dimethylaniline 34 Phenyltrimethylammonium Perchlorate . . . 36 Reaction of N,N-Dimethylaniline and Dimethylaniline hydrobromide • • • • • 37 Catalytic Hydrogenation of the Dehydro bromination Product of 2 <*•,4 <* -Dibromo- cholestan-3-one • • • .... • • • • • 38 Estimation of the Maximum Amount of N-Methylaniline in N,N-Dimethyl- aniline ........... • • • • ..... 40 2oc-Bromocholestan-3-one . . . . . . . . . 40 2 -Bromocholestan-3/3-ol . ............. 41 2 /3,3/3 -Epoxycholestane .......... 42 Cholestan-2/3-ol . . . . . . . . . . . . . 43 Cholestan-2-one . . . . . . . . . . . . . 43 A^.Cholestene .••.••• •• •*• •• 44 2 <* ,3<*-Epoxycholestane . . . . . . . . . 45 Reaction of 2 <*,3 -Epoxycholestane with .Boron Trifluoride Etherate ........... 46 A -Cholesten-3-one ................. 47 Preparation of Coprostan-3-one ........... 48 General Procedure for Fischer Indole Syntheses with -Methylphenylhydrazine 49 Indole from Cholestan-2-one ............. 49 Indole from Choiestan—3—one ••••••• 50 Indole from Coprostan-3-one .......... 51 Indole, from , A*-Cholesten-3-one ..... 51 Indole from A^—Cholesten—3—one • • • • • 52 iv V Page Hydrogenation of the Indole from the Reaction of A l-Cholesten-3-one with at -Methylphenylhydrazine . . . . . . . . 52 APPENDIX . . . . . . . ......... . . . . . . . . . 54 BIBLIOGRAPHY ..... ............................. 55 INTRODUCTION Dehydrobromination of sterol bromoketones, particularly! compounds which would lead to unsaturation in the A ring, with various bases has been widely studied since the resulting ketosterols are physiologically active. Before discovery of the lithiumhalide-dimethylf ormamide'*' method and 2 2,4-dinitrophenylhydrazine or semicarbazide methods most bases used for dehydrobromination were amines, i.e. pyridine, aniline and their analogs. Potassium acetate has ^ t also been used. Treatment of the same bromo- and dibromo- ketones with different bases has given a variety of different products. For example, when 2<<-bromo- 3 4 cholestan-3-one (1) was refluxed with pyridine * or with e' 2,6-dimethylpyridine , pyridinium salts were obtained in high yield, and no dehydrobromination product was observed. The pyridinium salt obtained from the reaction of 2 -bromocholestan~3-one and pyridine could be converted into an unsaturated ketone by pyrolysis, but rearrangement 1 4 / \ ,occurred and the product was mainly a -cholesten-3-one (2) Jnot A*-cholesten-3-one (3). On the other hand, dehydrobro mination of 2oC-bromocholestan-3-one with 2,4,6-trimethyl- 7 7 pyridine ( Jf -collidine) or 2,4-dimethylpyridine was reported to give A^-cholesten-3-one (3). On closer 1 8 investigation Jacobsen found the product from the reaction of 2ct-broraocholestan-3-one and 2,4,6-trimethylpyridine to be a mixture of A^-cholesten-S-one (3) and cholestan-3-one (4). If the dehydrobrominating agent vas potassium acetate Pyvi<L»w* > Pyvi<iinium Salt* iS) (3) (2. ) 3 in acetic acid at 200°, the socalled "hetero-A^-cho- i ■ 7 lestenone" was obtained from 2 ct-bromocholestan-3-one. e q ! This was later proved to be A -cholesteU-4-one (5), [Displacement of bromine of 2oC-bromocholestan-3-one by hydrogen to give cholestan-3-one (4) in the reaction with 4 N,N-dimethylaniline was reported and was confirmed in the present work. Dehydrobromination of 2 < < ,4 -dibromocholestan-3-one (6) with 2,4,6-trimethylpyridine to give A^’^-cho- lestadien-3-one®,*® (7) or 2 bromo- A^-eholesten-3-one** !(8) was found to proceed in good yield. However, with iN,N-dimethy1aniline Schwenk and Whitman^ obtained a -crystalline product containing only carbon, hydrogen and nitrogen from the reaction with 2 ,4 c* -dibromo- cholestan-3-one. Only dehydrobromination and the formation ,of pyridinium salts had been reported up to that time. The presence of nitrogen and the absence of oxygen suggested that condensation involving the keto group and the benzene ring had taken place. The purpose of this thesis is to establish the structural formula of Schwenk's compound and to suggest a :reasonable mechanism for its formation. DISCUSSION The reaction was carried out by refluxing 2 ,4* -dibromocholestan-3-one (6. ) and N,N-dimethylaniline for five hours* The reaction mixture was then poured into iced hydrochloric acid* The precipitated,organic product was taken up in ether and the ethereal solution was washed thoroughly with hydrochloric acid, water, sodium bicarbonate solution, water, and then dried and evaporated* A dark brown oil remained which was taken up in ethyl acetate to which alcohol was added* Light brown flakes precipitated which after recrystallization from ethyl acetate and alcohol had melting point 230-232°• The analytical data 4 of Schwenk and Whitman fitted the molecular formula ^33-34®47 49^ ra' * ' lier than ^35^53^ "^e latter was not excluded by their figures. The coupling reaction with ~ t 1 p-nitrobenzenediazonium ion in alcohol-acetic acid was found to give a deep wine-rred coloration* Schwenk and Whitman suggested three structural formulae, (9), (10) and (11), of which (9) was proposed as the most probable one. For structures (9) and (10), aromatization of ring A with loss of an angular methyl group under the conditions used seemed unlikely. Under acid-catalyzed reaction conditions leading to aromatization of ring A, only. 4 5 : (ii) «,Cx C 9) HC — Ch3 migration of the angular methyl group has been reported. When Xnhoffen and Huang-Minlon*^ treated A^'^-cholestadienone (7) with acetic anhydride and sulfuric acid, a phenol (12) was isolated in good yield. Aromatization with loss of an alkyl group occurred only if 1 1 O ' the dienone was heated above 300 • Schwenk and Whitman's ! i reaction was catalyzed by base and perhaps also by acid at about 200° which shpuld not be vigorous enough to aromatize ring A with loss of an angular methyl group. Therefore (9) and (10) seemed less likely than (11). Concerning the solubility of Schwenk's compound in hydrochloric acid, a compound of tertiary amine type, (10) and (11) should be basic enough to form a water soluble hydrochloride salt when :treated with hydrochloric acid, but diaryl amines are not basic enough to do so. With the work up conditions that |Schwenk and Whitman used (10) and (11) should not have j stayed in the ether layer. For all of these reasons |structures (9), (10) and (11) seemed unlikely. There were other structures which seemed possible for this dehydrobromination product. Some of these were (13) - (17) which could come from the condensation of 2 << ,4<*. -dibromocholestan-3-one and N,N-dimethylaniline. 03) (15) Examples of possible courses of formation of these compounds are suggested belows 0M OH i t M ✓ V These structures are also open to criticism on the grounds that they -would be expected to be soluble in dilute hydrochloric acid* Since commercial dimethylaniline is contaminated with N-methylaniline, the product may have come from this base* If this were the case, structures (18) - (21) would also possible. H C-N (18) CH (19) For example, (21) could be formed by the following path 9 OH t f & Dehydrobromination could, of course, occur before or after condensation. Any of the above possibilities was unusual enough that the structure of the product seemed worth investigation. Dehydrobromination of 2 <* ,4<*-.dibroraocholestan-3-one . 10 ' (6) with N,N-dimethylaniline was repeated under the same I 4 | conditions as had been used by Schwenk and Whitman except I under an atmosphere of nitrogen. The work up was slightly modified in that dimethylaniline was removed by steam I distillation. On trituration of the clear amber neutral ( i product with ether, there was obtained up to 10$> of 1 crystalline material which after recrystallization from > ethyl acetate had melting point 221-223° and - 24°. f This was presumably the same product as that obtained by Schwenk and Whitman. However, the compound was neutral since : it was insoluble in dilute hydrochloric acid and did not ^ give a precipitate from ether when hydrogen chloride gas wasj i i added. The coupling reaction with p-nitrobenzenediazonium ion in ethanol-acetic acid was found to be negative, no color being formed. N,N-Bimethylaniline does give a red color when coupled with the same diazonium salt. Perhaps Schwenk and Whitman did this test on material slightly I contaminated with a trace of dimethylaniline. , The infrared spectrum of Schwenk*s compound (Figure II, i i ip. 23) in carbon disulfide showed strong absorption at —1 —1 738 cm“ and no other strong peaks in the 670-800 cm 1 region. This is consistent with four adjacent hydrogens on 13 , a benzene ring which none of the structures previously i | discussed had. The ultraviolet spectrum (Figure I, p. 22) had maximum absorption at 239 na/< (& 21,900), 254 m/< (e 19,650), 261 m>c (€ 19,200), 286 m>c(fc 6,840) and 306 ib>x (4 5,710), which looked somewhat like the spectrum 14 of a earbazole. Quantitative analysis of carbon, hydrogen, and nitrogen was very close to the calculated values for the molecular formula (molecular weight 471.74). The molecular weight found by mass spectrometer* confirmed this molecular formula* One N-methyl group was also found by the I Herzig-Meyer analysis* i i For catalytic hydrogenation benzene seemed to be the jbest solvent in this particular case since the compound was ! not very soluble in acetic acid, ethanol, or ethyl acetate* On reduction with palladium-on-earbon catalyst the amount of hydrogen absorbed was one mole-equivalent* The crystalline product, Cg^Hg^N, m.p. 194-196°, - 7.4°, was isolated in 85$ yield* Since there was only one double bond reduced tinder the conditions used, structures con taining only aromatic rings and those with more than one double bond, i.e. all structures previously considered, were excluded. The dihydro Schwenk*s compound had an infrared spectrum (Figure III, p. 24) different from the starting material and a different ultraviolet spectrum *The mass spectrum was kindly determined by Dr. R. I. Reed and Mr. J. M. Wilson of the Chemistry Department, The University, Glasgow, W.2, Scotland, who reported as follows* "There is a very intense peak at mass 471 and a small one at mass 487. Their intensities are in the ratio 60:1, which is too large to be a fragment ion: molecular ion ratio. Therefore your compound has molecular weight 471 and probably contains a trace of impurity of molecular weight 487." (Figure I, p. 22) X max 232 in/* ( £ 30,000), 286 ( * 5,530), » ' 1 1294 mj* (fc 5,290) which was that of a typical indole. ; Schwenk*s compound therefore must be an N-methylindole with J i ' j a conjugated double bond. The formation of an N-methylindole! meant either the product was formed from N-methylaniline or i else demethylation occurred in a quaternary salt from N,N-dimethylaniline and the bromoketone. In agreement with , i this it was noticed that during the reaction a white solid i formed on the condenser and along the side of the flask. This was proved to be phenyltrimethyl ammonium bromide by |comparison of the perchlorate salt with an authentic sample.] i From a mechanistic stand point, if the product came ! from dimethylaniline, there were two reasonable structures j I of the N-methylindole that could be formed, (22) and (23) of which the former seemed more likely. It is well known that loss of bromine from occurs more rapidly than from Cg. 2 oC ,4oC-Dibromoeholestan-3-one (6) is rapidly dehydro- j I 4 t\2 ' Ibrominated to 2<*.-bromo— a -cholesten-3-one (8) by boiling , ■ collidine. It was assumed that (8) would then be N-alkylated i ■ ! !at Cg. Demethylation and cyclization to (22) could follow. The NMB* spectrum also supported (22) since it showed an I absorption at T 6.15 (tetramethylsilane = 0) which is I i i *The NMB spectra were kindly determined by Dr., J. B. Stothers through the courtesy of Professor P. de Mayo, Department of Chemistry, University of Western Ontario, 1London, Ontario, Canada, and by Dr. Lois Durham through the courtesy of Dr. E. J. Eisenbraun, Department of Chemistry, Stanford University, Stanford, California. 13 ! ctir a w H (i«-; (i4) CH (31) he HC~ HC-N (3 4) H cm (%*) CH, (0.?) 1 16 characteristic of vinyl hydrogen, and the area under the I .!peak corresponded to one hydrogen only. As chemical evidenc for this interpretation synthesis of dihydro (22) with 'trans A/B fusion was carried out by means of ai Fischer 17 Indole synthesis with oc-methylphenylhydrazine and cholestan-2-one which was prepared from chromic acid oxidation of eholestan-2y3-ol. The synthetic methyl indole had melting point 183-185°, + 64.3°. On admixture with dihydro Schwenk1s compound, the mixed melting point was depressed. ' Since the synthetic indole was not identical with the ( ! crystalline dihydro Schwenk* s compound, the latter may have ; been the Cg-epimer (26). Bather than try to make this A/B icis derivative, it appeared simpler to prepare (22). Dehydrogenation of (24), which could lead directly to (32), 18 by using one equivalent of chloranil was attempted but failed to yield the desired product.. Preparation of (22) 17 ; seemed possible by the Fischer indole reaction oi O A —cholesten—2—one (27) and -methylphenylhydrazine since 19 Rossner had reported the formation of an indole from the : reaction of A 4-cholesten-3-one (2) with phenylhydrazine. I To verify this reported reaction a Fischer indole reaction 1 of A^-cholesten-3-one (2) with ot-methylphenylhydrazine was attempted before preparation of (27) to see whether this reaction would proceed in good yield or not at all. A conjugated methylindole was^ isolated from this reaction and 15 unexpectedly found to be identical in every respect with Schwenk*s compound. Therefore the location of nitrogen attached to ring A was at Cg. The indole ring carbon must be at either Cg or C^. If the indole carbon were attached to ring A at Cg, the double, bond would have to be at G^-Cg (28), but if attached at C^, the double bond could either be at Gg-Cg (30) or at G^-Cg (31), Catalytic hydrogenation of (31) would give only one product, but from (28) and (30), two isomers might be obtained. Therefore, the hydrogenation of Schwenk*s compound was reinvestigated, and a non-crystalline • r ~ * i 24 o xndole, + 121 , was found in the mother liquor of the crystalline one. This evidence, together with tbe NMR spectrum, confirmed the location of the double bond at the ring junction Cg. Whether the double bond was at G^-Cg or Gg-Cg and the indole ring attached at Cg or C^ was not decided, 20 As it is well known that cholestan-3-one (4) (A/B trans) enolizes toward Cg and coprostan-3-one (29) (A/B cis) enolizes toward C^ preferentially, the Fischer indole reaction of these two ketones with < * - -methylphenyl hydrazine would give indoles attached to ring A at.Cg (32) from cholestan-3-one (4) and at C^ (33) from coprostan-r3-one (29), respectively. Regardless of the stereochemistry of the A and B rings, one of the two synthetic indoles must be identical with one of the two isomers from hydrogenation of Schwenk's compound. These were prepared and it was found that the N-methylindole from cholestan-3-one (4), 16 m.p. 215-217°, L<*]Jj4 + 67.7° (Figure IV, p. 25) was identical with neither isomer of dihydro Schwenk1s compound, I but that from coprostan-3-one (29), m.p. 151-153°, + 149°, had an infrared spectrum (Figure V, p. 26) identical with the non-crystalline dihydro compound (Figure VI, p. 27). The optical rotation of the N-methyl indole from coprostan-3-one was slightly different from that of the dihydro compound which probably was not pure. The stereochemistry of the non-crystalline product was therefore known to have the A/B cis configuration (33) since in the Fischer indole reaction of coprostan-3-one j(29), there was no possibility of affecting the t configuration at Cg. ' Since the A/B cis isomer of the dihydro compound isolated was not pure, even though it had an infrared spectrum identical with that of the N-methylindole from coprostan-3-one, it was desirable to provide more rigorous proof. This was done in such a way as to demonstrate conclusively the structures and stereochemistry of the various indole derivatives. The A/B trans isomer (34) was ! also synthesized by hydrogenation of the conjugated indole | obtained from the Fischer indole reaction of A^-cholesten-3-one (3) and -methylphenylhydrazine. It was conceivable that in this acid-catalyzed reaction the double bond could migrate from C^-Cg to C^-Cg. If this had happened, the unsaturated indole obtained would have been identical with that (30) from the reaction of A4-cholesten-3-one (2), but this was not found to be the |case. The methylindole from A*-cholesten-3-one, j m.p. 210-214°, + 153°, had ultraviolet (Figure I, p. 22) and infrared spectra (Figure VII, p. 28) different from those of the indole from &4-cholesten-3-one (29) and therefore must possess structure (31). Upon catalytic hydrogenation the amount of hydrogen absorbed was one mole-equivalent, and the dihydro product, m.p. 192-194°, 24 o £ - 6.6 , was identical with the crystalline dihydro Schwenk's compound in every respect. Therefore, it can be !concluded that structure (30) is Schwenk's compound, (34) jis crystalline dihydro compound of melting point 194-196°, and (33) is the non-crystalline dihydro product. From a mechanistic stand point, it seemed unlikely that Schwenk's compound came from the reaction of 2ot,4«c-di- bromoeholestan-3-one and N,N-dimethylaniline because there is no way to attach the nitrogen of a tertiary amine at a carbonyl group. It is more likely that the product came from N-methylaniline which could undergo addition to the carbonyl group. The amount of N-methylaniline present in the !dimethylaniline was 0.112^ as determined by quantitative i 'preparation of the toluenesulfonamide. With the amount of dimethylaniline used to react with 5 g. of 2 <*,4 oc-dibromocholestan-3-one, the maximum amount of N-methylaniline present was 0.443 mmole which was less than 18 the maximum yield (0.935 mmole) of Schwenk's compound isolated. It was suspected that N-methylaniline was formed in the reaction by disproportionation of dimethylaniline hydrobromide and dimethylaniline which also led to the formation of phenyltrimethyl ammonium bromide. If this were true, the amount of N-methylaniline plus Schwenk’s compound .formed should be equal to that of phenyltrimethylammonium bromide. A quantitative test showed this to be true within 'experimental error. The steam distillate from removal of the iexcess N,N-dimethylaniline from Schwenk's reaction (in which, I ; 0.64 mmole of (30) was isolated) was worked up and 7.93 i : mmoles of N-methylaniline was isolated by conversion to the i neutral j)-toluenesulfonamide. It was also found that 7.00 mmoles of phenyltrimethylammonium ion, identified by conversion to the insoluble perchlorate salt, formed in the same reaction was almost equal to the amount of the bromide ion, 7.60 mmoles. It was desirable to prove that dimethyl- aniline alone disproportionates to give the same products as obtained from Schwenk's reaction. A solution of dry dimethylaniline hydrobromide in dimethylaniline was refluxed under an atmosphere of nitrogen. As the solution started to K - boil, white solid formed on the sides of the flask. The amount of N-methylaniline and phenyltrimethylammonium bromide, isolated as described before, was 1.84 and 1.57 mmoles respectively. A mechanism for the formation of Schwenk's compound is 19 suggested as follows: 6v, : c & _ ( V — H 3y- +*7 (<>) 8y f N CH. (8) yCH7 <f>-N-H ( 8) + t-A-i ^ I 3 ♦ VI/ r* i (30) * * CH. <*X, 8r0 I I f ( 35) 20 In the cholestan-3-one series dehydrobromination of 4 ot-bromine is veil known to proceed more rapidly than 2 oc-bromine. When 2 <* ,4oc-dibromoeholestan-3-one (6) was refluxed with collidine, the 4ot-bromine was removed in 40 seconds to give (8). The basicity of collidine (pK^ 6*5, b.p. 172°) is only slightly different from that of N,N-dimethylaniline (pKf a 5.12) and its boiling point, 192*5-193.5°, is only 20° different. Therefore loss of the 4 (^-bromine postulated in this particular reaction is reasonable. As dimethylaniline hydrobromide was formed, it could disproportionate to give N-methylaniline and phenyl- trimethylammonium bromide. Both of these products were isolated. Once N-methylaniline was formed the unsaturated 4 ketone, 2<A-bromo- ^ -eholesten-3-one (8), could form an 21 enamine. Heyl and Herr have reported the formation of enamines such as (37) from pyrrolidine and A -3-ketosteroids in agreement with the proposed reaction OH i ! i 2 * course. The SN type cyclization of (35) with loss of the allylic 2<A-bromine is stereochemically possible. It might also be expected that eyelization by direct displacement of jbromine would occur to give (36). No (36) was isolated, but t CH. t CM, I CH (3 5) it may in fact be present in the mother liquor from crystallization of Schwenk's compound* I j The mechanism suggested above may be tested by the ! 4 . x reaction of 2«*-brorao- & -cholesten-3-one (8) and N-methyl- ; ! aniline which should give a better yield of Schwenk' s j |compound (30) if some such path is followed. I 35OO0*f!t 50000 25000 2000C 15000 10000 rr-n 5000 250 300 W qv« length 350 400 TRANSMITTANCE (% ) 4000 3000 2000 1500 CM-l 1000 900 800 700 100 INFR A C O R D .^ 137-1281 7 8 9 10 1 1 WAVELENGTH (MICRONS) Figure n TRANSMITTANCE (J5) I 4000 3000 2000 1500 CM-1 1000 900 800 700 100 80 60 40 20 0 INFRACORD 137-1281 WAVELENGTH (MICRONS) Figure III to r f K . TRANSMITTANCE (% ) 4000 3000 2000 1500 CM-i 1000 900 800 700 100 L INFRACORD . W 137-1281 WAVELENGTH (MICRONS) Plguce IV TRANSMITTANCE (%) 4000 3000 100 2000 1500 CM-i 1000 900 800 700 —i r-*= I L / I A / - t r^= = o . V - i r k — i/f ? v " £ P - - l t — - r f =c— — - __ --- " : i f - 7 • < (33? * Z " 1 ...... i - — f l z --. --i i — 1 — I ---- ! -- __s i IF R A C & R t) , m * 137■ 1 2 8 1 80 60 40 20 WAVELENGTH (MICRONS) Figure V TRANSMITTANCE (%) 4000 3000 2000 1500 CM-i 1000 900 800 700 100 INFRACORD tW 137-1281 WAVELENGTH (MICRONS) Figure VI N TRANSMITTANCE (%) 4000 3000 2000 1500 CM-i 1000 900 800 700 100 (31) IN F R A C O R P .W 137-1281 WAVELENGTH (MICRONS) Figure VII TRANSMITTANCE (% ) 4000 3000 2000 1500 ttlllillllllti i i i 100 CM-1 1000 900 800 700 I I I ! ^ i■ i - L i . , 1 U,u, ■ 1 i _ L _ t _ J_____u j_ 1111111 § 1 i iJ. J . . L f - l —l —i 1 1 | I l l 1 , T . —7= > - f — y s - TT =v-f k — -r- A- -J : “f f- V \ * d ~ d 4- — . . l- - f f C * * 4- ( — 4* (W -4 | — I d 1* < f « * « ? R D r 3 f W 1 ? 7 1 00 C N 80 60 40 20 WAVELENGTH (MICRONS) Figure -VIII to CD TRANSMITTANCE {% ) 4000 3000 2000 1500 CM-i 1000 900 800 700 100 (30) INFRACORD 137-128) WAVELENGTH (MICRONS) Figure IX CO o EXPERIMENTAL i f General .1 I M M M M M M M M M Melting points were taken on a microscope hot stage and are corrected for stem exposure. Ultraviolet spectra were taken in 95J& ethanol on a Cary Model 14 PM recording spectrometer. Infrared spectra were taken with a Perkin-Elmer "Infraeord" Model 137 spectrometer and wave length 'corrections were made from a polystyrene calibration jstandard. A 0.10 mm. thick sodium chloride cell was used. ■ NMR spectra were determined in deuteriochloroform solution on a 60 me. Varian HR-60 or A-60 spectrometer. Line positions are reported in terms of the dimensionless number X » where T - ( g^ in e.p.s. x 106)/(60 x 106) 4 (tetramethylsilane — 0). i Optical rotations were observed with a Rudolf Polari— meter Model 81 in a 1-decimeter tube. In working up reaction mixtures, ethereal, benzene and chloroform solutions were washed twice with saturated sodium chloride solution and dried over anhydrous magnesium sulfate before being filtered and evaporated. Alumina for chromatography was reagent grade Merck aluminum oxide. Activity determined by the method of 31 j 32 |Brockraann.22 ' 4 / i 1 A -Cholesten-3-one (2). This was prepared by the Oppenauer i |oxidation of cholesterol according to the procedure of 23 Organic Syntheses. From 100 g. of cholesterol, there was jobtained 46 g. (46$) of h^-eholesten-3-one, m.p. 79*5-80*5° ;(reported 79.5-80.5°).23 | i Cholestan-3y3-ol. (a) This was prepared according to the 24 method of Hershberg by catalytic hydrogenation of recrystallized commercial cholesterol, m.p. 147-150°. The reduction was carried out on a Parr shaker in 10-g. batches i ;dissolved in 150-170 ml. of warm reagent grade ethyl ; i f acetate with 150-200 mg. of commercial platinum oxide | (Englehard Industries) and two drops of 70# perchloric acid.! | The solution was heated to 60° and then hydrogenated with an initial pressure of 40 p.s.i. Complete hydrogenation took 10-30 minutes. From 70 g. of cholesterol, there was obtained 58.5 g. (84#) of cholestan-3/3-ol, m.p. 139-140° (reported2^ 139-141°)• i (b) Cholestan-3y3 -ol was also prepared by reduction of 4 25 1 h -cholesten-3-one according to the method of Diels* 1 i ! Ten grams of small pieces of sodium metal was carefully i dropped into a hot solution of 4.0 g. (0.010 mole) of &^-cholesten-3~one, m.p. 79.5-80.5°, in 135 ml. of isobutanol over a period of approximately 0.5 hour. If less alcohol was employed, alkoxide precipitated during the 33 reaction. Water was cautiously added and the alcoholic i i I solution was washed several times with water. The alcohol was evaporated under aspirator vacuum at 55-60° until the solution became syrupy and then methanol was added. There !was obtained 2.90 g. (72.5$) of short needles, m.p. 138-140° o 25 (reported 139-141 ). When this reaction was carried out I on a fourfold scale, there was obtained only 39$ yield of Cholestan-3-one (4). This was prepared according to the directions in Organic Syntheses. From 100 g. of ;cholestan-3y3-ol, m.p. 139-140°, there was obtained 82.5$ o ! of cholestan-3-one, m.p. 121-128 . One recrystallization I i from hot methanol gave 65.8 g. (65.8$) of needles, m.p. 127-128° (reported 129-130°).26 2 qC .4 oC-dibromocholestan-3-one (6). This compound was 27 prepared according to the method of Wilds. A small amount , (1-2 ml.) of a solution of 26.7 g. (0.17 mole) of bromine in 170 ml. of acetic acid was added to a solution of 30.4 g. (0.080 mole) of cholestah-3-one, m.p. 127-128°, in 3042 ml. of acetic acid. The solution was warmed gently until the color of bromine had faded, then cooled to room temperature, and the remaining bromine was added dropwise with stirring (Hershberg stirrer). After 2 hours, fine, long needles started to separate. The reaction mixture was allowed to stand at room temperature for 24 hours. The product was 34 collected on a filter, -trashed with acetic acid and then with water. After being dried in the oven (80°C) for 4 hours, the melting point was 187-191° (dec,) [reported 194—194,5°■(dec,)],^ The filtrate was diluted with a large volume of water and the white precipitate which formed was filtered. One recrystallization from petroleum ether gave long white needles, m.p, 187-191° (dec,). The total yield was 32 g* (75$). Dehvdrobromination of 2 d .4gC-dibromocholestan-3-one with purified JML -dimethylani1ine. (a) N,N-dimethylaniline was purified by distillation under reduced pressure, treatment with acetic anhydride, hydrolysis of excess anhydride and redistillation at reduced pressure. Five grams (5,00 g,, 9.20 mmoles) of 2 ct ,4 oC -dibromocholestan-3-one, m.p. 187-191° (dec,), was refluxed for 5 hours with 50 ml, of purified N,N—dimethylaniline under an atmosphere of nitrogen. The yellow solution turned blue after 10 minutes and became wine-red in another half hour, A white solid formed in the condenser. The cold reaction mixture was treated with 30 ml, of 10$ sodium bicarbonate solution and dimethylaniline was removed by steam distillation. The residue was taken up in 200 ml, of ether and washed twice with water. The dried ether solution was evaporated almost to dryness, cooled, and scratched. There was obtained 0.44 g. (10$) of slightly 35 yellow crystals, m.p. 209-210°. Three recrystallizations of the crude from ehloroform-ethyl acetate afforded 50 rag. of long, slightly yellow needles of (30), m.p. 221-223°, - 23° (e 1.4 chloroform), />] |4 - 24° (c 2.16 chloroform), (reported m.p. 230-232°).4 Ultraviolet spectrum: * max 239 m/t (e 21,910), 254 ra>* v (* 19,650), 261 m>t(e 19,200), 286 mjx (f c 6,840), 306 mM (e 5,710). ! ) -1 I Infrared spectrum: * 738 cm (four adjacent j m o X f jhydrogens on aromatic ring)12 and 1630 cm**1 (G - C).22 | Anal. Calcd. for C34H49N (471.74): C, 86.56; H, 10.47; jET-Cffg, 3.18; C-Ctt3, 15.92. Found: C, 86.57; H, 10*67; N-CHg, 3,88; C-CHg, 6.77; mol* wt. (mass spectrometer), 471. i The white solid in the condenser was dissolved in the i smallest possible amount of water and basified with potas sium hydroxide. Dimethylaniline which separated was removed by ether extraction. The aqueous solution was acidified with cold concentrated hydrochloric acid, then perchloric acid was added dropwise, long white needles were obtained. Four recrystallizations afforded large white needles, m.p. 179-181°, On admixture with authentic phenyltriraethylara- raonium perchlorate (see below) the melting point, 178-181°, was? not depressed. Anal. Calcd. for C9H14NC104 (235.63); C, 45.87; H, 5.97. Found: C, 45.91; H, 6.07. (b) From another reaction with 5.000 g, (9.20 mmoles) of 2 «i,4oC—dibroraoeholestan-3-one (6) and 50 ml* of dimethylaniline refluxed under nitrogen for 2 hours was isolated 303 rag. (0.64 mmole, 7$) of Schwenk’s compound (30^ m.p. 181-214°. From the acidified (nitric acid) aqueous 'steam distillation residue was precipitated 1.426 g. of silver bromide equivalent to 7.60 mmoles of bromide ion. The filtrate from separation of the silver bromide was concen trated and treated with excess solid sodium perchlorate and chilled to precipitate 1.642 g. (7.00 mmoles) of phenyl trimethyl ammonium perchlorate. The steam distillate was extracted with ether and the dried ethereal solution treated with p-toluenesulfonyl chloride. Dimethylaniline was removed by washing with dilute hydrochloric acid. The excess of p-toluenesulfonyl chloride was hydrolyzed by stirring the ethereal solution with dilute potassium hydroxide solution. Evaporation of the washed and dried ethereal solution left 2.071 g. (7.93 mmoles) of N-methylaniline p-toluenesulfonamide, m.p. 93-96.5°. Phenvltrimethylammonium perchlorate. An authentic sample was prepared by treatment of 5 ml. of dimethylaniline with 3 ml*, of methyl iodide. To an aqueous solution of the resulting methiodide salt, perchloric acid was added dropwise. Long white needles were formed which after four recrystal lizations from ethanol gave large needles, m.p. 179-181°. 37 Reaction of N.N-dimethvlaniline and dimethvlaniline hydro- bromide, (a) Dry hydrogen bromide gas was bubbled into 25 ml. of NfN-dimethylaniline for 2 minutes. The reaction mixture was then refluxed at 200° under an atmosphere of nitrogen ,for 5 hours. White solid started to form on the sides of the flask as soon as the solution started to boil. The white solid was washed down with water, and the mixture was steam distilled after Neutralization with 25 ml. of 10$ sodium bicarbonate. The aqueous residue was extracted twice with 150-ml. portions of ether to get rid of traces of amines.. The aqueous extract was then evaporated on a steam bath under aspirator vacuum to about 25 ml. The solution was acidified with perchloric acid and solid sodium perchlorate was added. On cooling there was obtained 369 mg. (1.57 mmoles) of phenyltrimethylammonium perchlorate, m.p. 178-181°. The ether extract from above was combined with the steam distillate and the amines were extracted. The ether .solution of amines was evaporated to about 100 ml. and 2.50 g. of p-toluenesulfonyl chloride was added. The reaction mixture was allowed to stand overnight at room temperature. The excess of p-toluenesulfonyl chloride was hydrolyzed by stirring (magnetic bar) with potassium' hydroxide until there was no p-toluenesulfonyl chloride left. The ethereal solution was washed with water until the wash solution was neutral. Dimethylaniline was separated 38 from N-phenyl-N-methyl-p-toluenesulfonaraide by extracting several times with dilute hydrochloric acid. The ethereal solution was then washed with water until free from acid and evaporated. After one recrystallization of the crude amide from ethanol there was obtained 450 mg. (1.84 mmoles) of N-phenyl-N-raethyl-p-toluenesulfonamide, m.p. 93-96°. On admixture with the authentic sample the mixed melting point was not depressed, 93-96°* (b) This reaction was also carried out by using dried crystalline dimethylaniline hydrobromide* A solution of 347 rag. (0.172 mmole) of dimethylaniline hydrobromide I (dried at 80°, p.< 0.01 mm.) and 3.645 g. of dimethylaniline1 was refluxed under an atmosphere of nitrogen for one hour. i White solid formed on the sides of the flask. The reaction mixture was worked up the same way as in (a)* There was isolated 219 mg. (0.190 mmole, 54$) of phenyltrimethyl- ammonium perchlorate and 52 mg. (0.20 mmole) of N-phenyl- N-methyl-p—toluenesulfonamide• Catalytic hydrogenation of the dehvdrobromination product i of 2 <*».4 oc -dibromocholestan-3-one. (a) A solution of 168 mg. (0.31 mmole) of the dehydrobromination product, m.p. 222-224°, in 5 ml. of benzene was hydrogenated with the aid of 50 mg. of 10$ palladium-on-carbon catalyst. Reduction was carried out in an atmospheric hydrogenator by stirring with a magnetic bar at room temperature for 24 hours. The 39 amount of hydrogen uptake could not be determined because of leakage. Upon filtration and evaporation of benzene, slightly yellow needles, m.p. 166-186°, were obtained. Four recrystallizations from ethyl acetate raised the melting point to 184-185°. Sublimation of the yellow crystalline product at 200° (^ 0.01 mm.) gave a colorless sublimate, m.p. 195-197°, 0 3 12 - 7.0° (c 1.00 chloroform). Ultraviolet spectrum: \ max 232 m>i ( 6 30,000), 286 mja. (fe 5,530), and 294 m>t(* 5,290). j CS2 -I j Infrared spectrum: ^ mctx cm (£°ur adjacent hydrogens on aromatic ring).*2 ! Anal. Calcd. for C34H5iN (473.75): C, 86.19; H, 10.85. j Found: C, 86.41; H, 10.79. • (b) The same hydrogenation was repeated with 191 mg. of Schwenk's compound, m.p. 220-222°, dissolved in 6 ml. of I benzene with the aid of 65 mg. of 10$ palladium—on—carbon catalyst. The minimum amount of hydrogen absorbed was 77$ of one-mole equivalent. After filtration and evaporation of benzene, there was obtained 185 mg. (97$) of the crude pro duct which after recrystallization from ethyl acetate gave 134 mg., m.p. 189-195.5°, of the first crop. The second 1 o crop, 16 mg., m.p. 187-193.5 , was almost pure. The total yield was 150 mg. (79$) of (34). Further recrystallization of these crops from ethyl acetate gave 122 mg. of white needles, m.p. 194—196°, Oljj^ — 7.4° [c 2.03 chloroform). The oily mother liquor of the first recrystallization, 40 36 mg. (19$), was dissolved in petroleum ether and passed through activity II alumina, and there was collected 20 mg. (11$) of colorless oil, + 121° (£ 2.05 chloroform). Ultraviolet spectrum: A. max 232 m>< (fc 28,000), 286 m>c (fc 5,570), and 294 m>< (£ 5,600). iCS2 -1 Infrared spectrum: V ma£ 732 and 738 cm (one peak 13 presumably from four adjacent hydrogens on aromatic ring). l Estimation of N-methylaniline in -dimethylaniline. A J . 1 solution of 19.043 g. of the N,N-dimethylaniline used for dehydrobrominations in 50 ml. of ether was stirred 1 (magnetic bar) overnight with one gram of p-toluenesulfonyl chloride. Dimethylaniline was removed by extraction with ' dilute hydrochloric acid; excess sulfonyl chloride was ( removed by stirring the ethereal solution with 10$ potassium hydroxide solution. The dried ether solution was evaporated to leave 52.0 mg. of N-methylaniline p-toluenesulfonamide which corresponds to 0.112$ of N-methylaniline contaminating the dimethylaniline. Control experiments were run to show that the reaction of the sulfonyl chloride with the N-methylaniline was quantitative and that there was no hydrolysis of the sulfonamide on stirring with potassium 1 hydroxide solution. 2 ol-Bromocholestan-3-one (1). This compound was prepared 29 according to the method of Fieser. A solution of 28.1 g. (0.17 mole) of bromine in 125 ml. of acetic acid was added 41 dropirise to a mixture of 62.8 g. (0.14 mole) of cholestan-3-one, m.p. 127-128°, in 1875 ml. of acetic acid .containing 2 ml., of 48$ hydrobromic acid. The reaction was t i jcarried out at room temperature with stirring (Hershberg I I !stirrer). After approximately 25 ml. of bromine solution was added, white crystals started to separate* The reaction mixture was stirred for another 5 minutes after the bromine solution had been added and the product was collected by ^filtration. The crude product, 62.1 g. (81.6$), m.p. 144-164°, was recrystallized from acetone-ethanol. There was obtained 44.2 g. (59.2$) of long, white needles, m.p. ^ 169-171° (reported 168-169°).^ From the mother liquor there1 F was isolated an additional 3 g* (4$) of less pure material, m.p. 159-167°. j 2 <A-Bromocholestan-3 .A-ol.* The reduction of 2<<-bromo- 29 cholestan-3-one was carried out by the method of Fieser. Sodium borohydride 2.50 g. (0.08 mole) was added in small portions to a suspension of 34.5 g* (0.070 mole) of 2 <*.-bromoeholestan-3-one, m.p* 169-171°, in 1475 ml. of 95$ ethanol at room temperature with stirring (Hershberg stirrer). White solid was suspended in ethanol. After 24 *Fieser and Dominguez reported that all was in solution after 2 hours stirring. In the present work, it was found that everything went into solution if absolute ethanol was used, but if 95$ ethanol was used, a precipitate remained throughout the reaction. hours stirring, the reaction mixture was poured into 5 1. of water and allowed to stand in an iCe-bath for 5 hours. The product was filtered and washed thoroughly with water. After drying overnight at 80°, 33.3 g. (96$) of crude product, m.p. 96-100°, was obtained. On recrystallization from ethanol, 30.1 g. (86.7$) of white needles, m.p. 93-95°, C®6 J 22 + 12.3° (c 4.08 chloroform) was recovered (reported m.p. 104-105°, C°Od + 25° + 2°).29 Pour recrystallizations of the crude material from the same Isolvent afforded 32.5$ of small crystals, m.p. 93-114°. The recrystallized compound was chromatographed on alumina I activity.I. The first crystalline fraction (0.11 g.) was taken off by ether-benzene (1:99), m.p. 109-112°, '03 22 + 11.9° (c 4.18 chloroform). -Epoxyeholestane. This compound was prepared 30 according to the method described briefly by Barton with slight modification. Two grams (0.43 mmole) of 2^-bromo- cholestan-3y3-ol, m.p. 95-106°, in 10 ml. of ether and 25 ml. of isopropanol was treated with 100 ml. of 4$ isopropanolic potassium hydroxide at 50-60° for 1.5 hours.- The reaction mixture was neutralized with 4.5 ml. of acetic acid.* The solution was evaporated to approximately *If the reaction mixture was allowed to stand overnight after acetic acid was added and then worked up, the epoxide was opened slowly, and a lower yield was obtained. 43 25 ml. and methanol was added until the solution started to ^ ■ ■ - become cloudy. The crude epoxide, 1.18 g. (71.5$), m.p. 85-89°, was recrystallized from ether-methanol, and there was obtained 1.04 g. (62.7$) m.p. 89-91.5°r £<*1 ^ + 58.2° (c 2*17 chloroform) of needles (reported^ m.p. 89-91°, t*3D + 55°). Cholestan—2fi-ol. Lithium aluminum hydride 1.03 g. (0.03 mole) was added in small portions to a solution of 0.85 g. (2.2 mmoles) of 2/3 ,3/3-epoxycholestane, m.p. 85-87°, in 35 ml. of ether. When the foaming had subsided,, the reaction mixture was refluxed for 5 hours. Wet ether was added dropwise to the cold solution until the reaction was no longer vigorous, whereupon water was added. Aluminum and I lithium hydroxides formed were dissolved in 10$ hydro chloric acid, Upon evaporation of the dried ether under aspirator vacuum at room temperature, there was obtained the crude product, m.p. 142-150°, loLJ ^ + 34.4° (c 2.18 chloroform) which was recrystallized from chloroform- methanol. There was obtained 0.45 g. (54$) of white plates, m.p. 151-153° (reported 152-154°).31 Cholestan-2-one3^ (25). A solution of 5.30 g. (0.014 mole) of cholestan-2y3-ol, m.p. 151-153°, in 125 ml. of benzene was added dropwise to a cold mixture of 7.00 g. (0.030 mole) of sodium dichromate dihydrate, 10 ml. of sulfuric acid, 6 ml*, of acetic acid and 60 ml. of water while agitating 44 with a magnetic stirring bar. The reaction mixture was stirred for another 8 hours at room temperature after all of the oxidizing agent had been added. The benzene layer was separated and washed twice with 25-ml. portions of water, three times with 25-ml. portions of 5$ potassium hydroxide solution and twice with water. The dried benzene solution was evaporated until it became viscous whereupon 60 ml. of hot methanol was added. On cooling, 3.53 g. ;(68.5$) of long needles, m.p. 131-132° (reported 128-129°),32 was obtained. A -Cholestene. This was prepared according to the method 29 of Fieser* A mixture of 30*1 g* (0#060 mole) of 2 ei-bromocholestan-3/3 -ol, m.p. 95-106°, and 60.3 g. (0.900 mole) of zinc dust was refluxed in 1.5 1. of acetic acid for 4 hours. The hot solution was filtered but did not show any sign of crystallization on standing overnight at room temperature. The reaction mixture was diluted with 2.5 1. of water and chilled to ice-bath temperature for 2 hours before the product was taken up in ether. The ethereal solution was washed twice with 250—ml. portions of water and once with 500 ml. of 5$ sodium hydroxide. Ether was evaporated and 24.1 g. (99.5$) of crude product, m.p. 45-91°, was obtained. One recrystallization from ether- methanol yielded 13.4 g. (52$) of unchanged melting point. The olefin was purified through the dibromide and 45 debrominated as follows. A solution of 2.90 g. (0.36 mole) of bromine in 5 ml. of acetic acid was added dropwise to a cold solution of 1.00 g. (2.57 mmoles) of A -cholestene, m.p. 45-91°, in 50 ml* of ether. The reaction mixture was allowed to stand at room temperature for 0.5 hour. The ethereal solution was washed with sodium bicarbonate, sodium bisulfite solutions and water. Evaporation of the ether gave white crystals which were recrystailized from ehloroform-methanol to give 0.45 g. (32$) of plates, m.p. 111-125.5° (reported for 2/3,3 -dibromocholestane30 123-124°) which was unchanged after drying in vacuum for 5 hours. Three grams (0.05 mole) of 2,3-dibromocholestane, m.p. 111-125.5°, was refluxed with 109 ml. of redistilled acetone and 5.45 g. (0.030 mole) of sodium iodide for 12 hours. The 1 colorless solution turned a clear light brown. On cooling long needles separated out of solution. The reaction mixture was diluted with 300 ml. of water and the organic product was taken up in ether. The ethereal solution was washed three times with 100-ml. portions of water, once with 10$ sodium thiosulfate solution and again with water. The crude olefin, 1.4 g. (67$), was recrystallized from acetone-ethanol to afford 1.2 g. (57$) of long, white needles of A^-cholestene, m.p. 73-73.5° (reported 74-75°).^ 2 <* . 3 o t . -Enoxvcholestane. This compound was prepared 46 31 33 according to the procedure of Fiirst. Perbenzoic acid, 14 ml* (0.55 g., 2.90 mmoles) was added to a solution of 2 n 1.0 g. (2*6 mmoles) of A -cholestene, m.p. 73-73.5 , in ,10 ml. of ether at -10°C. This temperature was maintained for 20 hours. The reaction mixture was diluted with 100 ml. of cold ether. The ethereal solution was washed 20 times iwith 25-ml. portions of 10$ sodium carbonate and twice with : water. After three recrystallizations of the crude product, ,1.2 g. (97$), from ether-ethanol there was obtained 0.50 g. (53$) of long needles, m.p. 102.5-104° (reported 105-1060)?1 Reaction of 2 <*.3 d-epoxycholestane with boron trifluoride etherate. To a solution of 0.35 g. (1.0 mmole) of I ^ 1 ~ " |2 ot,3 ot-epoxycholestane, m.p. 73-73.5°, in 10 ml. of dry benzene was added 0.31 ml. (2.9 mmoles) of boron trifluoride ! - ' (etherate. After mixing the change in optical rotation of the solution was as follows: Minutes L°°f2 obs 10 + 73.2 15 + 78.2 20 + 45.8 30 + 45.8 60 + 45.8 The reaction mixture was diluted with 25 ml. of dry benzene and washed with cold sodium bicarbonate solution. After evaporation of benzene, the infrared spectrum of the product 47 ! I shoved a strong absorption In the region 3630-3625 cm""* , (free -OH band of 1:2 diols is found to appear at ;3630 + 5) but no absorption in the 1650-2000 cm region* ! I | — : A -Cholesten-3-one. (a) By dehydrobromination of r 2oc_bromocholestan-3-one with lithium chloride in dimethyl- ;formamide1: A solution of 4*32 g. (2.32 mmoles) of impure 2 <*-bromocholestan-3-one, m.p. 145-157°, and 1.21 g. (31.4 mmoles) of lithium chloride (dried at 65° in vacuo) I in 40 ml. of dimethylformamide was heated at 120° for 24 ! hours under an atmosphere of nitrogen. The reaction mixture 'was then diluted with water and the organic compound was j 'taken up with ether. The ethereal solution was washed j i several times with water. After drying and evaporation of J i the ether solution, there was obtained a slightly yellow, partially crystalline product which after one recrystal lization from ethanol gave 2.34 g., m.p. 114-146°. The ;melting point was increased to 166-173° after the second l recrystallization. The qualitative ultraviolet spectrum of j presumably A^-choles;fcan-3-one showed no absorption above 210 m_M. The mother liquor from the first recrystallization i was evaporated, and there was obtained 0.62 g. of the I compound whose qualitative ultraviolet spectrum showed ! I maximum absorptions at 242 and 282 m/<. On chromatography A^-cholesten-3-one was eluted with benzene-petroleum ether (1:10) from activity II alumina. After one recrystallization from ethanol there was obtained 231 mg. (19$) of plates, m.p. 99-100° (reported*'* 98-100°), ^ max 232 m/A. ( £ 10*500) * • (b) By dehydrobromination of 2 -bromocholestan-3-one 2 ' with semiearbazide. A mixture of 1*66 g. (3.56 mmoles) of 2<<- —bromocholestan-3-one, m.p. 159-166° and 450 mg. (3.90 mmoles) of semiearbazide hydrochloride in 35 ml. of acetic acid was warmed on a steam bath for 0.5 hour. The reaction jmixture was diluted with water and the product was taken up I |with chloroform. The chloroform solution was washed once | jwith potassium hydroxide solution end worked up in the iusual way. There was obtained 1.42 g. (92.5#) of the crude | semicarbazone of A -cholesten-3-one which after one recrystallization from ethanol—chloroform gave 671 mg. (37#) j of semicarbazone, m.p. 225-228° (dec.)• The semicarbazone, 632 mg. (1.21 mmoles), was dissolved in 20 ml- of dioxane and 10 ml. of 45# sulfuric acid was added. The mixture was allowed to stand for 10-15 minutes and then diluted with water. ThO hydrolyzed product was extracted with ether. The ethereal solution was washed with water. Upon evaporation |of the dried ethereal solution there was obtained 612 mg. of: amber colored oil which after one recrystallization from l ethanol gave 487 mg. (88#) of A**cholesten-3-one, m.p. 92—99° which was not quite pure. Preparation of coprostan-3-one. A mixture of 2.00 g. (5.20 mmoles) of A^-cholesten-3-one, m.p. 78.5-79.5°, and 200 mg. 49 of 10$ palladium-on-carbon catalyst in 25 ml. of ethyl V’ acetate was stirred with a magnetic stirring bar in an atmosphere of hydrogen at atmospheric pressure. The amount of hydrogen uptake in 45 minutes was 143 ml, which was equal to one mole equivalent (theoretical 140 ml,). The solution was filtered and evaporated. Coprostan-3-one was isolated by chromatography on activity II alumina. There was obtained 1,22 g. of the crude product which after one recrystallization from ether-methanoli gave 1.01 g. (50$) of pure coprostan-3-one, m.p. 59.5-61.5°. 17 General procedure for Fischer indole syntheses with d -methylphenylhvdrazine. To a mixture of each ketone and d —methylphenylhydrazine in the molar ratio 1:3 was added an amount of polyphosphorie acid equal to twice the weight of ketone. The reaction mixture was then gradually heated over a period of 30 minutes in an oil bath. After being heated to the maximum temperature, the reaction mixture was cooled immediately and diluted with water. The organic product was taken up in ether. The ethereal solution was washed several times with water until the wash solution was neutral. The dried ethereal solution was evaporated to dryness and the product was recrystallized. Indole from cholestan-2-one (24). From 1.11 g. (2.90 mmoles) of cholestan-2-one (25), m.p. 131-132°, and 1.20 g. (9.90 mmoles of c*.-methylphenylhydrazine gradually heated with 2.46 g. of polyphosphorie acid to 216° was obtained 0.704 g. (54;$) of indole which had been recrystallized once from ethyl acetate, m.p. 178-182°. Three more recrystal lizations from the same solvent gave pure indole, white plates, m.p. 183-185°, Cefcl jj2 + 64.3° (c 1.02 chloroform). On admixture with the hydrogenation product of Schwenk*s compound, m.p. 193-195°, the mixed melting point was depressed to 154-186°. Ultraviolet spectrum: ^max 232 mju(e 38,000), 286 mju (* 7,760), and 292 my(£ 7,260). i es2 , Infrared spectrum: ' mav 738 cm (four, adjacent U l O A 13 hydrogens on aromatie ring)• Anal. Calcd. for C^BL^N (473.75): C, 86.19; H, 10.85; S., 2.95. Found: C, 86.41; H, 10.90; N, 3.08. Indole from cholestan-3-one (32). From 644 mg. (1.67 mmoles) of cholestan-3—one (4), m.p. 129-130°, and 875 mg. (7.20 mmoles) of -methylphenylhydrazine gradually heated with 1.85 g. of polyphosphorie acid to 210° was obtained 504 mg. of crude indole. Seven recrystallizations from chloroform-ethyl acetate gave 137 mg. (17.5$) of white, long needles of (32), m.p. 215-217°, + 67.7° (c 1.70 chloroform)• Ultraviolet spectrum: ^ max 232 my (g 35,400), 284 my (6 5,830), and 293 my (z 5,630). J CS2 -1 Infrared spectrum: r max 738 cm (four adjacent 13 hydrogens on aromatic ring)• 51 Anal* Calcd. for G34H51N (473.75): C, 86,19; H, 10*85. Found:, C, 85.78; H, 10.95. Indole from conrostan-3-one (33). From 438 mg.,(1.14 mmoles) of coprostan-3-one (29), m.p. 59.5-61.5°, and 450 mg. (3.70 mmoles) of -methylphenylhydrazine gradually heated with 1.30 g. of polyphosphorie acid to 210° was obtained 554 rag. (42.5$) of crude indole. The pure Indole (32) was isolated by chromatography on activity II alumina, using il:20 benzene-petroleum ether as eluent. Six recrystal- i jlizations from ethyl acetate-ethanol gave 86 mg. (15$) of > ‘ white plates, m.p. 151-153°, + 149° (c 1.67 chloro form). 1 Ultraviolet spectrum: A max 234 m>4. ( * 36,400), 286 m>* '(€ 6,360), and 294 mM- (£ 6,260)• .cs2 , Infrared spectrum: max and 738 cm (one peak from 4 adjacent H atoms on an aromatic ring).*® Anal. Calcd. for (473.75): C, 86.19; H, 10.85. Found: C, 86.54; H, 11.00. Indole from ^ 4—cholesten-3-one. From 566 mg. (1.45 i \ 4 o mmoles) of A -cholesten-3-one, m.p. 78,5-79.5 , and 800 mg. (6.60 mmoles) of <* -methylphenylhydrazine gradually heated with 1.62 g. of polyphosphorie acid to 150° was obtained the crude indole which after four recrystallizations from ethyl acetate gave 80 mg. (12$) of slightly yellow, long needles, m.p. 221-223°, OJ |4 - 22.4° (c 2.01 chloroform). Ultraviolet spectrum: Amax 242 rax (£ 23,620), 252 mj< 52 (£ 21,590), 260 ra m ( e 20,800), 283 m>t (€ 6,570), and 302 him (■6 5,520). ; CS2 -1 Infrared spectrum* * 738 cm (four adjacent u l a A hydrogens on aromatic ring). ^ Anal. Calcd. for C34H49N (471.74): C, 86.56; H, 10.47. Found: C, 86.14; H, 10.98. Indole from A^-.cholesten-3-one (31). From 645 mg. (1.68 mmoles) of A^-cholestea-3-one (3), m.p. 97—101°, and 930 mg. (7.70 mmoles) of -methylphenylhydrazine gradually heated with 1.89 g. of polyphosphorie acid to 180° was i obtained 703 mg. (53$) of crude indole. Five recrystal- ! " ' ' ' ' jlizations from chloroform ethyl acetate gave 160 mg. (28$) | of white plates of (31), m.p. 210-214°, +153° (c 1.62 chloroform). Ultraviolet spectrum:- * max 247 him ( £ 22,000), 308 m>t (£ 8,660), 321 m>t ( e 10,300), 336 m>t(£ 6,960), and 352 mm (e 6,100). cs Infrared spectrum: J 2 728 cm”' * ' , 736 cm”' * ' , 744 cm”* iDftX (triplet), and 765 cm”*. Anal. Calcd. for C34H49N (471.74): C, 86.56; H, 10.47. Found: C, 86.30; H,; 10.72. Hydrogenation of the indole from the reaction of A ^—cholesten—3—one with -methylphenylhydrazine. A mixture of 100 mg* (0.200 mmole) of the indole, m.p. 208-214°, and 30 mg. of 10$ palladium-on-carbon catalyst in 5 ml*, of 53 ! benzene was hydrogenated in an atmospheric hydrogenator while stirring with a magnetic stirring bar for 15 minutes. |The minimum amount of hydrogen absorbed was 4.5 ml. which jwas 72# of one equivalent. The solution was filtered and evaporated. There was obtained 95 mg. (95#) of the partially crystalline, slightly yellow, product which was recrystallized from chloroform-ethyl acetate to give 79 mg. (79#) of the indole, m.p. 192-194°, £*j24 _ 6#6< > (£ 2.13 chloroform)• The melting point was unchanged after the second recrystallization. On admixture with dihydro I iSchwenk's compound, m.p. 193-195 , the mixed melting point, |193-196°, was not depressed. i Ultraviolet spectrum: max 234 m^t ( 6 35,000), 286 m/< 1(4 6,480), and 296 m>* (* 6,310). ! J CS2 -1, Infrared spectrum: v 738 cm (four adjacent 13 hydrogens on aromatic ring) with slight shoulder at 724 cm"“^. APPENDIX Synthesis of cholestan-2-one was first attempted by treatment of 2 < * . ,3 -epoxycholestane with borontrifluoride ietherate since it involved fewer steps than a previous 30 synthesis. The reaction was followed through the change of optical rotation as done with epoxysteroids by 35 Henbest. The infrared spectrum of the crude product had absorption at ^ q^qi 3630-3625 cm”1 (hydroxyl), but no ® —1 absorption in the region 1725-1705 cm for 6 or 7 membered 36 ring ketone. Since an allylic alcohol could have been formed, the rearranged product was oxidixed with manganese i dioxide in chloroform, but no infrared absorption in the —1 37 ;region 1685-1665 cm for ,/s -unsaturated ketone was observed. The rearranged product was probably a diol which could be formed by hydrolytic ring cleavage if only a trace of water was present. 54 BIBLIOGRAPHY 1. R. P. Holysz, J. Am. Chem. Soc., 75, 4432 (1953). 2. V. R. Mattox and E. C. Kendall, J. Am. Chem. Soc., 70. 882 (1948); C. Djerassi, ibid.. 71, 1003 (1949). 3. A. Butenandi and A. Wolf, Ber., 68, 2091 (1935). 4. E. Schwenk and B. Whitman, J. Am. Chem. Soc., 59, 949 (1937). 5. H. H. Inhoffen, G. Zuhlsdorff, and Huang-Minlon, ' Ber., 73, 451 (1940). 6. L. Ruzicka, PI. A. Plattner, and R. Aeschbacker, Helv. Chim. Acta, 21, 866 (1938). i 7. A. Butenandt, M. Bannenberg, and M. Paland, Ber., 72, 1617 (1939). | 8. R. P. Jacobsen, J. Am. Chem. Soc., 62, 1620. (1940). 9. A. Butenandt and R. Bauer, Ber., 77, 397 (1944). 10. A. Wilds and C. Ojerassi, J. Am. Chem. Soc., 68, 1712 (1946). 11. C. Djerassi, J* Am. Chem. Soc., %1, 1003 (1949). 12. H. H. Inhoffen and Huang-Minlon, Naturwiss, 26, 756 (1938). 13. L. J. Bellamy, "The Infrared Spectra of Complex Molecules," John Wiley and Sons, Inc., Hew York, N.Y., 1957, p. 77. 14. R. A. Friedel and M. Orchin, "Ultraviolet Spectra of Aromatic Compounds," John Wiley and Sons, Inc., New York, N.Y., 1951, p. 338. 15. Ibid.. p. 192. 16. E. E. van Tamelen, S. H. Levin, G. Brenner, J. Wolinsky, and P. Aldrich, J. Am., Chem. Soc., 80, 501 (1958). 55 56 17. H. M. Kissman, D. W. Farnsworth., and B. Witkop, J. Am., Chem. Soc., 74, 3948 (1952). 18. B. M. Barclay and N. Campbell, J. Chem. Soc., 530 (1945). 19. W. Rossner, Z. Physiol., 249, 267 (1937). 20. L. F. Fieser and M. Fieser, “Steriods,t t Reinhold Publishing Corporation, New York, N.Y. , 1959, p. 282. 21. F. W. Heyl and M. E. Herr, J. Am. Chem. Soc., 75, 1918 (1953). 22. H. Brockmann and H. Schodder, Ber., 74, 73 (1941). 23. J. F. Eastman and R. Teranishi, Org. Syntheses, 35, 39 (1955). 24. E. B. Hershberg, E. Oliveto, M. Rubin, H. Staeudle, and L. Kuhlen, J. Am. Chem. Soc., 7£, 1144 (1951). 25. 0. Diels and E. Abderhalden, Chem. Ber., 37, 3092 (1904). 26. W. F. Bruce, Org. Syntheses, Coll. Vol. II, 139 (1941). 27. A. L. Wilds and C. Djerassi, J. Am. Chem. Soc., 68. 1712 (1946). 28. Bellamy, op. cit. * P* 34. 29. L. F. Fieser and X. A. Dominguez, J. Am. Chem. Soc., 75, 1706 (1953). 30. D. H. R. Barton and 0. H. Alt, J. Chem. Soc., 4284 (1954). 31. A. Fiirst and PI. A. Plattner, Helv. Chim. Acta, 32. 275 (1949). 32. J.C. Sheehan and W. F. Erman, J. Am. Chem. Soc., 79. 6050 (1957). 33. G. Braun, Org. Syntheses, Coll. Vol. I, 431 (1941) 34. Bellamy, oj>. cit.. p. 97. 35. H. B. Henbest and T. I. Wrigley, J. Chem. Soc., 4600 (1957). 57 36. Bellamy, oj>. cit., p. 147. 37. Ibid.. p. 136. UNIVERSITY OF SOUTHERN CALIFORNIA LIBRARY

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Creator Nonggai, Paetong Na (author)

Core Title The reaction of 22,42-Dibromocholestan-3-one with N,N-imethylaniline

Degree Master of Science

Degree Program Chemistry

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Permanent Link (DOI) https://doi.org/10.25549/usctheses-c17-797510

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