I. Synthesis of dl-cis-Tetrahydroeremophilone. II. Studies on Systems Free from Angular Strain Citation Murayama, Stanley Tetsu (1969) I. Synthesis of dl-cis-Tetrahydroeremophilone. II. Studies on Systems Free from Angular Strain. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/EF19-GE34. https://resolver.caltech.edu/CaltechTHESIS:03232017-140452739 Abstract I. The total synthesis of racemic cis-tetrahydroeremophilone (17) has been achieved. The key feature of the synthesis was a solvolytic cyclization that proceeded through a symmetrical cation 41 and gave rise to two major products, one of which had the stereochemistry required for the synthesis of tetrahydroeremophilone. II. Attempts on the synthesis of the alcohol 1 have been investigated in three related reaction sequences (Schemes 1, 4, 5, and 6). Although none of the reaction sequences gave the desired alcohol 1 that was intended for use in a solvolysis study, an unexpected product, the keto acetate 48, resulted in one sequence and afforded adamantanone (44) upon chromatography on alumina. Item Type: Thesis (Dissertation (Ph.D.)) Subject Keywords: (Chemistry) Degree Grantor: California Institute of Technology Division: Chemistry and Chemical Engineering Major Option: Chemistry Thesis Availability: Public (worldwide access) Research Advisor(s): Brown, Morris Thesis Committee: Unknown, Unknown Defense Date: 14 June 1968 Funders: Funding Agency Grant Number Caltech UNSPECIFIED NSF UNSPECIFIED Record Number: CaltechTHESIS:03232017-140452739 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:03232017-140452739 DOI: 10.7907/EF19-GE34 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 10102 Collection: CaltechTHESIS Deposited By: Benjamin Perez Deposited On: 24 Mar 2017 14:53 Last Modified: 03 May 2024 21:34 Thesis Files Preview PDF - Final Version See Usage Policy. 39MB Repository Staff Only: item control page

I. SYNTHESIS OF 2!,-£!!!,-TETRAHYDROEREMOPHILONE II. STUDIES ON SYSTEMS FREE FROM ANGULAR STRAIN Thesis by Stanley Tetsu Murayama In Partial Fulfillment of the Requirements For the Degree of Doctor of Philosophy California Institute of Technology Pasadena, California 1969 (Submitted June l4q 1968) ii ACKNOWLEDGMENTS The author is indebted to many persons who were helpful during the course of his graduate career: to Dr. Morris Brown for his guidance and advice throughout the course of this work; to Dr. David Chan for many fruitful discussions; to other members of the staff and to fellow graduate students at the California Institute for making a graduate education in Pasadena an enlightening experience; to Steve and Rita Baldwin for the preparation of the manuscript of this thesis; and to Dana Roth for his help in proofreading the manuscript. Financial support from the California Institute and from the National Science Foundation is gratefully acknowledged~ iii ABSTRACT I. The total synthesis of racemic cis- tetrahydroeremophilone (17) ,.,,..,.... has been achieved. The key feature of the synthesis was a solvolytic cyclization that proceeded through a symmetrical cation ,.,,..,.... 41 and gave rise to two major products, one of which had the stereochemistry required for the synthesis of tetrahydroeremophilone. II. Attempts on the synthesis of the alcohol 1 have """ been investigated in three related reaction sequences (Schemes 1, 4, 5, and 6)~ Although none of the reaction sequences gave the desired alcohol l that was intended for use in a solvolysis study, an unexpected product, the keto acetate 48, resulted in one sequence and afforded adamantanone (44) upon chromatography on alurninae .r.r. iv TABLE OF CONTENTS Page r. SYNTHESIS OF dl-cis-TETRAHYDROEREMOPHILONE 1 INTRODUCTION 2 DISCUSSION AND RESULTS 8 The Monocyclic Dienone 19 8 The Solvolytic Cyclization 10 Conversion of Alcohol 43 to cisTetrahydroeremophilone"""" 15 CONCLUSION 23 EXPERIMENTAL 24 Cyclopropylmethylcarbinol(27) . 24 """"' Preparation of trans-1-Bromopentene-3 (21} 25 Preparation of 4-Carbomethoxy-3-methyl-5isopropyl-2-cyclohexen-l-one (20) 25 Alkylation of 4-Carbomethoxy-3-methyl-5isopropyl-2-cyclohexen-l-one (20) 27 Preparation of Dienol 38 30 """"" ~ """"- ~ Formolysis of Dienol 38 ~ Preparation of Trienes 39 30 31 ~ Formolysis of Trienes 39 32 Reductive Cleavage of Formates 40 33 Chromatographic Separation of Alcohols 42 and 4 3 """"' 34 Preparation of 3,5-Dinitrobenzoate ,...,..,... 44 35 Reductive Cleavage of 3,5-Dinitrobenzoate 44 36 Ketone 49 37 v Page Olefin 50 37 Photo-oxidation of Olefin 50 A. Hematoporphyrin-pyridine 38 B. Rose Bengal-Carbon DisulfideMethanol-Ether 39 Ozonolysis of Crude Allylic Alcohol 51 40 Dehydration of Ketol 52 41 Ketone 55 41 Olefin 56 42 """""' ~ """""' Photo-oxidation of Olefin 56 ~ The Preparation of dl-Ketol 58 .rv"V'o 43 44 Dehydration of Ketol 58 """""' A. With Thionyl Chloride 45 B. Wi·th Phosphorous Oxychloride 46 Preparation of Keto Acetate _..,.. 59 46 Preparation of dl-cisTetrahydroerernophi!one (17) 47 ~ Preparation of d-cisTetrahydroeremophilone (17) ~ REFERENCES II. 48 50 STUDIES ON SYSTEMS FREE FROM ANGULAR STRAIN 52 INTRODUCTION 53 RESULTS AND DISCUSSION 56 Preparation and Reaction of Amine 8 ""'" (Scheme 1) 57 Preparation and Reaction of .Amines ,..,,... 9 and 10 (Schemes 3 and 4) 62 ~ vi Page Preparation and Reactions of Amines 11 and 12 (Schemes 5, 6, and 7) """"" · 67 CONCLUSION 80 EXPERIMENTAL 81 Preparation of cis- and trans- Quinitol (15) 81 Preparation of 1,4-Cyclohexadione (13) 81 Preparation of l,4-Dioxaspiro[4.S]decan8-one (7) 82 Preparation of Enamine 17 84 Alkylation of Enamine 17 with Acrolein 85 Preparation of Morpholino Ketone 20 85 Preparation of Amine 22 86 ~ """"' """"- '"""""" ~ ~ Amine Oxide 23 Pyrolysis 86 24 Preparation of Morpholino Ketone ,.._,....,.... 87 Amine Oxide Elimination on Amino Ketone 24 88 Morpholino Ketone 21 88 ~ """"" Preparation of Amine 25 "'-"'"' A. From Morpholino Ketone ,....,...,.. 21 89 B • . Preparation from Morpholino Ketone 24 89 Bicyclo[3.3.l]non-2-ene (26) A. From Amine ,..,,,........ 25 90 ~ Preparation of 1-Dimethylaminocyclohexene (28) A~ Calcium Hydride Method 91 B. Lithium Aluminum Hydride Method · 91 Preparation of Amino Ketone 29 91 Preparation of Amine 9 92 Bicyclo[3.3.l]non-2-ene (26) B. From Amine 9 ,...,...,...,.. ""' 92 vii Page Preparation of Enamine 32 93 ~ Dimethylamino Ketone 33 93 Wolf f-Kishner Reduction of Dimethylamino Ketone 33 94 Preparation of 8-Methylene-1,4dioxaspiro [4 .SJdecane (35) 95 """"' Preparation of 4-Methylenecyclohexanone (38) 97 Preparation of Enamine 39 98 Preparation of Morpholino Enone 40 99 Preparation of Morpholino Olefin 41 100 Hydroboration of Morpholino Olefin ,,...,...,.... 41 101 Acetylation of crystalline Amino Alcohol 42 102 ~ Amine Oxide Elimination on Crystalline Amino Acetate 46 Ae In Toluene at 110° 102 Be In DMSO at 90o 104 Acetylation of Liquid Amino Alcohol 43 104 Amine Oxide Elimination on Crude Acetate 49 105 Purification of the Acetate Mixture 50 106 Reductive Cleavage of Crude Acetate 50 108 Purification of Crude Alcohol ,.,..,,.. 45 109 111 REFERENCES PROPOSITIONS Proposition 1 114 Proposition 2 119 Proposition 3 125 viii Proposition 4 129 Proposition 5 133 PART I THE SYNTHESIS OF dl-cis-TETRAHYDROEREMOPHILONE 2 INTRODUCTION Erernophilone ,Gl' a non-isoprenoid sesquiterpene, has attracted the interest of chemists who are engaged in the elucidation of the structure of natural products, and also those who are working in organic synthesis. The molecular constitution of !-eremophilone ,,U:J. has been determined by Simonsen (1,2) and Djerassi (3,4) and 0 1 their co-workers. An important feature of structure ,...,.... 1 is the appearance of a ~-methyl group at CS ~ At some stage in the biogenesis of the eremophilane sesquiterpenes from farnesol (2) ,.,...,.... (Sa), possibly by way of an intermediate such as neo- intermedeal (3) (Sb), the methyl """""' group originally at c 10 in 2._has migrated to c 5 , as illustrated in a possible eremophilone precursor ,...,.... 4. Therefore, the rearranged structures do not follow the isoprene rule (6), which states that the structures of terpenes are composed of five-carbon isoprene units, 3 which are linked head-to-tail or tail-to-tail. OH 2 3 ,,...,... ~~~~~)>- Eremophilane sesquiterpenes The importance of eremophilone (1) as a natural ~ product has become enhanced recently, since it heads a rapidly expanding list of eremophilone sesquiterpenes. The skeletal characteristics of this class of sesquiterpenes is demonstrated by the following illustrative examples: eremophilone (l); hydroxyeremophilone (5) ,,...,..,... (3): furanoeremophilane (6) (7 ,8) 1 nootkatone (7) (9) 1 ~ ~ aristolene (8) ~ (10) 1 and a-ferulene ,,...,..,... (9) ~ (11) e The latter two compounds, qeing optical isomers, are included to illustrate the occurrence of some eremophilane sesquiterpenes in optically antipodal formsg 4 5 6 8 """" 7 9 """" As the discovery of new types of eremophilane sesquiterpenes has increased, attempts.at the total synthesis of these natural products have also been expanded. The first compounds related to eremophilone to have been synthesized (4) were ketone 10, which has """" the eremophilone stereochemistry, and ketone 11, which """" is a degradation product of eremophilone and has the hydroxyeremophilone stereochemistry. 10 """" Although neither 11 ~ 5 of these two ketones has been found in nature, they have played an important role in the assignment of the absolute configuration of eremophilone and related sesquiterpenes. Another degradation product of eremophilone ,ll..lr enone 12, has been prepared in racemic form by Piszkiewicz """"' (12). The main feature of this synthesis is a Michael reaction, which introduces all the asymmetric centers simultaneously, albeit in low yields. NaOMe,MeOH 700, 6 hrs.) 5% yield 0 Several steps > 12 ,,.,,.... The total synthesis of racemic isonootkatone ,,U.JJ, which contains only two asynunetric centers, has been reported by Marshall and co-workers (13)e This compound represents the first synthesis of a naturally occurring eremophilane sesquiterpene to be reportede The synthesis of racemic 4-demethylaristolone (14) has been successfully ~ completed (14), and also progress has been reported on 6 the total synthesis of aristolone ~· 13 ,..,...,... 14 15 """"" ~ The present work was initiated in an effort to prepare by solvolysis a symmetrical cation .,..,...,... 16, which would cyclize to give three ~-alkyl groups on an octalin carbon skeleton and would thereby lead to the synthesis of tetrahydroeremophilone 17 or dihydro"""" eremophilone 18e The results of this study are discussed """""' below in three sections. 16 ,,....,...,.. The first phase describes the 17 ,,....,...,.. 18 .,..,...,... preparation of the monocyclic dienone ,,....,...,.. 19, which was previously prepared by Chan (15} in this laboratory. Chan's work is summarized here in order to present a complete account of these synthetic studies. The second 7 19 .,...,..,... phase concerns the solvolytic cyclization, and the third phase describes the successful conversion of one product of the cyclization into racemic cis-tetrahydroeremophilone (17) 0 ~ 8 DISCUSSION AND RESULTS The Monocvclic Dienone ,,..,,.. 19. The first key mono- ~ ~ ~ cyclic intermediate was the dienone l2.., which was prepared by Chan (15) by the alkylation of enone ester 20 with trans-1-bromopentene-3 {21). """""' ._...,... The enone methyl ester 20 was prepared in quantity by Chan (15) who used """""' a modification of the procedure of Horning and coworkers (16) for the preparation of the corresponding ethyl ester. The condensation of two moles of methyl aceto- acetate with one mole of isobutyraldehyde in the presence - of piperidine catalyst yielded a monocyclic bis-ester 22, ,,...,... which was partially hydrolyzed and decarboxylated in the presence of sulfuric and acetic acids to give a mixture of enone esters in 69% yield. Vapor phase chromatography (v.p.c.) indicated the following composition of the ester mixture: 5% of 3-methyl-5-isopropyl-2-cyclohexen-l-one (23), 17% of 4-carbomethoxy-3-methyl-5-isopropyl-3- ~ - cyclohexen-1-one (24), and 78% of cis- and trans-4~ carbomethoxy-3-methyl-5-isopropyl-2-cyclohexen-l-one (20) • """""' Since all three enone esters {cis-20, trans-20, and 24) .,.,..,... """' """ would lead to the same enolate anion 25 upon treatment with - ~ a strong base, further purification at this stage was not necessary .. 9 In order to prepare the bromide ,,.,.,.. 21 that was required for the alkylation of enolate ,,.,.,.. 25, the procedure of Julia and co-workers (17a) was used by Chan (15). However, in another preparation by this author cyclopropylmethyl ketone (26) was reduced with lithium ,;v...,r.. aluminum hydride according to the procedure of Overberger and Borchert (17b) to the corresponding cyclopropylrnethylcarbinol ClZJ (96% purity) • The product analysis was done by v.p.c. on a Carbowax 20M columno When a sample of carbinol 27 (96% 27, 4% 26) was stirred with ,,...,,,, """ ,,.,,.. 48% hydrobromic acid for 10 min. at 25°, a mixture containing 5% ketone 26, 9% olefin, 50% bromide 21, and ~ ~ 36% of a second bromide 28 was obtained by v.p.c. analysis. """' However, bromide ~was converted completely to bromide~ when the mixture was filtered through a short column of alumina (I) e . Since Chan (15) observed cyclopropyl hydrogens in the n.m.ra spectrum in his preparation, bromide 28 is probably cyclopropylmethylcarbinyl bromide, a product ,,.,.,.. that was observed in the reaction of phosphorous tribromide with carbinol ,,.,,.. 27 {18)~ The alkylation of enone esters ,,.,.,.. 20 and ,,.,,.. 24 with bromide ,,.,.,.. 21 was conducted by Chan (15) with the use of sodium hydride in benzene-dimethylformamidee A 5:1 ratio of c-alkylated ester _.,,,... 29 to o-alkylated ester _..,..,, 30 was produced (54% yield). The mixture of esters _,..,.,,.. 29 and 30 was ~ 10 saponif ied mildly with potassium hydroxide in aqueous methanol. The neutral material isolated from the reaction consisted largely of the 0-alkylated ester ,...,...,... 30, and the alkaline residue gave crude acid ,...,...,... 31 upon acidification with hydrochloric acid in 72% yield. The crude acid 31 was decarboxylated thermally at 100-140 0 under water aspirator pressure to give a 77% yield (30% overall from esters 20 and 24) of the desired dienone 19, b.p. 90-92 ,...,...,... _...,... 0 ,IV\, (O.S mm.) .. The Solvolytic Cyclization. Solvolytic cyclizations ,,..,..,..,... of polyolef ins are established methods for the preparation ~ ~ of substituted octalins that are important intermediates in the synthesis of natural products. Johnson and co- workers (19, 20) have studied the cyclization of the dienol 32, which cyclizes in the direction of the secondary carbon """" rather than the tertiary carbon of the allylic cation _...,... 33 to give formate 34e Furthermore, by using the methyl """' homolog, Marshall and co-workers (21, 22) have shown that ) """"'ocHo OH 32 ,..,..,.... 33 ~ 34 _...,... 11 CHART A -22 H2 so 4 + > HOAc + 0 0 20 NaH 2 0 , 24 ""'" ""'" -- 24 23 ~ """"'" ~Br > 21 > AA + 0 29 ,,....,...,... 1) KOH 29 """"'" 2) HCL 30 ~ > 0 -31 -19 12 the dienol 35 readily cyclizes by way of the symmetrical ~ cation 36 to the octalyl ester -..,..;, 37, which has the angular ~ methyl group that is found in many sesquiterpenes and higher terpenes. > 35 \\'''OCHO > 36 37 """""' """""' One of the goals of our work in the synthesis of eremophilone-like structures is the formation of the three asymmetric centers of the bicyclic system in one solvolytic reaction. If an isopropyl group is added to the ring at c , and the butenyl side chain is extended to 5 a trans-3-pentenyl moeity, the symmetry of cation ,,...,.... 36 is retained. Because the dienol --. 38 or triene 39 ,,...,.... has a trans- double bond in the side chain, the solvolysis product 40 ,,...,.... from these precursors should contain two ~-methyl groups. For our purposes, a £1!-isopropyl group is required at c .. 7 There is a possibility that the isopropyl group may influence the stereochemistry of the methyl groups, since the carbonium ion can suffer nucleophilic attack by the double bond on either the surface syn to the isopropyl 13 group or on the ~-surface. An ~-attack will produce the desired all-~-arrangement of the alkyl groups, while a syn-attack will give an isopropyl group trans to the angular methyl group. OH 38 39 40 ~ ~ ~ CH 3 ~ ) CH3 CH ~ CH3 H 3 41 ,.,.,...,.. 41 ,,..,..,.... Anti-attack Syn-attack The c-1s ketone 19 was alkylated with methyl~ lithium to give the C-16 carbinol ,,...,..,... 38 that would generate a symmetrical allylic cation ,..,,..,... 41 upon treatment with formic acid. In the initial experiments when carbinol ,...,..,.. 38 was stirred in anhydrous formic acid~ a rapid dehydration to olef ins occurred first, as evidenced by the separation of an oily layer. Cyclization then occurred to give a 14 mixture of formates. In later experiments the alkylation of the C-15 ketone 19 was followed immediately by phosphorous oxychloride-pyridine dehydration to afford two trienes 39, ,..,,... on the basis of infrared Cir. · and v.p.c. analysis. The triene mixture ,..,,... 39 was stirred with anhydrous formic acid at 25° for 20 min. to produce a mixture of formates, which was crudely separated from olef ins and diformates by chromatography on Florisil. The crude formates 40 .,...,... obtained in 67% yield, were reduced with lithium aluminum hydride to yield two alcohols 42 and 43 ~ """'" in a ratio of 3:2. Careful chromatography on alumina (IV) yielded a crystalline alcohol ,,..,... 42, m.p. 91-93°, and an impure oily alcohol, which was purified by conversion to the 3,5-dinitrobenzoate 44. ,,...,... After having been recrystal0 lized from hexane, the ester 44, ,..,,... m.p. 117-119 , was reduced with lithium aluminum hydride to afford a second crystalline 0 alcohol .,,..._.. 43, m.p. 47-54 • The stereochemical assigmnent of these alcohols is based upon the conversion of alcohol 1J. to £l;!-tetrahydroeremophilone QJ.>, which is known to possess the all-~-configuration. The alpha orientation of the hydroxyl groups is supported by the findings of other workers (20, 21, 22) on related cyclizations and by the nuclear magnetic resonance (nemer.) splitting pattern of the c 3 hydrogen of the benzoate derivative of 13., and 15 and the 3,5-dinitrobenzoate 44. With both esters the C 3 ~ hydrogens appear as triplets (~ 2 = 10 Hz.) that are split = 4-5 Hz.). 1 This splitting pattern is consistent for an axial hydrogen into sextets by a smaller coupling constant (J adjacent to two other axial hydrogens and one equitorial hydrogen on a six-membered ring. 42 ~ 43 ,,...,...,... The transformation of the C-16 alcohol .,...,.. 43 to tetrahydroeremophilone required first the removal of the oxygen function at c • In order to remove the sixteenth carbon 3 by ozonolysis, the next step was to convert the methyl substituted double bond into a function containing an exo- cyclic methylene group by photo-oxidation. Marshall and co-workers (22, 23) used the hematoporphyrin sensitized photo-oxidation of methyl substituted double bonds in pyridine followed by lithium aluminum hydride reduction of 16 the hydroperoxides as a means of generating allylic alcohols 45, 47 from olefin """"""' 48. ,,..,.... 46, ,,..,.... and -... Forbes and Griffiths (24) reported a method of photo-oxidation that + 45 ,,..,.... 48 """' product ratio 9 . 46 ,,..,.... 47 ,..,.... 5 6 used rose bengal or hematoporphyrin as sensitizer in a solvent system composed of carbon disulfide, methanol, and ether in a ratio of 28:2:3. The advantages of this modifi- cation were the shorter reaction time {one to two hours} that was required for tetrasubstituted double bonds, the use of an incandescent light source, and the excellent yields of allylic peroxides obtainedo In the first series of reactions the isomeric alcohol 42 was oxidized with chromic acid (25) to the ketone 49, Wl.ich was reduced (26) to the olefin SOo When """"' ,..,.... olefin was photo-oxidized with hematoporphyrin in pyridine, a very complex mixture of products was obtained. However, when the modification of Forbes and Griffiths (24) was 17 42 49 ""'" 50 -.. ""'" 1)03' MeOH l /~/fl 02, hv ) ) Sens., 2)Zn, HOAc 51 -.. 52 -.. 52 -.. 54 -.. 53 ,,...,.. 18 used with rose bengal sensitizer in carbon disulfidemethanol-ether, the oxidation proceeded smoothly within two hours at 10° to give, after lithiu.~ aluminum hydride reduction, a mixture that contained two major allylic alcohols. After the most abundant component was purified by chromatography on Florisil, the allylic alcohol 51 was """"' treated with excess ozone in methylene chloride-methanol at -70°. Reduction of the ozonide with zinc dust in acetic acid afforded 1 after chromatography on Florisil, a low yield of ketol 52, m.p. 98-103°. The major product """"' appeared to be a keto ester 53 resulting from oxidative Ny'- ring fission. The ketol ~ when stirred with thionyl chloride-pyridine (27), smoothly underwent dehydration to give an .a,~-unsaturated ketone 2!r which was not dihydroeremophilone .,...,...,.. 18 by ir. analysis • After the model reactions were completed, the isomeric compounds were investigated. Alcohol .,..,...,.. 43 was oxidized with chromic acid in acetone(25) to afford ketone 57, b.p. 115-120° (l ~' in 98% yield. ,,...,... Wolff-Kishner reduction (26) of ketone ~ gave olefin i€ 1 b.p. 90-95° co.a mm.), in 71% yield. After clef in ~ was photo-oxygenated for two hours with rose bengal sensitizer and a 300-w. tungsten lamp at s0 in carbon disulfide-methanol-ether (24), lithium aluminum hydride reduction of the photoproduct gave a crude 19 43 1)0 2 , hv > 2) LiAlH 56 ,....,..,.. 55 ~ ~ ) 2)Zn, HOAc 4 57 58 -.. ~ Ac 2 o ~ Ca, 17 ~ > 20 allylic alcohol 57, which was used without further ~ purification. Immediately after the crude alcohol was subjected to ozonolysis by addition to one equivalent of ozone dissolved in methylene chloride at -10° according to the procedure of Johnson an<l co-workers (28), zinc dust and acetic acid were added to reduce the ozonide. Chromatography on Florisil gave ketol .,...,..,... 58, m.p. 70-71°, in 45% yield. The stereochemistry of ketol 58 is based ,,...,... upon previous work (21, 23), which showed that the oxygenation is expected to occur from the less hindered side of the molecule. An attempt to dehydrate the ketol 58 ~ with thionyl chloride-pyridine gave rearranged dehydrated products as evidenced by infrared spectral analysis. Phosphorous oxychloride-pyridine at 25° gave back starting Because the a-isopropyl group at c ketol 58. 7 L~poses considerable steric strain on the trans-fused product, the relief of steric strain may be the decisive factor for the trans-diaxial methyl migration to supersede the transdiaxial removal of a proton. Since the amount of ketol ~ on hand was small, the dehydration or an acetate pyrolysis (29) wan not examined in further detail. Ketol 58 was acetylated with acetic anhydride and ~ phosphoric acid (30) to afford the corresponding keto acetate 59, m.p. 46-48°, in 44% yield. ~ When the keto 21 acetate 59 was subjected to calcium and liquid ammonia """' - reduction {3), racemic cis-tetrahydroeremophilone {17) was produced in 84% yield. """"' The ir. spectrum of the racemic ketone 17 was identical in all respects to the """' ir. spectrum of the d-ketone 17 that was prepared ~ according to the procedure of Djerassi and co-workers. {3). The iro spectra are shown in Figure 1. The v.p.c. retention times of the racemic ketone and the d-ketone 17 ""' were identical by the peak enhancement method. The ir; spectra of the racemic 2,4-dinitro-phenylhydrazone 60, ~ m.p. 141-143°, and 2_-2,4-dini.tro-phenylhydrazone ~ m.p. 181-183°, lit. m.p. 178-179° (1) and 179-180° (31), were identical. ~ ~ ~ H :::> .t:.l ~8 ti) H ~ 8 ES :z: 0 Figure 1. 3 5 6 8 WAVELENGTH (MICRONS) 7 9 10 11 Hand-drawn tracing of the infrared spectra of d- and dl-cistetrahydroeremophilone. ~ --- 4 12 dl d N N 23 CONCLUSION The total synthesis of racemic ~-tetrahydro­ eremophilone (17) has been accomplished. """" The key feature of the synthesis is the solvolytic cyclization, which proceeds through a symmetrical cation 41 and gives rise ./'V". to two major products. Since one of these products has three ~-alkyl groups, the cyclization reaction can be used to prepare eremophilone-like sesquiterpenes. The ancillary goal of this work to prepare dihydroeremophilone 18 has been unsuccessful to date1 however, its preparation """" from keto acetate 59 may be possible by an acetate ~ pyrolysis reaction. 24 EXPERIMENTAL Melting points (m.p.) were determined on a Reichert melting point hot stage and are corrected. (b.p.) are uncorrected. Boiling points Infrared {ir.) spectra were determined on a Perkin-Elmer Infracord Model 137 spectremeter. Nuclear magnetic resonance (n.m.r.) spectra were obtained on a Varian Associates A-60A spectrometer and are given in delta (o), parts per million (p.p.m.) downfield from tetramethylsilane. Vapor phase chromatography {v.p.c.) was performed on a Perkin-Elmer Model 881 Chromatograph with a hydrogen flame detector. The activity of the alumina used for chromatography was standardized according to the procedure of Brockmann and Schodder {32) • Microanalyses were performed by Spang Microanalytical Laboratory, Ann Arbor, Michigan, and Galbraith Laboratories, Inc., Knoxville, Tennessee. 27. ,,....,.. A. ,,....,.. The procedure of Julia and co-workers (17a) was used by Chan {15) to prepare carbinol 27. ,...,..., B. ~ The procedure of Overberger and Borchert (17b) was used by this author to prepare carbinol ,,..,,.. 27: b.p. 118-120°, 1it. b.p. 123123.5° (17b). 25 ~~trans~ CU,). A modification of the procedure of Julia and co-workers (17a) was used. A 76.6-g. (0.89 mole) sample of cyclo- propylmethylcarbinol 27 {96% 27, 4% 26 by v.p.c.) in A.IV'. """" """" 100 ml. of ether was treated with 200 ml. of 48% hydrobromic acid. After the reaction was stirred for 20 min. at 25°, the aqueous layer was separated and extracted with two 100-ml. portions of pentane. The combined organic extract was washed with water, saturated sodium bicarbonate solution, water, and finally saturated brine. The extract was dried over anhydrous magnesium sulfate, filtered, passed through a short column of alumina (I), and then concentrated by distillation through an eight inch Vigreaux column. The concentrated bromide was distilled through a four inch Vigreaux column to give 94.1 g. colorless, crude trans-1-bromopentene-3 1310, lit. b.p. 125-126° (17a): v.p.c. (71%) of (~): b.p. 114- (6 ft. of 2% Carbowax 20M) 85% bromide 21, 5% ketone 26, ,,..,,.. and 10% olefin. ~ This bromide mixture was used without further purification. 2-c The procedure of Horning and co-workers (16) for the preparation of 4-carboethoxy-3methyl-5-alkyl-2-cyclohexen-l-ones was adapted for the synthesis of the corresponding methyl ester (15). 26 In each of three 500-ml. flasks were placed 186 ml. (186 g., 1.6 mole) of methyl acetoacetate. The flasks were chilled in an ice-salt bath, and 70 ml. (55.S g., 0.77 mole) of isobutyraldehyde were added to each flask. The contents were cooled to o0 , and 2 ml. of piperidine in 5 ml. of ethanol were added to each flask with shaking. After the flasks were kept in an ice-salt bath for 6 hr., the contents were combined and placed in a refrigerator. The mixture was kept in the refrigerator for two days and finally kept at 25° for one day; a mixture of 3-ml. piperidine and 5-ml. ethanol was added each day during this time. The crude !?,i!-ester (yellow oil) was added to a mixture of 600 ml. of acetic acid and 40 ml. of concentrated sulfuric acid. A 10-g. portion of boiling chips was added, and the mixture was heated under reflux for 1 hr.1 during this time there was a vigorous evolution of carbon dioxide. The mixture was poured with mechanical stirring into 2 1. of ice water and extracted with ether. The organic layer was stirred with 1.2 1. of water and neutralized by the slow addition of solid sodium carbonate. The ethereal solution of the crude material was washed with 100-ml. portion of 5% sodium hydroxide, dried and crudely distilled under reduced pressureQ The fraction boiling at 94-110° co.s-o.7 mm.)u 364 g. (78%), was fractionated through a 27 six inch Vigreaux column yielding 320 g. (69%) of yellow oil: b.p. 92-97° (.15mm.)1 v.p.c. (6 ft. of Carbowax 20M) indicated a mixture of 5% of 3-methyl5-isopropyl-2-cyclohexen-l-one, 17% of 4-carbomethoxy3-methyl-5-isopropyl-3-cyclohexen-l-one and 78% of cisand trans-4-carbomethoxy-3-methyl-5-isopropyl-2-cyclohexen-1-one. 2-c clohexen-1-one ~· by Chan (15). This preparation was performed A 8.16-g. (0.34 mole) portion of sodium hydride, which was prepared by washing 13.9 g. of commercial sodium hydride (58.6% mineral oil dispersion) with dry pentane, was suspended in a solution of 300 ml. of dry benzene and 100 ml. of dry dimethylformamide (DMF) and maintained under a nitrogen atmosphere. A 73.56-g. sample (0.35 mole) of 4-carbornethoxy-3-methyl5-isopropyl-2-cyclohexen-l-one (20) in 30 ml. of dry .IVV'benzene was added over a period of 45 min. with cooling in an ice bath. After the addition was completed, the resulting solution was stirred for another 45 min., until the reaction was deep red and homogenous. A solution of so.2 g. {0.34 mole) of trans-1-bromopentene-3 (21) ,,...,.,.. in 25 ml. of benzene was added rapidly, and the resulting mixture was stirred at 25° for 57 hr~ The inorganic salt 28 was removed by filtration, the filtrate was washed with a 300-ml. and 100-ml. portion of water. The aqueous washings were back extracted with three 50-ml. portions of benzene. The combined benzene extract was washed with 100 ml. of water, 100 ml. of brine and dried over anhydrous magnesium sulfate. Distillation gave 50.49 g. (54%) of the desired alkylated products as a pale yellow oil: b.p. 125-133 0 (0.2 mm.): v.p.c. (6 ft. of Carbowax 20M) 83:17 ratio of C-alkylated to 0-alkylated products contaminated by traces of starting materials. The 50.49-g. products was (0.18 mole) sample of alkylation dissolved in a 100 ml. of methanol, and the solution was cooled in an ice bath~ A solution of 14.43 g. of potassium hydroxide in 50 ml. of methanol and 15 ml. of water was added with stirring. Since the solution turned cloudy at the end of the addition, a 20-ml. portion of methanol was added to insure homogeneity. The reaction was stirred at 25° for 15 hr. and then at 46° for 2 hr. The methanol was removed on the rotary evaporator to yield a deep red oil. A 250-ml. portion of water was added, and the resulting solution was extracted with two 100-ml. portions of ether to remove any neutral material. The combined ethereal extract was washed with water, dried over magnesiu.~ sulfate, filtered and evaporated on the rotary evaporator to give 14.56 g. (29%) of neutral oil, which was largely 29 the o-alkylated product on the basis of the n.m.r. spectrum. Distillation gave a forerun of 2.62 g. of low boiling material, b.p. 60-117° (0.8 mm.), and 12.36 g. of the o-alkylated product: b.p. 117° (0.8 mm.); ir. (film) S.90 (ester), 6.10 (C=C), 6.40 (C=C) and 10.35 (trans C=C)1 n.m.r. o0.82 (d., 6, ~ = 6 Hz, i-propyl CH3), 1.65 {d., 3, - - J - = 4 Hz., CH-3 C=C), 2.13 (s., 3, ring c~ C=C), 3.62 (s., 3, 3 (t., 2, ~ 3 c~ o), 3.74 = 7 Hz., OCH2CH2), 4.81 (s., 1, ring C~=C) and 5 • 4 5 p .. p .ms (m. , 1, CH=C) • Anal. Found: Calcd. for c 17 a~ 6 o 3 : C, 73.351 H, 9.41. c, 73.24: H, 9.46. The alkaline, aqueous solution was acidified with cold 7 ~ hydrochloric acid and extracted with two 100-ml. portions and one 50-ml. portion of ether. The combined ethereal extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated on the rotary evaporator to yield 36 g. (72%) of crude acid 31: ir. (film) 5.78 (COOH), 5.82 (COOH), 6.00 (enone), 6.10 (C=C) , and 10. 35 µ : (trans C=C) • The 36-g. sample of crude acid was heated from 1001400 (20-30 mm.) for a period of 30 min., while carbon dioxide evolution ensued. Distillation gave a forerun of 3.83 g. of low boiling materia~, b.p. 63-83° (0.5 mm.), 30 and 23.3 g. (77%, 30% overall from keto ester 20) of monocyclic dienone 19: b.p. 90-92° (0.5 nun.), ir. 6.00 (C=O), 6.13 (C=C), and 10.38µ n.m.r,. ~ = 3 Hz., c~3 CH=C}, 1.90 (s., 3 Cm., 2, (trans C=C): !!". = 6 Hz., C!!JCHC!!J), 1.60 (d., 3, 0.92 (d., 6, 5.33 p.p.m. (film) C~=C~)1 ring vinyl C~), and 1 v.p.c. (6 ft. Carbowax 20M) Calcd. for c15 H24 o: c, 81.76; H, 10.98. 95% purity. ~· Found: c, 81.63: H, 10.83. Preparation of Dienol 38. A 2.20-g. (10.0 mmoles) """ sample of dienone 19 was dissolved in 20 ml. of dry ether ~""" ~ ~ and treated with a 7.0-ml. (12 nuuoles) portion of 1.6 M solution of methyllithium in ether. After the reaction was stirred at 25° for 8 hr., a saturated solution of sodium sulfate was added. After another hour the ethereal solution was filtered and concentrated on the rotary evaporator to give 2.44 g. (100%) of crude dienol ~: 6. 03 (C=C), and 10. 39 p (trans C=C) • ir. (film) 2.97 (OH), The crude dienol 38 """ was used without further purification. Forrnolvsis of Dienol 38. ~~~~ To a 2.12-g. (9.00) mmoles) sample of crude dienol 38 was added with stirring 40 ml. ~ of anhydrous formic acid. After 1.5 min. the reaction was poured into an ice-cold solution of 44 g. of sodium hydroxide in 400 ml. of water. The neutral solution was 31 extracted with ether; and the ethereal extract was washed successively with saturated sodium bicarbonate solution and saturated brine, was dried over anhydrous magnesium sulfate, filtered, and concentrated on the rotary evaporator to give 2.28 g. of oil. Distillation gave a 0.3-g. forerun of mainly olefin 39: """ b.p. 75-76° (O.l mm.); ir. (film) 3.24 (vinyl CH), weak S.78 (formate contaminant), 6912 (C=C), 6.21 (C=C), and 10.38 ~· (trans C=C) • The main distillate was ·1.7 g. (72%) of formates 40: b.p. 76-90° (0.1 nun.); ir. {film) 3.66 (formate CHO), 5.78 (C=O), and 8.45µ (C-0}. Preparation of Trienes 39. A s.oo-g. (22.7 mmoles) ~--~~ -- sample of monocylic dienone 19 (~5% pure by v.p.c.) dissolved in 10 ml. of anhydrous ether was treated with 16 ml. (26 nunoles) of 1.6 ~ethereal methyllithium at 25°. After being stirred for 30 min., the alcoholate was converted to olefins by the dropwise addition of 2 .. 0 g. (25 mmoles) of dry pyridine and 1.2 g. (8.0 mmoles) of phosphorous oxychloride dissolved in 10 ml. of anhydrous ether; the reaction was cooled in an ice bath. resulting mixture was stirred overnight. The After the mixture was poured into 50 ml. of ice water and extracted with two 50-ml8 portions of ether, the combined ethereal extract was washed with dilute hydrochloric acid to remove the 32 excess pyridine and with three portions of brine, dried over magnesium sulfate, and concentrated on the rotary evaporator. The resulting dark oil was dissolved in ligroin (30-60°) and filtered through a short column of alumina (I) with 200 ml. of ligroin. Concentration of the filtrate on the rotary evaporator gave 3.63 g. (72%) of colorless olefin 39: ir. (film) 3.25 (vinyl CH), 6.12 (C=C), 6.23 (C=C), 10.40 (trans-C=C) and 11.52µ· (vinyl C=CH 2 ). The triene mixture was used without further purification. A small sample was molecularly distilled (75°, O.l mm.) for an analytical sample. ~· Found: Calcd. for c H 16 26 : C, 88.00; H, 12000. c, 87.957 H, 12.09. Formolvsis of Trienes 39. ~ """"" ~ """ A 3.63-g. (16.6 mmoles) sample of the triene mixture 39 was stirred with 75 ml. """"" of anhydrous formic acid for 20 min. at 25° under nitrogen. The reaction was poured into an ice-cold solution of 100 g. (4.0 moles) sodium hydroxide in 500 ml. of water. The product was extracted with two 100-ml. portions of ether; the combined ethereal extract was washed twice with water and with brine, dried over magnesium sulfate, concentrated on the rotary evaporator to give 3.64 g. (89%) of crude product that was chromatographed on Florisil (Table 1) to give 2.92 g. (67%) of formates which were used without further purification. Molecular distillation at ao 0 33 (0.03 mm.) gave an analytical sample: ir. (film) 3.67 (formate CH), S.79 (formate C=O) and 8 . 50µ Table 1. (C-O). Chromatography of the formolysis products. Solvent Vol. Ligroin (30-60°) 1:49 Ether-ligroin 1:49 Ether-ligroin 1:19 Ether-ligroin 1:9 Ether-ligroin 1:4 Ether-ligroin 1:1 Ether-ligroin (ml.) Wt. of residue (g.) 200 100 100 200 100 100 100 0.38 0.01 0.66 2.24 0.02 (olefin) (olefin) (formate 40) (formate 19) (formate .!QJ o.o3 (diformate) 0.30 (diformate) Calcd. for C H O : C, 77.22; H, 10.67. 17 28 2 Found: c, 77.34; H, 10.83. Anal. ~~~~~· A 2.92-g. (11.2 rnmoles) sample of formates ,,..,,....,.. 40 obtained from the chromatography of the formolysis products was used without further purification. The ester 40 was dissolved in 100 ml. ~ of anhydrous ether and stirred with 450 mg. of lithium aluminum hydride for one hour. was cooled in an ice bath. (large excess) The reaction After one hour the excess reagent was destroyed with saturated sodium sulfate solution, and was poured into 500 ml. of water. The layers were separated and the aqueous layer was extracted with 100-rnl. portion of ether. The combined ethereal extract was washed with twice saturated brine, dried over magnesium sulfate, 34 filtered, and concentrated on the rotary evaporator to -- -- give 2.95 g. of alcohols 42 and 43: and 9.77 µ- ir. (film) 3.00 (OH) (C-0); v.p.c. (6 ft. of 2% Carbowax 20M, 170°) two principle alcohols 42 and 43 in a ratio of 3:2. """" """' Chromatographic Separation of Alcohols 42 and 43. ~~"""""~"""" """"""'-,.,,,,,... A 3.42-g. sample of crude alcohols ,..._.. 42 and ,...,.,.. 43 was chromatographed on 200 g. of alumina (IV) (Table 2). Isomer ,,..,..,... 43 obtained from the first 1:99 benzene-ligroin (30-60°) fraction was later purified by means of the 3 1 5-diniotrobenzoate derivative """' 44 (see below). The alcohols ,,..,.... 42 and . 43 .obtained from the second 1:99 benzene-ligroin fraction and the 1:19 benzene-ligroin fraction was rechromatographed on alumina. Isomer 42 obtained from the 1:9-1:1 benzene~ ligroin fractions was recrystallized from pentane to give colorless alcohol 42: and 9.74 µ (C-0) .. Anal. Found: Table 2. m.p. 91-93°; ire (KBr) 3.07 (OH) Calcd. for c16 H28 o: c, 81.,291 H, 11.94. c, 81.181 H, 11.95. Chromatography of the alcohols AA and AA• Solvent Ligroin (30-60°) 1:99 Benzene-ligroin 1:99 Benzene-ligroin 1:19 Benzene-ligroin 1:9 Benzene-ligroin 1;4 Benzene-ligroin 1:1 Benzene-ligroin Vol. (ml.) 500 500 500 500 500 500 1000 Wt. of residue (g.) 0.37 o.66 o.sa 0.49 0.38 0.35 0.39 (Olefins) (Alcohol 43) (Alcohols"'"if3 and 42) (Alcohols tr and 42> (Alcohol ~ (Alcohol~ (Alcohol ,,..,..,... ~ -- 35 The benzoate of alcohol 42 ,,_ was an oil: ir. (film) 3.28 (aromatic CH), 5.81 (C=O), 6.23 (phenyl), and (C-O); n.m.r. (Ccl ) 5 7 .98 (m., 2, phenyl hydrogens 4 next to the carboxyl group), 7.38 (m., 3, remaining phenyl 7 .90µ hydrogens), 4.98 (sextet, 1, axial c~-o), 4.58 (s., 3, J1 = 4 Hz., ~2 - 10.5 Hz., = cc~3 ), and 0.90 p.p.m. (m., 12, four CH 3 ). Preparation of 3,5-Dinitrobenzoate 44. ~,,..,.... ~ An 875-mg. (3.7 mmoles) sample of crude alcohol 43 was dissolved in 10 ml. of 1:1 pyridine-benzene. After the solution was cooled to oo, 1.1 g. (4.8 mmoles) of· recrystallized 3,5-dinitrobenzoyl chloride was added with stirring. After 5 min. at o0 the reaction was warmed to 25° and left stirring overnight. The reaction was poured into ice water and extracted with two 70-ml. portions of ligroin (30-60°). The combined ligroin extract was washed with dilute hydrochloric acid, with two portions of water, and with saturated sodium bicarbonate solution. The extract was dried over sodium sulfate, filtered, and concentrated on the rotary evaporator to give 1~89 g. of yellow oil, which crystallized when treated with ligroin. The ester was recrystallized twice from ligroin (60-70°) and finally from ~-hexane to give fine needles: m.p. 117-119°: ir. (KBr) 3.23 (aromatic CH), 5.81 (C=O), 6.14 (phenyl), 6.46 (N0 2 ), 7.43 (N0 2 ), and 13.95µ: (C-N-0); 36 n.m.r. (CC1 4 ) B 1.67 (s., 3, vinyl C.!.!,3 ) 1 5.21 (sextet, 1, !LJ. = 5 Hz., ~2 = 10 Hz., axial CH-O), and 9.09 p.p.m. (m., 3, aromatic li>• Anal. Calcd. for c 23 n30 N2o6 : N, 6.51. Found: C, 64.17: H, 7.02; C, 64.321 H, 7.02; N, 6.39. Reductive Cleavage of 3,5-Dinitrobenzoate 44. """" ~~~ An 832-mg. (1.93 mmoles) sample of the dinitrobenzoate 44, ~ m.p. 117-119°, was dissolved in 100 ml. of anhydrous ether and stirred with excess lithium aluminum hydride for 1.5 hr. at 10°. After the reduction complex was destroyed with saturated aqueous sodium sulfate , the mixture was filtered. The filtrate was concentrated on the rotary evaporator to give 431 mg. of yellow oil, which was chromatographed on silica gel. The 1:3 ether-ligroin (30-60°) fractions gave 387 mg. (85%) of alcohol 43, which slowly crystallized. ~ Sublimation at 50° (l mm.) gave colorless, crystalline alcohol 1J..: and 9~79µ· m.p. 47-54°; ir. (CC1 4 ) 2.76 (OH), 2.99 (OH) (C-0); v.p.c .. (6 ft. of 2% Carbowax 20M, 170°) one peak with no isomeric alcohol ..,..,... 42 present • Anal. Found: Calcd. for c16 n28 o: _C, 81.291 H, 11.94. c, 81.391 H, 12.03 37 Ketone 49. A 156-mg. (0.662 mmole) sample of alcohol 42 was dissolved in 50 ml. of reagent grade """""' acetone and treated with excess chromic acid (25) at o0 • After 30 min. the excess reagent was destroyed with isopropanol. Anhydrous magnesium sulfate was added to superficially dry the solution, which was then diluted with 100 ml. of ligroin (30-60°). The solution was filtered and concentrated on the rotary evaporator to give a residue that was taken up in 50 mlo of ligroin and redried over anhydrous magnesium sulfate. The solution was re- filtered and reconcentrated as before, and the concentrate was filtered through a column of alumina (III) with 50 ml. of ligroin to yield after concentration on the rotary evaporator 113 mg. (73%) of ketone ,,...,... 49: (C=O); n.m.r .. (CHC1 3 ) o 1.62 {s., 3, ir. (film) 5.84µ vinyl C!.!,3 } and 0.83 p.p.m. {m., 12, four cg3> ~ The semicarbazone was recrystallized from ethanolwa ter: m.p. 183-189° dee.; ir. (KBr) 5.91 (C=O), and 6.30µ Olefin so. ,,...,... ~ 2.89 (NH), 3.16 (NH), (C=N). A 400-mg. (l.38 mmoles) sample of the semicarbazone of ketone 49 was combined with 6.0 g. (60 """""' rnrnoles) of 100% hydrazine hydrate, 20 ml. of reagent grade diethylene glycol, and 2.6 g. (40 nunoles) of 85% potassium hydroxide. The reaction flask was placed in an oil bath 38 heated to 200°. After the reaction was heated for 1 hr. under reflux, the lower boiling constituents were removed by distillation. The temperature was then main- tained at 220° for 2 hr. After the reaction was allowed to cool to 25°, the distillate and the pot residue were diluted with water, combined, and extracted with pentane. The pentane extract was washed twice with water, dried over anhydrous magnesium sulfate, and filtered. Evaporation of the filtrate on the rotary evaporator gave 275 mg. (91%) of oily olefin ,,..,.. 50: ir .. (film) 3.40 µ Photo-oxidation of Olefin SO. A. (CH) .. Hematonornhvrin- ~ ~~~,,...,,...~ ~· A 125-mg. (0.568 nunole) sample of crude olefin 50 was dissolved in 12 ml. of anhydrous pyridine that con""' tained 0.01% hematoporphyrin dihydrochloride. The solution was irradiated with fluorescent lamps for 15 hr., at which time a sample analyzed by the v.p.c .. showed the presence of little starting olefin. The reaction was diluted with a large volume of water, and the aqueous solution was extracted with ethere The ethereal extract was washed successively with several portions of water, with dilute hydrochloric acid, and again with water. After decolorizing charcoal and anhydrous magnesium sulfate were added, the solution was filtered and concentrated on the rotary evaporator to give 138 mg. of crude hydroperoxide, which 39 was reduced in anhydrous ether with excess lithium aluminum hydride. After the reduction complex was des- troyed by saturated sodium sulfate solution, the ethereal solution was filtered and concentrated to yield 129 mg. of oil that contained more than 23 components by v.p.c. analysis. ~~Disulfide-Methanol-Ether. An 83-mg. (0.38 mmole) sample of olefin .,,...,..,.. 50 was dissolved in 15 ml. of 28:2:3 carbon disulfide-methanol-ether (24) that contained 1.0 mg./ ml .. of rose bengal sensitizer. The sample was irradiated for· 2 hr. at 12° with a 300-w. tungsten lamp. After the solvent was removed on the rotary evaporator, the residue was taken up in ether. The ethereal solution was filtered and treated with excess lithium aluminum hydride for 1 hr. After the reduction complex was destroyed with saturated sodium sulfate solution, the ethereal solution was filtered and concentrated to give 80 mg. of crude allylic alcohol .;vv... 51, which was chromatographed on Florisil. The 1:49 ether-ligroin (30- 600) fraction yielded 21 mg~ (24%) of allylic alcohol 51: """" ir. (film) 2.89 (OH), 3.26 (=CH), 6.,08 (C=C), and 11.18µ (=CH2); n .. m.. r .. (CCl4) B 4.70 (m., 2, =C!f2>, 0.87 (m., 9, three CHC!!3 ), and 0.68 p.p.m. (s., 3, CC!.!J), v.p.c. {6 ft. 0 of Carbowax 20M, 160 ) 77% purity. 40 ~~ ..~~~~· A21-mg. (0.089 nunole) sample of crude allylic alcohol ,,...,... 51 was used -- without further purification. The alcohol 51 was dis- solved in 5 ml. of methylene chloride and 3 ml. of methanol. After being cooled to -10° in a Dry Ice-acetone bath, the solution was saturated with ozone from a Welsbach generator until a persistent blue color remained. The solution was then flushed with oxygen for 10 min. and warmed to o0 in an ice bath. A 100-mg. portion of zinc dust and 1-ml. portion of acetic acid were added, and the ensuing mixture was stirred for 75 min. The reaction was then diluted with water and extracted with a SO-ml. portion of ligroin (30-60°). The ligroin extract was washed twice with water and then with brine, was dried over anhydrous sodium sulfate, filtered, and concentrated on the rotary evaporator to yield 21 mg. of colorless oil that was chromatographed on alumina (III). The 1:1 benzene-ligroin (30-60°) gave 13 mg. of keto ester ~: (ester C=O) and 5.85µ (s., 3, 3 OC~ ) (CC1 4 ) 5.74 n~m.r. (Ccl 4 ) 53.52 (m., 12, four CC~). The (ketone C=O); and 0.80 p.p.m. ir. ether-benzene-ligroin fractions gave 6 mg. (30%) of ketol 52: ~ m.p. 98-103°; ir. ccc1 4 ) n.m.r .. (CHCl3) CHC~ ), and 0.88 p.p.m. 3 2.87 (OH) and 5.85 µ · 50 .. 63 (s., 3, CC~3>1 (d., 6, :!:_ (C=O); 0.75 (d., 3, = 5 Hz., 3 :!:. = 7 Hz., C~ CHC!!.J). 41 Dehydration of Ketol 52. ~,,..,...~~ Fieser Bl> was used. The procedure of Heymann and A 6-~g. (0.003 nunole) sample of crude ketol 52 was dissolved in 2 ml. of anhydrous pyridine. ~ the solution was cooled to o0 After in an ice bath, a 0.1-ml. por- tion of thionyl chloride was added. After a period of l hr. the reaction was diluted with ice water and extracted with a 30-ml. portion of ligroin (30-60°). The ligroin extract was washed with three 50-ml. portions of water, dried over anhydrous sodium sulfate, filtered, and evaporated on the rotary evaporator to give an oil that was chromatographed on alumina (III). The 1:3 benzene-ligroin (30-60°) fraction gave 4 mg. of (60%) of enone ~: ir .. (CC1 4 ) 592 (C=O) and 6.14W(C=C). A 345-mg. (l.46 mmoles) sample of alcohol _...,... 43 (m.p. 47-54°) was dissolved in 100 ml. of reagent grade acetone, and the solution was cooled to o0 in an ice bath. Excess chromic acid (25) was added, and the solution was stirred for 25 min. A 1-ml. portion of i-propanol was added to destroy the excess reagent, and after 5 min. an aqueous solution of potassium carbonate was added dropwise until the solution was neutral to litmuso A 100-ml. portion of ligroin (30-60°) and some anhydrous magnesiu.~ sulfate were added. After the solution was filtered, the filtrate was concentrated on the rotary evaporator. The oily residue was dissolved in 10 ml. of ligroin (30-60°) and filtered through a short column of alumina (V) with 90 ml. of ligroin (30-60°). After the solution was concentrated on 42 the rotary evaporator, the colorless residue (345 mg.) was distilled to give 337 mg. (98%) of ketone 55: b.p. 115""""' 120° (1 mm.); ir. (film) 5.85µ (C=O); n.m.r. (CC1 ) B 1.68 4 (s., 3, vinyl CH ) and a.as p.p.m. (m., 12, four CH ). 3 3 ~· Calcd. for c H o: C, 81.997 H, 11.18. 16 26 Found: c, 82.07; H, 11.22. Olefin 56. ~~ A 327-mg. (1.40 mmole) sa~ple of ketone 55 was dissolved in a mixture of 6 ml. of 95% ethanol and 6.0 g. of 100% hydrazine hydrate. After the mixture was stirred at 25° for 30 min., 20 ml. of reagent grade diethylene glycol and 2.8 g. of 85% potassium hydroxide were added. The reaction was gradually heated under nitrogen to remove the ethanol and the excess hydrazine hydrate by distillation during a period of 1 hr.; the heating bath temperature was raised during this time from 25° to 180°. The bath temperature was raised to 200° and maintained at that t~nperature for 2 hr. After the reaction flask was cooled, its contents and the distillate were poured into 200 ml. of ice water, which was then extracted with two 50-ml. portions of ligroin (35-40°). The combined ligroin extract was washed twice with water, dried over magnesium sulfate, and filtered through a short colUi.~n of alwnina (I) with 50 ml. of 0 ligroin (35-40 )o After the filtrate was concentrated by 43 distillation through a short Vigreaux column, the concentrate was distilled to give 218 mg. olefin 2i,: b.p. 90-95 0 (0.8 mm.) 1 n.m.r. (71%) of (CC1 4 ) 5 1.60 (s., 3 1 vinyl C!!J) and 0.83 p.p.rna (m., 12, four C!!J). Anal. Found: Calcd. for c16 H28 : c, 87.19: H, 12.81. c, 87.13; H, 12.85. Photo-oxidation of Olefin 56. The procedure of ~""""' ~ .rvv-. Forbes and Griffiths (24) was used. mmole) s~~ple An 181-mg.. (0. 822 of the olefin ,,..,..,.. 56 was dissolved in 50 ml. of 28:2:3 carbon disulfide-methanol-ether that contained l.O mg./ml. of rose bengal sensitizer.. The reaction flask was flushed with oxygen and maintained under a positive oxygen pressure during the course of the reaction. The solution was stirred magnetically. cooled to The flask was a0 in a water bath and irradiated with a 300-w. tungsten lamp for 2 hr. The solvent was removed on the rotary evaporator; ether was added to the residue, and the ether suspension was filtered. The colorless filtrate was stirred with excess lithium aluminum hydride for 30 min. The reduction complex was destroyed by dropwise addition of saturated sodium sulfate solution. the reaction mixture was filtered. After 1 hr. The filtrate was concentrated on the rotary evaporator to give 191 mg. 44 -- (98%) of crude allylic alcohol 57: ir. (film) 2.90 (OH), 3.26 (=CH), 6.10 (C=C) and 11.07 µ · (=CH 2 ); v.p.c. (6 ft. of 2% Carbowax 20M, 160°) two alcohols in a ratio of 3:1. The crude alcohol 57 was used without further ~ purification. The Preoaration .,_,,_ of .dl-Ketol _.... 58. ~ ~ ~ An 191-mg. (0.81 mmole) sample of crude allylic alcohol _.... 57, prepared by the photo-oxidation of the olefin ,,..,...,.. 56, was dissolved in 2 ml. of methylene chloride and cooled to -10° in a Dry Ice-acetone bath. The methylene chloride solution was added with stirring to 31 ml. of methylene chloride saturated with ozone (0.81 mmole) at -10°; an additional 5 ml. of methylene chloride was used to complete the transfer of allylic alcohols to the reaction vessel. A 0.1-g. portion of zinc dust and 1 ml. of acetic acid were added, and the reaction mixture was warmed to ice bath. o0 in an After 15 min. another 0.1 g. of zinc dust and 1 ml. of acetic acid were added, and the mixture was stirred for a total of 1.5 hr~ The reaction mixture was poured into sodium bicarbonate solution. The product was extracted with two 75-ml. portions of ether. The combined ethereal extract was washed with water and saturated brine, dried over sodium sulfate, filtered, and concentrated on the rotary evaporator to give 196 mg. of yellow oil, which 45 deposited a small amount of yellow gum upon trituration with ligroin (30-60°). After the ligroin solution was filtered through cotton, the co.l orless filtrate was combined with a 23-mg. sample of ketol 58 prepared in a ~ previous run. The ligroin solution was placed on 60 g. of alumina (III) and chromatographed. Ketol 58 was ob- tained from the 2:9:9 and 1:2:2 ether-benzene-ligroin (30-60°) fractions and was recrystallized from 50% aqueous ethanol to give colorless needles: m.p. 70-71°; ir. (KBr) 2.95 (OH), 5.90 (C=O) and 9.91µ (C-0) ~ ~· Found: Calcd. for c15 H2602: c, 75e58; H, 10.99. c, 75.59; H, 11 . 10. Dehvdration of Ketol 58. ~,,.,,... ~ ~ A 5.0-mg. A. """'" With Thionvl Chloride. ~ ~ ~ (0.021 mmole) sample of ketol 58 was dissolved in 1.5 ml. of dry pyridineo A 0.1-mle (large excess) portion of thionyl chloride was added dropwise with stirring at 25° under nitrogen. After 1 hr~ the reaction was poured on a small amount of ice and diluted with another 50 ml. of ice water~ The reaction mixture was extracted with a 50-ml. portion of pentane. The organic extract was washed with two 50-mlo portions of ice water, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated on the rotary evaporator giving an oil that had undergone dehydration with rearrangement: 5.84 (saturated C=O) and 6.10 µ ; (C=C); v.p.co ir. (CC1 4 ) (6 ft., of 2% 46 Carbowax 20M, 160°) one peak with a shoulder that was also unresolved at 140°. ~ ~~~· A 5.0-mg. (0.021 mmole) sample of ketol ,,...,... 58 was dissolved in 1.5 ml. of dry pyridine and stirred with 0.1 ml. (large excess} of phosphorous oxychloride at 2s 0 for 17 hr. under nitrogen. The workup described above gave an oil that was 95% starting material: ir. (CC1 4 } identical to starting material; v.p.c. (6 ft. of 2% Carbowax 20M, 200°) 95% starting ketol and 5% dehydrated product. Preparation of Keto Acetate 59. ~,,...,...~~,,...,... A 56-mg., (0.20 mmole) sample of ketol 58, ,,...,... m.p. 68-70°, was dissolved in a solution of 25 mg. of 85% phosphoric acid and 5 ml. of acetic anhydride. After 16 hr. at 25° the reaction was thrown into ice water, and the product was extracted with a SO-ml. portion of ligroin (30-45°). The ligroin extract was washed successively with water, saturated sodium bicarbonate ·solution, water and then saturated brine. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated on the rotary evaporator to give an oil, which was chromatographed on Florisil. The keto acetate 59 from the 1:19 and 1:9 ether-ligroin (30-60°) fractions crystallized (m.p. 40-44°) . Recrystallization from ethanol {-70°) and sublimation (50°, 1 mm.) gave keto acetate ,,...,... 59: 47 m.p. 46-48°; ir. cc1 4 ) S.74 (acetate) and shoulder at 5. 8 0 µ ( C=O) • Anal. Found: Calcd. for c 17 H28 o3 : C, 72.82; H, 10.06. c, 72.741 H, 10.04. A 29-mg. (0.73 mmole) sa.~ple (large excess) of calcium metal was dissolved in 20 ml. of liquid ammonia that had been previously distilled from sodium metal. (0.021 nunole) sample of dl-keto acetate ~ A 6.0-mg. dissolved in 0.3 ml. of dry tetrahydrofuran (THF) was added; another 0.3-ml. portion of THF was used to complete the transfer of the keto acetate to the reaction vessel. After a 5 min. reaction time solid am.~onium chloride was added, and the reaction was stirred until the blue color was completely discharged. A 20-ml . portion of ether was added, and the ammonia was removed with a stream of nitrogen. After the ethereal slurry was filtered, the filtrate was concentrated on the rotary evaporator. To oxidize any alcohol formed during the reduction, the colorless residue was dissolved in 5 ml. of reagent grade acetone and treated with excess 0 chromic acid reagent (25) at o • The reaction was diluted with water and extracted with ligroin (30-60°). The ligroin extract was washed twice with water, dried over sodium sulfate and concentrated on the rotary evaporator. 48 The oily residue was chromatographed on Florisil. The 4.9 mg. (100%) of ketone obtained from the 1:19 etherligroin (30-60°) fraction was molecularly distilled (80°, 32 mm.) giving 4.0 mg. (84%) of ~-~-tetra­ hydroer~~ophilone (17): ir~ ~ (film) 5,86 (C=O) and the entire spectrum was super.imposable with that of d-cistetrahydroeremophilone (17) prepared according to """""""' Djerassi and co-workers (31); v.p.c. (6 ft. of 2% Carbowax 20M, 170°) identical retention time (peak enhancement) -- as d-cis-tetrahydroeremophilone (17). ,,..,...,.. 'l'he racemic 2, 4-dini trophenylhydrazone .,,..,.. 6 0 was prepared and recrystallized from ethanol giving orange needles: m.p. 141-143°; ir. (KBr) 3.00 (NH), 3.23 (aromatic CH), 6.17 (C=N), 13.48µ 6~29 (phenyl), 7.49 (nitre} and (C-N-O}, and was superimposable with ir. spectrum of the ~-2,4-dinitrophenylhydrazone 60, m.p. 181-183°, ~ lit. m.p. 178-179° (1) and 179-180° (31), prepared according to Djerassi and co-workers (31). -- Preparation of d-~-Tetrahydroeremophilone (17). ~.,,..,..;;:;;;. ,,...,..,.., The procedure of Djerassi and co-workers (31) was used. A 41.S-mg. (0.19 mmole) sample of erernophilone, m.p. 38400, was hydrogenated in 5 ml. of methanol with 13~5 mg. of 5% palladium catalyst. After the catalyst was removed by filtration, and the solvent was removed on the rotary 49 evaporator, the crude cis- and trans-tetrahydroeremophilones were dissolved in 1.5 ml. of methanol and 0.5 ml. of 3 ~ hydrochloric acid. The solution was heated under reflux for 30 min., cooled, and neutralized with saturated sodium bicarbonate solutionG The reaction mixture was extracted with ligroin (30-60°); the extract was dried over anhydrous sodium sulfate, filtered, and concentrated on the rotary evaporator. The residue was chromatographed on Florisil giving 30 mg. of d-cis-tetrahydroeremophilone (17) in the 1:19 ether-ligroin (30-60°) fractionG ~ The oily ketone was molecularly distilled (90°, 32 nun.) to yield 28.5 mg. S.86 µ (63%) of d-cis-ketone 17: """ -- ir. (film) (C=O). The 2,4-dinitrophenylhydrazone was recrystallized from ethanol: m.p. 181-183°, lit. m.p. 178-179° (1), m.p. 179-180° (31); ir. (KBr) 3.00 (NH), 3.23 (aromatic CH), 6.17 (C=N), 6.29 (phenyl), 7.49 (nitro), and 13.48 µ (C-N-0). 50 REFERENCES (l} A. E. Bradfield, A. R. Penfold, and J. L. Simonsen, J. Chem. ~., 2744 (1932}. (2) A. R. Penfold and J. L. (3} c. Djerassi, R. Mauli, and L. H. Simonsen,~., 87 (1939}. Zalkow, J. Am. Chem. Soc., 81, 3424 (1959}. --"""""" (4} L. H. Zalkow, F. ibid., 82, 6354 -"""""" (5) (a) For a recent review of sesquiterpene biogenesis see w. Parker, J. s. Roberts, and R. Ramage, Quart. Rev., 21, 331 (1967); - (b) x. Markley, and c. Djerassi, (1960). """""" v. B. Zalkow, A. M. Shaligram, and L. H. Zalkow, Chern. Ind. (London} , 194 (1964) • - (6} L. Ruzicka, Experientia·,,,_,2, 357 (1953). (7} L. Novotny, (1961}. (8} J. Hochmannova, L. Novotny, and v. Herout, Collect. Czech. Chern. Conunun., 27, 2711 (1962}. - v. Herout, and F. Sorin, .!!:.E.• ~., 697 ~ (9} w. D. MacCleod, Jr., ~· ~., 4779 (1965). (10} P. Pesnelle and G. Ourisson, ~· ~· ~· ~., 912 (1963). (11) s. Carboni, A. Da Settimo, v. Malaguzzi, A. Marsili, and P. L. Pacini, ~· ~., 3017 (1965}. (12} L. w. Piszkiewicz, Ph. D. Thesis, California Institute of Technology, Pasadena, California, 1967. (13} J. A. Marshall, H. Paubl, and T. M. Warne, Jr., Commun., 753 (1967}. ~· (14} E. Piers, w. de Waal, and R. 188, (1968). (15) D. Chan, unpublished results. w. Britton, ~· 51 (16) E. c. Horning, M. o. Denekas, and R. E. Field, £!.• Org. Chem., :i! 547 (1944). (17) (a) M. Julia, s. Julia and s.-Y. Tchen, Bull. Soc. Chim. (b) ~·, 1849 (1961}; c. G. Overberger and A. E. Borchert, J. k~. Chem. Soc., 82, 4896 (1960). - (18) Y. M. Slobodin and I. N. Shankhor, Zh. Obshch. Khim., 22, 208 (1952); Chem. Abstr.-;-46, lOllh ID"°5'2) • ,,....,... (19) - "'""" See review article by w. s. Johnson, Acc. Chem. Res., 1, 1 (1968). ~ - (20) ~ - ,,....,... "'""" w. s. Johnson, P. J. Neustaedter, and K. K. Schmiegel, Soc., 87, 5148 (1965). --- J. Am. Che~. ~ Cohen,~., (21) J. A. Marshall and N. (22) J. A. Marshall, N. Cohen, and A. R. Hochstetler, ibid., 88, 3408 (1966). - 87, 2773 ,,....,... (1965). ~ ~· ~., (23) J. A. Marshall and A. R. Hochstetler, 31, ,,..,.., 1020 (1966). (24) E. J. Forbes and J. Griffiths, (1967) • (25} K. Bowden, I. M. Heilbron, E. R. H. Jones, and B .. c. L. Weedon,~·~·~., 39 (1946). (26) Huang-Minlon, J. Am. (27) H. Heymann and L. F. Fieser, ibid., 73, 5252 (1951). (28) w. L. Meyer, D. D. Cameron, and w. s. Johnson, ~· ~· ~·, ~, - J. Org. ~., ~, Org. Conunun., 427 2487 (1946). ~ 1130 (1962). Chem.~· (29) R. B. Bates ands. K. Paknikar, 2170 (1966). (3 O) G. saucy, R. Marbet, H. Lindlar, and o. Isler, ,....,,.,,,., Helv. Chim. Acta, 42, 1945 (1959). (31) c. Djerassi, R. Riniker, and B. Riniker, J. Am. ___ H. Brockmann and H. Schodder, Chem. Soc., 78, 6362 (1956). - ~ (32) (London), - - ~ Chem. Ber., 74, 73 (1941). .,,,,..,,.. PART II STUDIES ON SYSTEMS FREE FROM ANGULAR STRAIN 53 INTRODUCTION The goals of this investigation were the synthesis of the alcohol 1 and solvolysis of the ester 2. ./V". ,,...,.. Tne solvolysis of the ester 2 is expected to generate the ./V". OH H TI H 0 1 .-... 2 ;..,,.. 2-adamantyl cation_,l by way of the £!-route, in contrast to the sigma-route used by Schleyer and Nicholas (1). The interest in the possible reactivity of ester. ;..,,.. 2 arose when 2 CJ,..route > < H 3 ./V". the anchirnerically assisted participation of a double bond was observed in the solvolysis of the unsaturated aliphatic 54 arenesulfonates 4 (2), 5 (3), and 6 {4). """' """' """' If the alcohol, ~ can be readily prepared, the solvolytic E2:_-route could be an useful approach to the preparation of substituted 2adamantanols. ~R 4, R = !Q_OAc HOAc so-O-ca 3 6 .,..,.., The attempts on the synthesis of alcohol 1 starting """' from l,4-dioxaspiro[4.S]decan-8-one below in three parts9 Cl( is discussed The first section involves the preparation of amine .,..,,... 8 and the pyrolysis of its amine oxide • The second part discusses the preparation of amines 9 and """' 10. Finally, the third section deals with the preparation of amino acetates ,,...,...,... 11 and ,,...,...,... 12 and with the pyrolysis of their corresponding amine oxides. 55 ,.rrN (CH3) 2 9 ....,.., 10 """"' OAc 11 """"' OAc 12 """"' 56 RESULTS AND DISCUSSION The key intermediate required for all the synthetic efforts was l,4-dioxaspiro[4.5]decan-8-one (7), which had """'" been prepared previously by several workers (5, 6 1 7, 8). The method adopted in this investigation required 1,4cyclohexadione C11)· The large scale preparation of dione 13 was carried out in two steps. ,..,..,... Hydrogenation of hydro- quinone (14) according to the procedure of Owen and Robins """"' (9) gave cis- and trans-quinitol (~ in 86% yield. The quinitol (15) was then oxidized with chromic acid reagent ~ (10) in acetone at o0 • Because the dione 13 was water soluble, the acetone solution was decanted from the inorganic by-products, and the inorganic sludge was extracted with acetoneo The combined acetone extract was superficially dried over calcium chloride and distilled under reduced pressure to give dione ~, b.p. 118-120° (15 nun.), which crystallized from ether affording 51% yield of the desired dione 13, m.p. 77-78° {lit. m.p. 78°) {11). ~ OH c=OH OH Ts OH OH OH 14 ,,..,,..,... ~ 15 > + 0 13 ~ 7 ,..,.. 16 ,,..,,..,.. 57 The method of courtot {8) was used for the preparation The dione 13 ,,_ was ketalized in the presence of of ketone,l. 1.5 equivalents of ethylene glycol and a trace of E_-toluene- sulfonic acid in benzene. The crude product was then stirred with aqueous sodium bisulf ite forming the soluble addition compound, and the aqueous solution was extracted with benzene to remove the diketal ,,...,... 16, m.p. 79-80° {lit. m.p. 79-79.5°) (8). The ketone 7 was regenerated from J'V'. the addition compound by decomposition with potassium carbonate. The ketone 7, m.p. 72-73° {lit. m.p. 72-73°) J'V'. (5, 8), was subsequently isolated in 35% yield. Preparation and Reaction of Amine 8 (Scheme 1). ~~ ~ ,,...,...~,,...,... ~.-- preparation of the amine ,,_ 8 is outlined in Scheme 1. The The ketone ,,_ 7 was converted to the morpholino enamine ,,...,... 17, b.p. 130° (0.7 rrun.), by an adaptation of the procedure of Hunig and co-workers (12) who prepared 1-morpholinocyclohexene {18). ,,_ When enamine 17 was alkylated with acrolein in an """"' adaptation of the procedure of Stork and Landesman {13), a 0 quantitative yield of vinyl ether ,,_ 19, m.p. 80-87 , was obtained. The vinyl ether 19 had infrared Cir.) maxima at """"' 3.29 {vinyl CH) and 6.05 µ (vinyl ether) and the nuclear magnetic resonance {n.m.r.) spectrum showed the presence of two vinylic hydrogens, one at 8 6.16 (doublet, ~ = 6 Hz., O-C!!_=CH) and the other at 8 4. 65 (multiplet, 0-CH=C!:!,). 58 Scheme ,,_ 1 ~ 0 17 .,,..,... W.K. > 19, .,,..,... 100% 20, ,,_ 23% > 24 22 """" The vinyl ether 19 was heated under reflux for two """'" days in benzene to afford morpholino ketone 20, m.p. 134- """' 135°, in 23% yield. 5.80 µ'. , Their. carbonyl absorption was at and the n.m.r. spectrum showed the presence of the ethylenedioxy group at o 3.92 (singlet) and the morpholino group at o 3.67 (multiplet, N-C.!:!,2 ). 2 ) and o 2. 44 (multiplet, Since Foote and Woodward (14) converted enamine .,..,,.. 18 0-C!!, 59 into morpholino ketone 21 ,,...,... in good yield, and this author obtained a 70% yield for the same reaction (see below), the low yield of the ketone 20 in this step was a ,,...,... manifestation of the 1,3-steric interactions presented by the ethylenedioxy group to the development of the threecarbon bridge by way of the reversible Mannich reaction. 1,3-interactions 20 ~ The ketone 20 underwent Wolff-Kishner affording an 88% yield of amine~. reduction (15) The n.murG spectrum of this amine .,,_,.. 22 showed the presence of the ethylenedioxy group at o 3.48 (multiplet, (singlet) and the morpholino group at o-C!!,i) and o 2.05 (multiplet, N-c~ ). 2 o 3.27 The amine 22 was then oxidized with hydrogen peroxide in methanol ~ until the solution was neutral to litmus. After the excess hydrogen peroxide was destroyed with a trace of catalase, the resultant amine oxide 23 was dried under reduced pressure ~ and pyrolyzed at 180 0 (20 mm.). The reaction observed was 60 the transformation of the amine oxide _...,..,, 23 to a black, tarry residue; probably a result of elimination in the morpholino ring and subsequent polymerization. A small amount of distillate obtained appeared to be starting amine 22 ~ by n.m.r. analysis. o~ > <:::::( ) polymer 23 _... Since the amine oxide 23 _... failed to undergo a Cope -- elimination upon pyrolysis, the ketal group of the amine 22 was hydrolyzed with hydrochloric acid in aqueous acetone -- to produce the amino ketone 24. The ir. carbonyl absorp- tion appeared at 5.88 µ, and the n.m.r. spectrum had the morpholino bands at o 3.70 {multiplet, O-CH 2 ) and o 2.35 (multiplet, N-C~2 ). The amino ketone 24 was oxidized with hydrogen peroxide, and the resultant N-oxide was residue, and no keto olefin was obtained . Because these two attempts on the synthesis of olef ins from amines .,..,..,,... 22 and 24 had failed, the structure of these ~ 61 amines was in doubt. Therefore, an investigation was undertaken to verify the postulated structure of the amine 27. ,,..,... Wolff-Kishner reduction {15) of amino ketone ,,...,... 24 gave amine 25, whose identification was confirmed by an inde~ Morpholino ketone 21, b.p. 123-133° ,;y... pendent synthesis. (0.6 mm.) (lit. b.p. 141-147 0 1 mm.) 1 (14), which was prepared in 70% yield according to the procedure of Foote and Woodward (14) by the alkylation of enamine ,,...,..,,... 18 with acrolein, underwent Wolff-Kishner reduction under the condition used for keto amine ,,..,... 24 affording amine ,,...,... 25, b.p. 88-89° (0.2 mm.), in 32% yield. The latter sample of amine 25 had an infrared spectrum identical to the sample ~ prepared from keto amine ~ • Hydrogen peroxide oxidation Scheme 2 ~-.. 0 6 CH2=CHCHO ~--- 21 18 ,,...,.., ,;y... > 2) /:::,. 32% 25 ,...,._ 26 _.... 62 of amine 25 _.... prepared from amino ketone 21 ,,....,... gave the corresponding N-oxide, which was pyrolyzed at 125-140° under reduced pressure {20 mm.) . to yield bicycle [3.3.l]non2-ene {26), m.p. 99-101° {lit. m.p. 103-105°) .,..,,...,... yield. (16), in 38% The transformation of amino ketone 21 to olefin 26 has also been carried out satisfactorily by Hartmann {16). _.... -- Although the N-oxide of amine 25 underwent pyrolysis -- affording olefin 26 in reasonable yield, the N-oxide of the more substituted amines -.. 22 and -.. 24 gave only undesired black polymer due to elimination in the morpholino ring. If the ethylenedioxy substitution at c 7 was the main cause of the difficulty, then there were two approaches that one could take to circumvent the difficulty in the pyrolysis. The first approach would be the replacement of the rnorpholino group by the dimethylamino group; if the corresponding amine could be prepared, then the N-oxide elimination would occur in only one direction. The second approach vwu ld be the substitution of a less bulky functionality at c 7 e The first approach is discussed in the next section, and then the second approach is covered in the final section. Preparation and Reaction of Amines 9 and 10 {Schemes ~--~~~.,...,...,..,..,,.....,...,...~ 3 and 4). .,...,....,...,_.,..,... The preparation of dimethylamino enamines was investigated. Because the equilibrium: 63 "'-> Enamine + Water Ketone + Secondary amine ""' lies on the side of the ketone, the formation of enaroines requires the removal of the water. When morpholine, b.p. 129°, is used, the water-benzene azeotrope can be used to remove the water from the system and, thus, can effect the formation of the desired enamines. However, when dimethylamine, b.p. 7°, is used, water cannot be removed as an azeotrope, and other methods must be applied in order to form the enamines. Drying agents--calcium oxide (17) or molecular sieves (18)--and an acidic catalyst--£-toluenesulfonic acid (19)--have been employed in the preparation of dimethylamino enamines. In order to examine the feasibility of the preparation and alkylation of dimethylamino enamines and to investigate the Wolff-Kishner reduction of the resultant a.111ino ketone, a model reaction scheme starting from cyclohexanone (27) ~ was first studied (Scheme 3). When cyclohexanone (27) was """' stirred with excess dimethyla.mi.~e in the presence of calcium hydride, as a drying agent, under a Dry Ice condenser, 1-dimethylaminocyclohexene (28), b.p. 168° (760 mmo) """' b.p. 175.50 ) (20), resulted in 46% yield. (lit. Vapor phase chromatography (v.p.c.) indicated the product contained 75% enamine ~ and 25% cyclohexanone en>. The enamine 28 was not purified further but was """' transformed in the following four steps to the olefin ,,...,... 26 in 64 Scheme 3 ~--- CU 3 CC53 HN(CH 3 ) 2 ;:;. ~CH3 "• . > p K CH2=CHCHO~ CaH 2 -- 29, 55% 28, 46% ,,...,...,... 27 ,,...,...,... CH 3 GI 3 I J, l: CH3 H202 0 > ' CH 3 > -- 26, 80% 30 9, 41% ~ ~ 18% overall yield. Crude enamine 2§.... (75% pure) was alkylated with acrolein in an adaptation of the procedure of Stork and Landesman (13) to give the amino ketone _...,... 29, b.p. 60-90 (O.l mm.), in 55% yield. at 5.83 µ • 0 Their. carbonyl absorption occurred Wolff-Kishner reduction (15) of the amino ketone 29 afforded the amine ,,..,,.. 9, b.p. so 0 (O.l mm.), in 41% yield. The n.m.r. spectrum showed the presence of the dirnethylamino group at 5 2.08 (singlet). After the amine,,j_ was oxidized with hydrogen peroxide in methanol, pyrolysis of the resultant N-oxide 30 at 180° under reduced pressure (20 mm.) ~ resulted in a vigorous decomposition affording the olefin 26 ~ in 80% yield. 65 Since the reaction sequence starting from cyclohexanone {27) was reasonably successful, an atta~pt was ""' made to prepare the di.TUethylamino enamine of the ketone 7. """""' However, no enamine was formed from the ketone ,,...,... 7 under the conditions used above for cyclohexanone. Therefore, the formation of the enamine 28 was re-examined. Lithium aluminum hydride {replacing the calcium hydride) and excess dimethylamine were first allowed to form a complex in ether, and then the cyclohexanone {27) ,,...,.. was added to the reaction flask. After having been stirred at 25° overnight, the reactio·n mixture was concentrated by distillation at atmospheric pressure. Further distillation under reduced pressure gave the enamine ,,..,,... 28, b.p. 30 0 in 54% yield. (1.5 mm.), The ir. spectrum had the 3.30 (vinyl CH) and 6.10 µ {C=C) absorptions. However, the absence of a 5.83 µ ir. carbonyl band and an ir. hydroxyl absorption revealed the enamine 28 to be uncontaminated with either cyclo~ hexanone (27) or cyclohexanol (31). ~ """"' Even though the reaction conditions were probably not optimum, the results of this experiment indicated that this method might warrant further study. Since a successful method for the preparation of dimethyla.~ino enamines appeared to have been found, the sequence of reactions starting from the ketone 7 was again ""' studied as outlined in Scheme 4. When the ketone ,....,.... 7 was 66 stirred with the lithium aluminurn hydride-dimethylamine reagent, and after the reaction was worked up as described above, the desired enamine 32, b.p. 85-90° (0.8 mm.), """" resulted in 35% yield. The ir. spectrum had an absorption at 6.09 µ (C=C) and no carbonyl band, which indicated that the enamine 32 was uncontaminated with starting ketone 7. """"' """' Scheme 4 ~,,..,.. > 32, 35% ~ 'cH3 CH 3 + W.K.) 10, 4.3% 34' 7 5 % """' """' The enamine 32 upon alkylation with acrolein gave 33 ,,....,.... I 48 % """ the crude a.~ino ketone 33 in 48% yield. The ir. carbonyl ~ absorption appeared at 5.81µ .• The amino ketone 33 under- went Wolff-Kishner reduction (15) giving amine 10, """' b.p. 103-108° (0.2 mm.), in 4.3% yield and the ketal 34 in """' 67 75% yield. The n.m.r. spectrum of the amine ,,..,,,.,... 10 showed the presence of the ethylenedioxy group at and the dimethylamino group at o 3.62 (multiplet) o 2.04 (multiplet). The . n.m.r. spectrum of the ketal ,,..,,,.,... 35 indicated the nresence of the ethylenedioxy group at o 3.70 group adjacent to two hydrogens at (singlet) and a methyl o 0.98 (triplet, J = 6 Hz.). The formation of ketal 3 4 in the Wolff-Kishner reduction of amino ketone 33 was a manifestation of a retroMannich reaction that occurred under the conditions of the reduction and that was enhanced because a dimethylamino Mannich base is a stronger base than a morpholino Hannich base. Since the yield of amine 10 ,,...,.... from the w~ino ketone 33 ,,.,,... was so low, this synthetic route was abandoned, and attention was redirected toward the morpholino derivatives. Prenaration and Reactions of F.mines 11 and 12 ~ ~ ~-""'"'" ~,...,,,...,, ~"""""" (Schemes 5, 6, and 7'. ~"-""',,,.,,,...~N( The use of the morpholino group as the w~ino moiety in the synthesis of the bicyclic structures was reinvestigated. The purposes of these experiments were the replacement of the ethylenedioxy group by a methylene group to relieve some of the steric interaction that hindered the formation of amino ketone ,,..,,,.,... 20 and the investigation of the amine oxide pyrolysis with an acetoxymethyl group at c 7 instead of the ethylenedioxy group . Although the syn- acetoxymethyl group of amino acetate ,,..,,,.,... 11 could exert a 68 steric interaction with c , this effect could be relieved 3 by ring B assuming a boat conformation. OAc 11 ,,..,... In the sequence of reactions outlined in Scheme S, the ketone ,,..,... 7 was first transformed into 8-methylene-1,4-dioxaspiro[4.5]decane (35) by an adaptation of the procedure of ~ Greenwald and co-workers (21), who modified the Wittig reaction (22) by employing dimethylsulfoxide (DMSO) as solvent and its conjugate base for the formation of phosphorous ylides. ~ Methylsulfinyl carbanion was formed in by the action of sodium hydride on D.MSO and was used to generate methylenetriphenylphosphorane (36) from methyl"""'" triphenylphosphonium iodide (37). The ketone 7 was added to the DMSO solution of the ylide 36 forming the olefin 35, """"" ,,..,... 0 b.p. 89-90 (22 mm.), in 65% yield. Their. spectru.~ had absorptions at 3.28 (vinyl CH), 6.08 {C=C), and 11.02 µ. (exocyclic methylene); and the n.m.r. spectrum showed the 69 presence of the exocyclic methylene hydrogens at o 4.58 (broad band) and the ethylenedioxy hydrogens at o 3.83 (singlet). The olefin 35 was heated in aqueous acetone with """' dilute hydrochloric acid in order to hydrolyze the ketal group. 0 The 4-methylenecyclohexanone (50 nun.), resulted in 85% yield. (38), b.p. 87-90 """' Their. spectrum had bands at 3.28 (vinyl CH), 5.82 (C=O), 6.05 (C=C), and 11.13 µ (exocyclic methylene); and the n.m.r. spectrum showed the presence of the exocyclic methylene hydrogens at (broad band) and the ring hydrogens at o 4.58 o 2.16 (broad band). The 2,4-dinitrophenylhydrazone melted at 154-155°. The preparation of the morpholino enamine 39 was carried out in the same manner that was used in Scheme 1 for the preparation of enamine 17. The enamine 39, b.p. 80-84° ,,...,... (0.4 mm.), was prepared in 69% yield from the enone 38. """' """' Their. spectrum had absorptions at 3.27 (vinyl CH), 6.08 (C=C), and 11.18 µ (exocyclic methylene); the n.m.r. spectrum confirmed the presence of the exocyclic methylene hydrogens at o 4.82 {broad band), the ring vinyl hydrogen at o 4.58 (triplet,~= 3.5 Hz.), and the morpholino hydrogens at 53.67 (multiplet, 0-C~) and o 2.30 (multiplet, N-C~2 ). -- The enamine 39 was alkylated in benzene with freshly distilled acrolein that was stabilized with a trace of hydroquinone. The vinyl ether intermediate was dissolved in tetrahydrofuran (THF), and the THF solution was heated 70 Scheme 5 ~.,..,,,... HC1,H 2 0 {C H5 ) 3 P=CH2 6 > 36 ,,....,.... > 38, 85% 35, 65% ,,...,.,,.. 7 ,,....,.... 0-H """"" > CH 2 CH 2 -- 39, 69% CH 2 95% 40, 74% """"" 1) B2H6 7 2) H2 o 2 ,Na0H 0 :i. + " ~ OH H 42, 43% ,,....,.... 43, .,..,,,... 53% > 71 under reflux for 60 hr. Molecular distillation (75-100°, 0.05 nun.) of the crude product afforded the morpholino e none 40 in 74% yield. ~ The ir. carbonyl band appeared at 5.80 µin addition to the bands at 3.27 (vinyl CH), 6.09 (C=C}, and 11.36 µ {exocyclic methylene). The n.m.r. spectrum indicated the presence of the exocyclic methylene hydrogens at 5 4.75 (broad band) and the morpholino hydrogens at 5 3.52 (multiplet, (multiplet, o-c~ ) 2 and at 5 2.28 2 N-c~ ). The enone 40 underwent Wolff - Kishner reduction under the conditions used for the preparation of amine ,,...,...,.. 25 (Scheme 2). A 95% yield of morpholino olefin 4 1, b.p. 69° (0.06 nun.), ~ resulted, and its ir. spectrum had absorptions at 3.28 (vinyl CH), 6.10 (C=C), and 11.40 µ (exocyclic methylene). The n.m.r. spectrum dernonstrated the presence of the exocyclic methylene hydrogens at 5 4.61 (broad band) and the morpholino hydrogens at 5 3.55 (multiplet o-c~2 ) and at 5 2.27 (multiplet, N-C!:!,2 ). Hydroboration of the morpholino olefin ,,...,.. 4 1 with diborane in THF (23) produced a crystalline amino alcohol 42, ,,...,.. m.p. 104-105°, in 43% yield from ether. Evaporation of the mother liquors gave a 53% yield of an oily amino alcohol ,,...,..,... 42. The ir. absorption at 3.10 µ spectrUL~ of alcohol ,,...,.. 4 2 had a hydroxyl (KBr), and the hydroxyl band of alcohol 43 appeared at 2.93 µ · (film). ~ The assignment 72 of the configuration of the hydroxymethyl group at c 7 of the alcohol _..,..., 42 rested upon the subsequent conversion of this alcohol to adamantanone (4A.I'.4 ) (Scheme 6). The configuration at c The 2 will be discussed later. configuration at c of the alcohol ~ was assigned on 7 the basis that this alcohol was converted to the hydroxy olefin _..,..., 45 (Sche."Ue 6} that did not give 2-adamantanol upon solvolysis. The configuration at c 2 of the alcohol~ will also be treated later. Sche."Ue 6 ~.,,...,,.. Ac20, Py. R----)~ . . .01) > 2} .6. OAc -- 46, 100% _..,..., 48, 28% 44 73 Acetylation of the crystalline amino alcohol .-v-. 42 with acetic anhydride in pyridine afforded a quantitative yield of the amino acetate 46, m.p. 57-60°; the ir. spectrum """""' had acetate bands at 5.72 (C=O) and 8.05 µ Hydrogen (C-0). peroxide oxidation of the amino acetate .-v-. 46 gave the corresponding amine oxide 47. The amine oxide 47 ,,_ was dissolved in toluene, and the solution was heated under reflux for 12 hr. The toluene was diluted with pentane and washed with dilute hydrochloric acid to remove any basic material. then chromatographed on alu.~ina (I). The product was The ether fraction of the chromatogram gave a 37% yield of a crystalline ketone that was identified as adamantanone ( 44 ) by its ir. spec- """""' trum (5. 79 µ C=O band) (lit. ir. 5. 79 µ) comparison with an authentic sample (25). (24), and by The mass spectrum, which had a .M+ peak of m/e 150 (base peak, 100%) and peaks of m/e 151 (11%) and m/e 152 (0.8%), also supported a molecular formula of c1 0 H14 o. However, if the product in the toluene-pentane solution was chromatographed on Florisil, the ether fraction gave a 28% yield of the keto acetate 48. ~ Their. (C=O} and 8. 08 µ spectru.~ (C-0) had acetate bands at 5.74 and had a ketone band at 5. 85 p;:. The n.m.r. spectrum revealed the presence of the acetate methyl hydrogens at 5 2.03 (singlet) and the presence of two hydrogens on carbon adjacent to oxygen at 5 3. 90 74 (d o ublet,~= 5 Hz., CH-c~ -o). 2 When the keto acetate 48 was c hromatographed on alumina (I), adamantanone ( _... 44 ) was produced. A DMSO solution of amine oxide _..,..., 4 7 was heated at 80-90° f o r 4 hr. (26), and the crude product was chroma to- graphe d o n alumina (I) giving a 9% yield of adamantanone (44). ,,..,...,.. In a c o rresponding sequence of reactions (Scheme 7 ) the crude alco ho l ,,..,..,.... 4 3 was acetylated with acetic anhydride in pyridine giving an oily amino acetate _... 49 in 81% yield. The ir. spe ctrum of this acetate had absorptions at 5.75 (C=O ) and 8. 06 µ (C-0) • Scheme _... 7 ~ ~O, Ac o, Py. 2 43 ,,..,...,.. > 2) 3 H20 ~ ~ !:::,. LiAlH ~ ,.. 4 > I. OH OAc 49 50 45 _... The oily amino acetate _... 4 9 prepared from alcohol "Y'o 43 was oxidized with hydrogen peroxide, and the resultant amine oxide dissolved in dry D.MSO (26) was heated under nitrogen for 4.5 hr. at 80° to afford the crude acetate 50 _... in 35% 75 yield. Analysis by v.p.c. revealed a mixture of acetates containing 84% of acetate ....,.. 50 and 16% of another acetate ,.,,,........ 51, whose structure is discussed below. Chromatography of the acetate mixture on Florisil gave the acetate ,,..,,..., SO, which was rechromatographed on Florisil and molecularly distilled at 50° (5 mm.) to yield the colorless acetate ,,..,,..., 50 of 99% purity (v.p.c. analysis). The ir. spectru.u of the acetate 50 had absorptions at 3.34 (vinyl CH), 5.74 ,,..,,..., 6.08 (C=C), and 8.04 µ (acetate c-o). (acetate C=O), The first chromate- gram also gave a 10% yield of keto acetate 48, ,,..,,..., which probably arose from the presence of the amino acetate 46 ,..,..,, in the amino acetate ,,..,,..., 49 preparation. The acetate ,,..,,..., 51 was not obtained pure by further rechromatography on Plorisil. The crude acetate 50 was transformed into the alcohol 45 by reduction with lithium aluminum hydride. The ~ E-nitrobenzoate derivative 26,.r m.p. 71-77°, was prepared and stirred in 50% aqueous acetone at 25° for 24 hr. in an attempted solvolysis that gave back starting ester 52. ~ When the ester 52 was stirred in 67% aqueous dioxane at 70° for 80 min., the starting ester ,,..,....,.. 52 was again isolated, m.p. 7779°. Their. spectrum of the ester 52 had bands at 3.32 ~ (vinyl and aromatic CH), 5.78 (ester C=O), 6.55 (nitro), 7.45 (nitro), and 7.88 µ (ester c-o). The crude alcohol 45 was purified by chromatography on Florisil, and the purified alcohol 45 had ir. and ~ 76 n.m.r. spectral properties that were in accord with either structure 45 or structure lo The ir. spectrum had bands at 3.00 (hydroxyl), 3.33 (vinyl CH), and 6.07 µ (C=C}; the n.m.r. spectru.rn showed the presence of two vinyl o 5.65 (multiplet, C~=cg) and the presence of the hydroxymethyl hydrogens at o 3. 50 (doublet, :I. = 5 Hz., hydrogens at CH-C!!.2-0} and at o 2.83 (singlet, OH). However, because the ester 52 was unreactive under solvolytic conditions, the ~ anti-configuration was assigned to c 7 of alcohol ~· The minor alcohol 53 obtained from the Florisil chromatogram above was rechromatographed on Florisil. alcohol 53 The (99% pure by v.p.c. analysis) had ir. absorptions ~ at 3.00 (hydroxyl), 3.33 (vinyl CH), and 6.07 µ and (C=C) produced a n.m.r. spectrum that revealed the presence of two vinyl hydrogens at o 5.52 (multiplet, CH=CH}, the presence of three methyl hydrogens at o 0.92 (doublet, !I_ = 6 Hz., C H-CH 3 ) , and the presence of a hydrogen on carbon adjacent to oxygen at o 3.13 (multiplet, CE-0). These data suggested the structure of alcohol 53 as that illustrated ~ below, and, thup the acetate 51 had the structure also ~ illustrated. ~1:lese products are a manifestation of the migration of the exocyclic double bond into the ring at some stage prior to the hydroboration of olefin 41. ~ The amount of alcohol 53 available was too small to determine ~ the position of the double bond. 77 53 In order to formulate the stereochemistry of the morpholino group of the alcohols 4 2 and 43, the eight ~ """"" possible conformers 4la-h of the two isomers of the olefin ~ 41 are exan1ined. The most stable conformer of each isomer should have the bulky morpholino group equatorial. isomer ~' which has a ~-morpholino In the group on ring A, conformer 4lb has both rings in the more favorable chair ~ conformation. Thus, conformer 4lb should be the predominate ~ species of the isomer 4 la-d. ~ The isomer 4le-h, which has a trans-morpholino group ~ on ring A, requires ring A to be in a boat conformation, if the morpholino group is to be equatorial. Ring B should assume the chair conformation as in conformer ~1 however, if this ring also takes on the boat conformation, as in conformer 4lh, the bicyclo [ 3.3.l]nonane rigidity and becomes flexible. skeleton loses its By becoming twist-boats, both rings can be relieved of some of the eclipsing interactions that are produced in the boat conformation. Thus, the conformer 4lh may either be approximately equal in ~ 78 CH 2 CH2 ~ ....... R 2 CH 2 ~ /R . R H CH -7.1(CH2 ' l/j H ' d ~ H H 4la 4J.b 4lc 4ld ~ ~ ~ ~ l(CH2 CH2 ~;-> >.. H' v( """" R 4le 41f ~ CH2 >.. ~ ~ ~ 4lh ~ OH HO H OH R H 42a ~ R = R 42b ~ H R R R R 43a ~ 79 stability to conformer ~ or be even more energetically favorable than conformer ~· Thus both conformers 4lg ~ and 4lh may be present in the mixture of the olefin 41. """"" """"" When the olefin 41 is hydroborated, the borane """"' should attack the double bond from the less hindered side. Hydrogen peroxide oxidation of the alkylborane then should give the alcohol 42a from conformer 4lb, alcohol 42b .,..,..,,... from ~ ~ conformer ~' and alcohol~ from conformer ~· 80 CONCLUSION Attempts on the synthesis of the alcohol 1 starting """" from l,4-dioxaspiro[4.5]decan-8-one (7) have been unsuccessfui """"" to date. The main difficulty that arose in two reaction sequences (Scha~es 1, 5, and 6) was the removal of the morpholino group by an amine oxide pyrolysis reaction. In the case where amine 8 was oxidized, and the resultant """" amine oxide was pyrolyzed, no elimination products were obtained. In the case where amine 11 was carried through ~ the same reactions sequence (oxidation followed by pyrolysis), the keto acetate ,,..,...,,... 48 was obtained instead of the desired acetate ,,..,...,,... 54. The keto acetate 48, ,,,_ however, afforded adamantanone (44) upon chromatography on alwnina (I). """" OAc 54 ,,....,... In a third reaction sequence (Scheme 4) the dimethylamino moiety replaced the morpho l ino group. A reasonably good general method for the preparation of dL~ethylamino enamines was developed, but, since the Wolff-Kishner reduction of amino ketone 33 afforded amine 10 in only 4.3% yield, ,,..,...,,... """" the sequence was abandoned. 81 EXPERIMENTAL Melting points (m.p.) were determined on a hot stage and are corrected. Boiling points (b.p.) are uncorrected. Infrared (ir.) spectra were determined on a Perkin-Elmer Infracord Model 137 spectrometer. Nuclear magnetic resonance (n.m.r.) spectra were obtained on Varian Associates A-60 and A-60A spectrometers and are reported in delta (o), parts per million (p.p.m.) downfield from tetramethylsilane. Vapor phase chromatography (v.p.c.) was performed on Loenco Model 15B and Model 70 chromategraphs with a thermal conductivity detector and on a Perkin-Elmer Model 881 chromatograph with a hydrogen flame detector. The activity of the alumina used for chromato- graphy was standardized according to the procedure of Brockmann and Schodder (27). Microanalyses were performed by Spang Microanalytical Laboratory, Ann Arbor, Michigan, and Galbraith Laboratories, Inc., Knoxville, Tennessee. Preparation of cis- and trans-Quinitol (15). Hydro""""" quinone was hydrogenated under 146 atm. pressure for 5 hr. at ~""""""'~~~~ 100° according to the method of Owen and Robins (9) to afford in 86% yield cis- and trans-quinitol (15); """" (KBr) 3. 08 µ ir. {OH) • Preoaration of 1 , 4-C clohexadione (13). ~ """' ~ A 200-g. (lo72 mole) sample of cis- and trans-quinitol {15) dissolved """ 82 o0 in 800 ml. of reagent grade acetone was oxidized at by dropwise addition of 858 ml. (2.29 moles) of 2.67 P chromic acid reagent. (10) to the stirred solution of the diol 15. After the addition of oxidant was completed, the reaction mixture was stirred for 1 hr., and then the acetone supernatant was decanted from the inorganic sludge, which was washed with two portions of acetone and discarded. The combined acetone solution was dried super- f icially over calcium chloride and was reduced in volume on the rotary evaporator. The concentrate was treated with sodium bicarbonate to neutralize any acid present, was filtered, and was distilled to give 136 g. of crude dione 13, ,,...,,... b.p. 118-120 0 (15 :rrun.), which upon crystallization from ether afforded 98.0 g. (51%) of dione ,,,,_... 13: lit. m.p. 78° (11); ir. (CHC1 ) 5.80 µ 3 o 2.38 p.p.m. m.p. 77-78°, (C=O); n.m.r. (CHC1 ) 3 (s.). The procedure of Courtot was used (8). A 56.0-g. (0.500 mole) sample of 1,4-cyclohexadione (13), a 47.5-g. .,.._ (0.766 mole) portion of ethylene glycol, 0.50-g. (2.5 mmole) sample of £-toluenesulfonic acid monohydrate, and a 100-ml. portion of benzene were placed in a 500-ml. flask fitted with a magnetic stirring bar and a water separator under the condenser. After the reaction was stirred for 1.5 hr. at 83 25°, the solution was heated under reflux for 15 min., and the water was re.'noved \·; ith the aid of the separator. The solution was cooled to 25 0 , and washed with a dilute solution of potassium carbonate to remove the acidic catalyst, was washed with water, dried over anhydrous magnesium sulfate, filtered, and was concentrated on the rotary evaporator to give 82.5 g. of crystalline residue, which was shown to be a mixture of ketone 7 and diketal 16 by v.p.c. analysis. The mixture was divided into two approximately equal portions, and each portion was dissolved in a 200-ml. portion of ethanol (95%). Each ethanol solution was added to a stirred solution of 120 g. (0.57 mole) of sodium bisulfite in 90 ml. of water. The crystalline addition compound was removed by filtration, washed with ethanol, and then dissolved in water. The aqueous solution was extracted with benzene to ra'nove any remaining diketal 16. The """' ethanol filtrates were concentrated on the rotary evaporator, and the residues were combined with the combined benzene extract, which was washed with brine, dried over anhydrous magnesiu.iu sulfate, and ·was concentrated to afford 42. 2 g. (42%) of diketal 16: ~ m.p. 79-80°, lit. m.p. 79-79.5° (8); ir. (CHCl3) 3.38 p, (CH); n.m.r. (CHC13) 0 3.48 (s., 8, ethylenedioxy C!!.2) and 1.30 p.p.m. (s., s, carbocyclic CH 2 ). 84 The aqueous solutions of the bisulfite addition compound were made basic with potassium carbonate and extracted with three portions of benzene. The combined benzene extract was washed with brine, dried over magnesium, and was concentrated on the rotary evaporator to give 36.9 g. of crystalline residue, which was recrystallized from ether-ligroin (30-60°) affording 27.4 g. ketone 7: (35%) of m.p. 72-73°, lit. m.p. 72-73° (5, 8}; ir. (CHC1 ) 5.82 µ {C=O}; n.m.r. 3 (CHC1 ) o 3.59 {s., 4, 3 ethylenedioxy CH 2 ), 2.05 (m., 4, CH 2 C!!.2C=O), and 1.57 p.p.m. (m., 4, c~2CH2C=O). Preparation of Enamine 17. A 5.20-g. (33.3 mrnoles) """""' ~ """" sample of ketone 7 was dissolved in 50 ml. of benzene. A ~ 5.60-g. (66.6 rnmoles) portion of morpholine and 0.1-g. portion of E_-toluenesulfonic acid monohydrate were added, and the reaction mixture was heated under reflux overnight under a water trap. After the benzene and excess morpholine were removed by distillation, the product was distilled to give 5.54 g. (74 %) of colorless enamine 17: A/'- (0.7 nun.); n (C=C); n.m.r. 24 b.p. 130° -D 1.5134; ir. (film) 3. 28 (=CH) and 6.08 (benzene) o 4.43 (m., 1, =C.!:!_), 3.82 (s., 4, o-c!!_2C!!,2 -o), 3.60 (m., 4, {0-C!!_2 CH 2 -N), and 2.68 p.p.m. (m., 4, o-CH2CH2-N). µ, 85 Alkyla tion of Ena.."'Tline 17 'tvi th Acrolein. """""° ~,,....,,. ,,..,,,.,,...,. ~ ~ A 2. 5-g. sample (45 mmoles) of freshly distilled acrolein (Matheson, Coleman, and Bell) containing a trace of hydroquinone was added · slowly to a solution of 9.84 g. {43.7 m.."1'toles) of enamine 17 ~ in 50 ml. of dry methanol under a nitrogen atmosphere. The reaction was stirred at 25° for 24 hr., then the methanol was removed under reduced pressure. The residue crystallized upon trituration with methanol, and the solid was recrystallized from dry methanol to give 12.2 g. ether 19: m.p. 80-87°; ir. (C=C); n.m.r. 4.65 (m., 1 1 (benzene) C~=CH-0), (100%) of vinyl (CHC1 ) 3.29 (=CH) and 6.05 µ · 3 o 6.16 (d., 1, and 3.67 p.p.m. ~ = 6 Hz., 0-CH=CH), (s., 4, Prenaration of Mornholino Ketone 20. ~,,..._....~~,,....,,. 2 2 O-CH c~ -o). A 12.2-g. (43.5 mmoles) sample of vinyl ether 19 prepared above was """" dissolved in 20 ml. of dry methanol and heated under reflux for 1.5 hr. under nitrogen. After the methanol was removed on the rotary evaporator, the residue, which was examined by ir. spectroscopy, showed no change in composition. The residue was dissolved in 20 ml. of benzene and heated under reflux for two days under nitrogen. The reaction mixture was concentrated on the rotary evaporator to give an oil that deposited 2.79 g. trituration with ether. (23%) of crystalline material upon Recrystallization from acetonitrile gave co l orless morpholino ketone .,..,,...,,... 20: m.p. 134-135°; ir (KBr) 86 (C=O) 1 n.m.r. (CHC1 3 ) o 3.92 (s., 4, O-C!!,2C!!, -o), 2 3.67 (m., 4, o-c~2CH2-N), and 2.44 p.p.m. (m., 4, O-CH2CH2-N). 5.80 µ ~- N, 4.98. Calcd. for C15H23N04: Found: c, 64.041 H, 8.241 C, 64.131 H, 8.32: N, 5.260 Preparation of Amine 22. ~_..,,..~-- A 1. 00-g. (3. 6 nunoles) sample of morpholino ketone ,....,.._ 20 was combined with 1.0 ml. (16 nunoles} of 85% hydrazine hydrate, 10 ml. of redistilled diethylene glycol, and 3 ml. of benzene. After the mixture was heated under reflux for 30 min. under nitrogen, a 0.50-g. portion of 85% potassium hydroxide was addedv The bath temperature was raised to 180°, and the lower boiling constituents were removed by distillation. After 1 hr. the reaction mixture was cooled to 25° and was poured into 30 ml. of water. The aqueous solution was extracted repeatedly with ether. The ethereal solution was washed with brine, was dried over anhydrous magnesium sulfate, filtered, and was concentrated on the rotary evaporator to -- give 0.92 g. (38%} of oily amin.e 22: ir. (film) 3.40 µ (CH) 1 n.m.r. (CHC1 3 ) o 3.48 (s., 4, OC!!,2C!!, 20}, 3.27 (m., 4 1 OC!!_iCH2N), and 2.05 p.p.m. (m., 4, OCH2C!!.2N). Amine Oxide 23 Pvrolvsis. ----~--~ A 0.92-g. (3.4 nnnoles) sample of amine 22 dissolved in 5 ml. of methanol was """"' oxidized with 1.0 g. (8.9 romoles} of 30% hydrogen peroxide. The reaction was heated under reflux for 1.5 hr. The 87 solution was concentrated on the rotary evaporator, and the residue dissolved in water in order to decompose the excess peroxide with a trace of catalase. The water was removed by azeotropic distillation with ethanol and benzene on the rotary evaporator to give a residue, which was heated under reduced pressure (20 nun.) at 100° for 30 min., at 150° for 15 min., and finally at 180-200° for 2 hr. When the temperature reached 180°, the contents of the pyrolysis flask very quickly turned black, and the small amount of distillate collected still had the morpholino group: n.m.r. (CCl4) o 3o81 (s., 4, OC!!,2C!!_20), 3.68 (m., 4, OC!!,2CH2N), and 2.48 p.p.m. (m., 4, OCH2CH2N); the rest of the spectrum closely resembled that of the starting amine ;v.. 22. Preparation of Morpholino Ketone 24. A 1.5-g. ,,..,... (5.6 nunoles) sample of morpholino ketal 22, which was pre~ ~ ~ ~ ~ pared by the Wolf f-Kishner reduction of the crystalline morpholino ketone 20, was dissolved in a 10-ml. portion· of ~ 1:1 acetone-water. A 0.5-ml. portion of concentrated hydrochloric acid was added, and the reaction was heated under reflux for 5 min. After the acetone was removed by evaporation on the rotary evaporator, the acidic solution was neutralized with potassium hydroxide. The solution was extracted with ether, and the ethereal extract was washed 88 with brine, dried over anhydrous magnesium sulfate, filtered, and was concentrated on the rotary evaporator to give an oily residue. Molecular distillation of the residue at 160° (0.4 mm.) yielded 1.1 g. (90%) of morpholino ketone 24: ~ ir. (film) 5.88 (C=O) and 8.93 µ (C-0); n.m.r. (benzene) 03.70 Cm., 4, o-c!,!_ 2ca 2 -N) and 2.35 p.p.m. Cm., 4, o-cH 2 cH 2 -N}. Amine Oxide Elimination on Amino Ketone 24~ ~~~.--~~~ A 0.31-g. (1.4 mmole) sample of amino ketone ,,_ 24 was dissolved in 1 ml. of methanol. A 0.45-g. (4 nunoles) portion of 30% hydrogen peroxide was added, and the solution was allowed to stand at 25° for 19 hr. After the methanol was removed on the rotary evaporator, and after the residue was dissolved in water, a trace of catalase was added to destroy the excess peroxide. The water was removed by azeotropic distillation with ethanol and benzene on the rotary evaporator, and the residue was pyrolyzed at 200° (20 mm.) a The con- tents of the pyrolysis flask turned black, and nothing was collected in the receiving traps .. Morpholino Ketone 21. ~~-- Morpholino ketone 21 was ~ prepared in 70% yield from 1-morpholinocyclohexene (18) according ~ to the procedure of Foote and Woodward (14): (O.l mm.), lit. b .. p. 141-147° (1 mm.) lit. E.25 Q_ 1.5182 (14-); ir .. (CHC1 ) 5.84 µ (14). 3 b.p .. 106-110° (14); !!20E. 1.5202, (film) 5.83 µ , (C=O), litG ir. 89 Preparation of Amine 25. A. From Morpholino Ketone 21. .,...,... ~~~.,...,... A 23.6-g. (0.106 mole) sample of morpholino ketone ,.,.., 21 pre~"""~-- -- pared from 1-morpholinocyclohexene {18) was combined with 49.5 g. (l.O mole) of 100% hydrazine hydrate and 300 ml. of reagent grade diethylene glycol. The mixture was heated under reflux for 2 hr., and a 30.0-g. portion of 85% potassium hydroxide was added. The lower boiling solvents were removed by distillation, while the temperature of the heating bath was raised to 240°. After 3 hr. a 240° the reaction was cooled to 25°, diluted with water, and extracted with four 50-ml. portions of benzeneo The benzene extract was washed twice with brine, was dried over anhydrous sodium sulfate, filtered, and was concentrated on the rotary evaporator to give an oily residue. Distillation of the -- residue gave 7.04 g. (32%) of amine 25: 25 ~ b. p. 8 5-8 6° ( O. 3 mm.) ; £ 105109; n.m.r. {benzene) o 3.70 {m., 4, o-c~ 2cH 2 -N) and 2.35 p.p.m. {m., 4, 8.92 µ OCH2C~2-N); ir. (film) 3.43 (CH) and (C-0 or C-N). ~· N, 6.69. B. ,,..,.. Calcd. for C13H23NO: Found,: c, 74.59; H, 11.07; c, 74.89; H, 11.10; N, 6.89. Preoaration from Moroholino Ketone 24. ~ ~~ ~-- A 1.00-g. {4.48 mmoles) sample of morpholino ketone .__,.. 24 prepared from -- morpholino ketal 22 was combined with 2.43 ml. of 100% hydrazine hydrate and 20 ml. of reagent grade diethylene 90 glycol. The reaction was carried out as described above to give after molecular distillation (80°, 0.6 mm.) a.so g. (53%) of colorless amine 25: ir. (film) 3.43 (CH), and """"" 8.92 ~ (C-0 or C-N), identical to their. spectrum of -- amine 25 prepared from morpholino ketone 21; n.m.r. (benzene) """"" Bicyclo[3.3.l]non-2-ene (26). ,,..,... A. From Amine 25. A S.2-g. (25 mmoles) sample of amine 25, which was prepared ~ ~~~ ~ from morpholino ketone 21 .,.._ was combined with a 4.0-g. (36 mmoles) portion of 30% hydrogen peroxide and 10-ml. portion of methanol. The solution was heated under reflux for 5 hr., and the excess peroxide was then destroyed with platinum black. The solution was filtered and concentrated on the rotary evaporator to yield a colorless residueu The residue was heated at 125-140° {20 mm.) with a receiver cooled to -10° until no more decomposition was observed. in the receiver was dissolved in ether. The residue The ethereal solution was washed in succession with water, dilute hydrochloric acid, dilute sodium bicarbonate solution, and brine. The solution was dried over anhydrous magnesium sulfate, filtered, and was carefully concentrated by distillation yielding 1.15 g. (38%) of olefin ,.,.. 26: m.p. 99-101°v lit. m.p. 103- 105° (16); ir. {CC1 4 ) 3.33 {=CH), 5.98 (C=C), and 14.25 µ (cis CH=CH) 1 n.m.r. (CHCl3) 8 S.84 p.p.m. (m., 2, C!!_:::;C!,!.). 91 ~ ~ _..._""">Jv.."""'VV""""-...~"""'>Jv.."-VV'Ae ,_ CalcitUn Hvdride Method. ~~~ A benzene suspension of 9.8 g. (0.10 mole) of cyclohexanone, 2.1 g. (0.050 mole) of calcium hydride, and 10 g. of dL~ethylamine was stirred for 6 hr. under a Dry-ice condenser. The solution was distilled to give after a forerun of benzene 5.8 g. {46%) of the enamine 28: b.p. 168° (760 nun.), lit. b.p. 175.5° (15); ir. (film) 3.30 (=CH), 3.60 (CH), and 6.10 µ (C=C), v.p.c. (6 ft. of 5% Carbowax 20M) 75% purity (25% cyclohexanone). B. Lithium AlurnintUn Hvdride Method. ---~~~~ In a flask fitted with a Dry-ice condenser, a 1.9-g. (50 mmoles) sample of lithitUn aluminum hydride {95%, Metal Hydrides, Inc.) was dissolved in 25 ml. of dry ethero Excess dimethylarnine was added, and after 1 hr. a 9.80-g .. (0.100 mole) sample of cyclohexanone was added with stirring. The reaction was stirred overnight, and the excess dimethylamine was allowed to escape through a drying tube. Distillation of the residue, after re~oval of the solvents, gave 6.8 g. {54%) of colorless enamine 28: ~ b.p .. 30 0 (1 .. 5 mm .. ); ir. (film) 3.30 (=CH), 3.60 (CH), and 6.10 µ (C=C) .. Preparation of Amino Ketone 29. ~"""' ~ ~,..,..,.., A 11.0-g .. {65 rnmoles) sample of 1-dimethylarninocyclohexene (28) (75% pure by . """' v.p.c.) prepared by the calcium hydride method was dissolved in 10 ml. of dry methanol. A 3o65-g. (65 mrnoles) portion 92 of freshly redistilled acrolein was added dropwise while the reaction flask was cooled in an ice bath. After the reaction was stirred at 25° for 15 hr., the solution was concentrated on the rotary evaporator, and the residue was distilled to give 6. 7 g. (55% based on acrolein) of dimethylamino ketone 29: ~ 3.62 {CH) and 5.83 µ b.p. 60-90 0 {O.l nun.) 1 ir. (film) {C=O). Preoaration of Amine 9. ~~~~ A solution of 6.7 g. {37 nunoles) of the ketone 29, 25 g.,· (0.50 mole) of 100% ~ hydrazine hydrate, 150 ml. of reagent grade diethylene glycol, and 10 g. of 85% potassium hydroxide was heated for 3 hr. under reflux. After the lower boiling liquids were removed by distillation, the reaction was heated for 1.5 hr. at 200°. The usual workup as described for amine 25 gave ~ 2.5 g. {41%) of the amine 9: ~ b .. p ., 5 0 0 ( 0 .1 mm • ) ; ir • ·(film) 3.62 µ (CH); n.rn.r. (benzene) 8 2.08 p.p.m. (s., 6, CH NCH ). 3 3 Bic B. ~ From Amine 9. ~~~ A methanol solution of 2.5 g. (15 mrnoles) of amine 9 and 2.2 g. (20 mmoles} of 30% hydrogen peroxide was stirred overnight at 25° and then heated under reflux for l hr. After the excess peroxide was destroyed with platinum catalyst, the solution was filtered, and concentrated on the rotary evaporator, to give the amine oxide 30 that was dried under ~ 93 reduced pressure in a desiccator. The dried amine oxide 30 ~ was heated to 180° under reduced pressure (20 nun.) while vigorous decomposition took place. The distillate was dissolved in pentane, and the pentane solution was washed with dilute hydrochloric acid and water, dried, and was filtered through a short column of alumina (I). Distillation through a 12 in. Widmer column removed most of the pentane, and the residual solvent was removed at o0 under slightly reduced pressure {about 100 mm.) to give 1.45 g. (80%) of crystalline olefin _....,... 26 : m.p. 99-101°, lit. m.p. 103-105° (16) 0 Preparation of Enamine 320 ~~~-- A 15.6-go (0.100 mole) sample of ketone 7 was added to a mixture of 1.9 g. (50 ~ nunoles) of lithium aluminum hydride (95%, Metal Hydrides, Inc.) in 25 ml. of dry ether. and excess dimethylamine as described in the preparation of enamine 28. Distillation of ""' the reaction residue gave 6.61 g. (36%) of enamine 32, ""' b.p. 75-88° co.a mm.), which was redistilled to yield 6.44 g. of enamine 32: _... 6.09 µ b.p. 85-90 0 (O.Smm.); ir. (film) (C=C) .. ~~.U· A 1.97-g. (35.2 nunoles) sample of freshly distilled acrolein stabilized with a trace of hydroquinone was added slowly to a solution of 6.44 g. 94 (35.2 mmoles) of enamine ,,..,,... 32 in 10 ml. of dry methanol with cooling in an ice bath. After the reaction was stirred for two days at 25°, the solvent was removed on the rotary evaporator, and the residue was distilled to give 3.92 g. of oil, b.p. 110-142° (0.2 mm.), which had an infrared band at 6.05 µ {C=C) due to the vinyl ether. The distillate was dissolved in methanol and heated under reflux with 100 mg. of dimethylamine hydrochloride. After 3 hr. the reaction was cooled to 25°, and potassium carbonate was added to neutralize the amine hydrochloride. The solution was filtered and was concentrated on the rotary evaporator to give a residue that was dissolved in ether and centrifuged to remove inorganic solids@ The clear supernatant was concentrated on the rotary evaporator to give 4.0 g. of a dimethylamino . ketone ,,....,.. 33: ire (48%) (film) 3.61 (CH) and 5.81 p. (C=O). ~~~~~»· A mixture of 3.71 ge (15e5 mmoles) of dimethylamino ketone 33 and 20 g. {0.40 mole) of 100% hydrazine hydrate was stirred ;v.... at 25 0 for 2 hr. A 3.31-g. portion of 85% potassium hydroxide and 60-ml. portion of reagent grade diethylene glycol were added. After the reaction was heated under reflux for 4 hr., the te.~perature of the heating bath was raised to 200°, and the lower boiling liquids were removed 95 by distillation. Steam distillation of the reaction mix- ture gave a cloudy distillate, which was extracted with ether. The ethereal extract was washed with water and brine, dried over anhydrous magnesium sulfate, and was concentrated on the rotary evaporator to give 2.14 g. (75%} of ketal .,,...,... 34; ir. (film} 3.42 µ (CH}; n.m.r. (benzene) 5 3.70 (s., 4, o-c~ c!!_ -o) 2 2 and o.98 p.p.m. (t., 3, J = 6 Hz., CH2c!!.3>. The pot residue from the steam distillation was diluted with water and extracted with chloroform. The extract was washed with water and brine, was dried over anhydrous magnesimn sulfate, and was concentrated on the rotary evaporator to give 1.47 g. of dark oil, which was distilled to yield an oil, b.p. 98-115° (0.2 nun.). Redistillation of the oil gave 0.13 go (4.3%) of amine 10: ,,.,,,... b.p. 103-108° (0.2 nun.); ir. (fiL-n} 3.62 µ : (CH}; n.m.r. (CHC1 3 ) o 3.70 (m., 4, o-c!!.2C!!.2-o) and 2.04 p.p.m. (rn. , 6, CH -N-C!!_ ) • 3 3 ~· Calcd. for C13H23N02: c, 69.29; H, 10.29; N, 6.22. Found: c, 68.97; H, 10.26; N, 6.50, 6.47. ~.N-..N'-~._.._...f'VV'-'V'~'V'J"..N'......,...IV"""1V'~~~~""",-;x,l;,7'. (35). ~ An adaptation of the procedure of Greenwald and co-workers (21) was employed. A 20.5-g. (12.0-g. sodium hydride, 0.500 mole) portion of 58 . 6% sodium hydride 96 dispersion (Metal Hydrides, Inc.) was added to a 1-1. flask fitted with a magnetic stirring bar. After the hydride was washed with 50 ml. of anhydrous ether, a 250-ml. portion of dry dimethylsulfoxide (DMSO, Baker Analyzed Reagent) was added. The reaction was heated in a nitrogen atmosphere at 55° (oil bath) for 4 hr. with stirring and then was cooled to 25°. A solution of 202 g. (0.500 mole) of methyltriphenylphosphonium iodide (37) ,,...,.. prepared from triphenylphosphine and methyliodide in 500 ml. of DMSO was added, and the resulting solution was stirred for 30 min. at 25°. A 76.0-g. {0.487 mole) portion of 1,4- dioxaspiro[4.5]decan-8-one (7) was added slowly, while the .;v-.. flask was cooled in an ice bath. After the addition was completed, the ice bath was removed1 and the solution was stirred overnight at 25°. The DMSO solution was extracted with five 200-ml. portions of a solvent composed of equal parts of ether and pentane. The extract was washed once with water and then with brine, was dried over anhydrous magnesium sulfate, and was concentrated on the rotary evaporator at 5° to yield 56.8 g. of oil. The DMSO solution was then diluted with 500 ml. of ice water and was reextracted with five 200-ml. portions of ether-pentane. After being washed, dried, and concentrated as described above, the second extract gave an additional 16.5 g. of oil. The combined crude product (73.3 g.) was distilled to yield 97 48.7 g. (65%) of olefin 35: .;v... b.p. 89-90 0 (22 mm.); ir • (film) 3.28 (=CH}, 6.08 (C=C}, and 11.02 µ (=CH); 2 (CC1 ) o 4.58 (broad band, 2, =c~ }, 3.83 4 2 (s. 1 4, OC_!! CH 0), 2. 25 (m., 4, c . and. c allylic hydrogens}, 2 2 7 9 and 1.59 p.p.m. (m., 4 1 c and c hydrogens}. 10 6 Anal. Calcd. for c a o i c, 70.10; H, 9.15. 9 14 2 Found: c, 70.15; H, 9.06e n.m.r. ~ ~ 4-~1ethylenecyclohexanone solution of 23.0 g. ~) • To a (0.15 mole} of 8-methylene-1,4- dioxaspiro [4.S]decane (35} _... in 70 ml. of acetone was added 60 ml. of 2 ~hydrochloric acid. After having been heated under reflux for 5 min., the solution was cooled and neutralized with 4.81 g. of sodium hydroxide pellets (pH 7). The solution was diluted with brine and extracted with four 70-ml. portions of methylene chloride. The organic extract was dried over anhydrous magnesium sulfate and concentrated to yield 22.5 g. of oil, which was· distilled through a six inch Vigreux colu.~n to give 15.8 g. of enone 3g : b.p. 86~ 95 0 (50 mm.}. To remove traces of ethylene glycol, the distillate was diluted with pentane and was washed with water. The organic layer was· dried and concentrated to· yield 14.0 g. (85%) of enone ,,,..,.., 38 that was contaminated with 10% (v.p.c. analysis} of the starting ketal. The crude enone 38 _... was satisfactory for the preparation of the morpholino 98 An analytical sample was purified by a second enamine 39. hydrolysis and distillation to give enone 38: ,,_ b.p. 87- 90° (50 nun.); ~22£ 1.4729; ir. (film) 3.28 (=CH 2 ), 5.82 (C=O}, 6.05 (C=C}, and 11.13 µ (=CH 2 } 1 n.m.r. (CC1 4 ) 54.58 (broad band, 2, =C!f2) and 2.16 p.p.m. (broad band, 8, ring hydrogens) • Anal. Calcd. for C7H100: C, 76.33; H, 9.,15. c, 76.43; H, 9.11. Found : The 2,4-dinitrophenylhydrazone was prepared and recrystallized from ethanol: Anal. N, 19.30.. m .. p .. 154-155 0 .. Calcd .. for c 13 Hi 4 N4 o4 : Found: C, 53.94; H, 4.84; N, 19.24. P~ep~~A~~9I1- of Enamine 39. ~.--~.-- 13.0 g. C, 53.,79; H, 4.86; A benzene solution of (0.12 mole) of crude 4-methylenecyclohexanone (38) ,,...,... that contained 10% (v.p.c. analysis) of 8-methylene-l,4dioxaspiro [4 .5]decane (36), 30.5 g. ' ,,....,...,.. (0.35 mole) of morpholine and a trace of £-toluenesulfonic acid was heated under reflux overnight with a water trap in a nitrogen atmosphere. Most of the benzene was removed by distillation at a'bnospheric pressure. A small quantity of powdered barium hydroxide was added to the flask to neutralize the acidic catalyst, and the remaining solvent was removed under reduced pressure (1 nun.). Distillation of the· residue gave 14.9 g .. of oil: b.p. 77-84° (0 .. 4 nun.). Redistillation of the oil gave 99 14.5 g. (69%} of colorless enamine ...,,... 39: b.p. 80-84 0 (0.4 mm.}; ir. (film} 3.27 (=CH 2 }, 6.08 (C=C-N}, and 11.18 µ (=CH 2 }; n.m.r. (C6I-I6} 5 4.82 (broad band, 2, =CH 2 }, 4.58 (t., 1, J = 3.5 Hz., C~=C"':'N}, 3.67 (m., 4, C!!,2-0}, 2.30 (m., 4, 2.92 (m., 2, c allylic hydrogens), and 2.70 p.p.m. 3 (m., 4, c 5 and C6 allylic hydrogens). c~ -N}, 2 Anal. N, 7.81. Calcd. for c 11 H17 NO: Found: C, 73.70; H, 9.56; C, 73.70; H, 9.71; N, 7.72. Preparation of Morpholino Enone 40. In a nitrogen ,,_ ~ ~"""' atmosphere a 4.54-g. (81.0 nunoles) portion of freshly ~ redistilled acrolein (Matheson, Coleman and Bell) stabilized with a trace of hydroquinone was added to a solution of 14.S g. (81.0 mmoles) of l-morpholino-4-methylenecyclohexene (39) ...,,... in 30 ml. of dry benzene. After the reaction had been stirred at 25° for 5 hr., the solution was concentrated on the rotary evaporator, the residue was redissolved in 70 ml. of dry tetrahydrofuran (THF}. The THF solution under nitrogen was heat~d under reflux for 60 hr., during which time the course of. the reaction was followed by the removal of small aliquots that were examined by ir. and n.m.r. spectroscopy until the 5. 8 0 µ ir. band no longer increased in relative intensity. The solvent was removed on the rotary evaporator, and the residue · was purified by a single molecular distillation (75-100° I Q·9 05 mm.) tO yield 14 .1 g • 100 {74%) of colorless morpholino ketone 40: ir. {film) 3 .27 {=CH2), 5.80 (C=O), 6.09 {C=C), and 11.36 µ (=CH 2 ); n.m.r. 5 4.75 (C6H 6 ) (broad band, 2, =C.[2), 3.52 (m., 4, C!!.2-0), and 2.28 p.p.m. Anal. N, 5.95. (m., 4, C!!,2 -N). Calcd. for c 14 H21 No 2 : Found: c, 71.46; H, 8.99; C, 71.43; H1 8.911 N, 6.12. Preparation of ~lorpholino Olefin 41. A solution of ~""'~~~ 8.27 g. (35.2 nunoles) of the enone 40, 124 g. {2.48 moles) of 100% hydrazine hydrate and 40 ml. of ethanol was allowed to stand at 25° for 1 hr. A 330-ml. portion (3.5 moles) of diethylene glycol and a 51-g. ·(0.78 mole) portion of 85% potassium hydroxide pellets were added. The reaction was heated for 5 hr. in a nitrogen atmosphere at a bath ta~perature of 200 6 , while the lower boiling constituents were r~~oved by distillation. The pot residue and the distillate were each diluted with water and separately extracted with ether. The extracts were washed with water, dried over anhydrous sodium sulfate, and concentrated to yield 5.13 g. of oil from the pot residue and 2.63 g. of oil from .the distillate. The combined crude product was distilled to give 7 .33 g. (95%) of amine 41: b.p. 69 0 . {0.06 mm.); ir. {film) 3.28 (=CH ) , . 6.10 (C=C), and 2 11.40 µ (=CH ); n.m.r. 2 (C6H6) 5 4.61 (broad band, 2, =C.!!2), 101 3.55 (m., 4, C!!.2-0), and 2.27 p.p.m. ~· N, 6.33. Calcd. for Found: CJ_ 4 H 23 No: (m., 4, C.!!i-N). C, 75.97; I-I, 10.47; C, 76.02; H, 10.40; N, 6.41. Hvdroboration of Morpholino Olefin 41. ~,,...,,....~~,,...,,.... atmosphere a 52-ml. (17 mmoles) portion of 0.33 M diborane in tetrahydrofuran (THF) solution of 7.18 g. In a nitrogen (23) was added dropwise to a THF (32.5 mmoles) of morpholino olefin .,..,,... 41 • After the solution was stirred at 25° for 12 hr., a 13-ml. portion of 3 N sodium hydroxide and 13-ml. portion of 30% hydrogen peroxide were added. After having been stirred for 45 min., the solution was extracted with ether. The ethereal solution was dried over anhydrous magnesium sulfate and concentrated to give 7.93 g. of viscous oil, which partially crystallized. The solid was recrystallized from ether yielding 3.36 g. (43%) of colorless amino alcohol 42: -- m.p. 104-105°; ir. (KBr) 3 .10 µ'. (OH) • Anal. N, 5.85. CalGd. for C14H25N02: Found: c, 70.25; H, 10.53; C, 70.32; H, 10.50; N, 5.77. The mother liquors gave 4.13 g. (53%) of oily amino alcohol ,,..,,,...,.. 43, which -was molecularly distilled at 100° ( 0. 03 mm.) to yield an analytical sample: 2.93 ~ µ ' ir.. (film) (OH). Anal.. N, S.85. Calcd. for c 14 H25 No 2 : Found: c, 70.25; H, 10.53; -c, 70.35; H, 10.41; N, 5 .. 820 102 Acetvlation of Crvstalline A.i."'!lino Alcohol 42. A ~.....,...~~~""" 500-mg. (2.08 mmoles) sample of crystalline amino alcohol 42 was dissolved in 4.8 ml. of dry pyridine. ,,...,.... After a 1.6-ml. (large excess) portion of acetic anhydride was added, the reaction was heated at 95° for 10 min. The solution was cooled and was concentrated on the rotary evaporator. In order to remove the residual reagents, the residue was dissolved in toluene, and the solution reconcentrated on the rotary evaporator to give an oil, which crystallized upon standing to afford 622 mg. of amino and 0 acetate~: rn.p. 57-60 ; ir. (100%) (CC1 4 ) 5. 72 {acetate) a.o5 µ cc-o). Anal. N, 4.98. Calcd. for c16 H2 7 No 3 : Found: c, 68.29; H, 9.67; ·C, 68.07; H, 9.59; N, 5.14. Amine Oxide Elimination on Crvstalline A.i."'!lino Acetate ~~~~~~~ 46. .....,... A. """" In Toluene at 110°. """" ~ ~ ~ A 1.00-ge (3.56 mmoles) sample of crystalline amino acetate 46 dissolved in 10 ml. of npropanol was oxidized with 1.0 ml. hydrogen peroxide. (9.6 rrunoles) of 30% The reaction was heated under reflux for 12 hr., and the excess hydrogen peroxide was destroyed with platinum catalyst, which was then removed by centrifugation. The supernatant was concentrated on the rotary e v a porator to give an oil, which was dissolved in 10.0 ml. of dry benzene. Aliquots of this solution (solution A) were used under the following conditions to study the amine oxide elimination. 103 A 1.0-ml. portion of solution A was concentrated on the rotary evaporator, and the resulting oil was redissolved in 15 ml. of toluene. The toluene so+ution was heated under reflux for 10 hr. under nitrogen. After the toluene solution was cooled at 25°, diluted with pentane, washed with dilute hydrochloric acid, water and brine, was dried over anhydrous magnesium sulfate, and filtered, the organic product was chromatographed on alumina (I). mg. Ether gave 20 (37%) of crystalline ketone, which was identified as adamantanone ~): ir. (CC1 4 ) 5.79 µ (C=O), spectrum was identical to an authentic sample (25); mass spectrum (70 eV.) m/e (rel. intensity) 150 (100), 151 (11), 152 (0.8), 79 (82), mol. formula q_ 0 H14 o. In order to determine whether the adamantanone (44) ,,..,,.. was produced in th~ thermal r~action or ·whether it was formed in the chro~atography of the crude product, a 2.0-ml. portion of solution A was concentrated, and the resulting oil was heated under reflux in toluene as before. The product was isolated as before except that after the dried toluene-pentane solution was filtered, its volume was adjusted to 50.0 ml. with pentane. ~ One-half of this solution was d:hromatographed on alumina (I) yielding 14 mg .. of adamantanone (44). .,...,...,.... (26%) The r~~aining 25-ml .. portion of the solution was chromatographed on Florisil giving in the ether, fractions 21 mg. (28%) of keto acetate 48: .-... ir • . (film) 104 5. 74 (acetate C=O), s.ss (ketone C=O), and S .08 µ (acetate C-0); n.m.r. (CHC1 3 ) 5 3.90 (d., 2, J = 5 Hz., CH 0Ac) and 2.03 p.p.m. (s., 3, 2 c~ co). 3 When a 4-mg. sample of keto acetate 48 ,,...,... was chromatographed on alumina (I), 2 mgo of adamantanone (44) ,,..,,.., was obtained. B. ,,..,,.., In DMSO at 90°. ~~,,..,,..,~ A 200-mg. (0.712 rrunole} sample of crystalline amine acetate 46 ,,..,,.., was oxidized with 0.50 ml. (4.8 mmoles) of 30% hydrogen peroxide in 4 ml. of ~-propanol. The reaction was heated under reflux for 12 hr., and the resultant oily amine oxide obtained as before was dissolved in a 5-ml. portion of dry DMSO. The DMSO solution was heated at 80-90° for 4 hr. under nitrogen. The solution was diluted with water and was extracted with ether. The ethereal extract was washed twice with water, once with brine, dried over anhydrous magnesium sulfate, filtered, and was concentrated on the rotary evaporator to give 153 .mg. of oil, which was chromatographed on alumina (I). ether fractions afforded 13 mg. The {9.4%} of adamantanone (44) ~ identified by its ir. spectrum. Acetylation of Liquid Amino Alcohol 43. ~.;v.. ~ ~ ~ The mother """ liquors from the hydroboration product were concentrated, and the crude alcohol 43 .,...,... was used without further purification • A 4.13-g. (17.3 rrunoles) sample of crude amino alcohol ,,..,,.., 43 was dissolved in 40 ml. of dry pyridine. After a 14-ml. 105 portion of acetic anhydride was added, the reaction was heated at 100° for 10 min. ~oved The excess reagents were re- on the rotary evaporator with the aid of toluene to give 5.05 g. of yellow oil. The oil was dissolved in , ether, treated with charcoal, filtered, and concentrated to ¥ield 4.77 g. of pale yellow oil, which was molecularly distilled at 90° (0.05 mm.) to afford 3.94 g. colorless amino acetate 45: 8 • 06 µ ir. (81%) of viscous (film) 5.75 (acetate) and ( c-o) • ~· N, 4 • 9 8 • Calcd. for c 16 H 27 No 3 : Found: A.~ine C, 68.29; H, 9.67; . c, 6 8 • 4 2; H, 9 • 6·6; N, 4 • 9 2 • Oxide Elimination on Crude Amino Acetate 49. ~~~~~~~,,,...,,... The acetate _...,... 49 prepared from the crude amino alcohol 43 .. _...,... was used without further purification. A 2.59 g. sample of oily amino acetate 49 and a 26-ml. . .IV\. (9.24 rnmoles) {25 mmoles) portion of 30% hydrogen peroxide solution were dissolved in 25 ml. of ~-propanol. The solution was heated under reflux until the solution was no longer basic to litmus (4.5 hr.). The reagents were removed on the rotary evaporator with the aid of toluene. The residue was dissolved in 30 ml$ of dry 0 DMSO and was heated under nitrogen·. for 4.5 hr .. at 80 .. After having been cooled to 25°, the solution was poured into 125 ml. of ice water. The aqueous solution was extracted with four SO-ml. portions of ether·. The combined ethereal 106 extract was washed first with a SO-ml. portion of water, then with several portions of 0.01 ~hydrochloric acid until the aqueous layer remained acidic to litmus. ?he ethereal layer was rewashed with water and was dried over anhydrous magnesium sulfate. After the solution was concentrated on the rotary evaporator at 10°, the residue was dissolved in SO ml. of pentane. The pentane solution was dried over anhydrous magnesium sulfate and was filtered through a column of 20 g. of silicic acid with a total of 100 ml. of pentane. Evaporation of the solvent afforded 0.649 g. {3S%) of crude acetate 49: ir. {film) 3.32 (=CH), """"' s. 73 {acetate) and 8. OS µ . (C-0); v .p.c. {6 ft. of Carbowax 20M) two compounds, the one with the shorter retention time (acetate 50) amounted to 16% of the mixture, the compound """ with the longer retention time {acetate 49) amounted to 84%. """ Purification of the Acetate Mixture SO. ~,...,.., """"'~ ~,,...,....,... A 198-mg. sample of crude acetate SO was chromatographed on Florisil """ ( 60/100 mesh), and the results are summarized in Table 1. Each fraction was analyzed by v.p.c. on Carbowax 20M. The mixture of acetates .l'VV-. SO and 51 obtained from the 1:99 ether~ pentane was rechromatographed on Florisil {Table 2). 107 Table 1. Chromatography of crude acetate &Q.• Vol. Solvent 150 50 50 50 50 50 25 25 50 50 Pentane 1:99 Ether-pentane 1:99 Ether-pentane 1:99 Ether-pentane 1:19 Ether-pentane 1:9 Ether-pentane 1:3 Ether-pentane 1:1 Ether-pentane Ether Ether Table 2. (ml.) Wt. of residue (mg.) 20 0 42 34 45 23 (Hydrocarbons) 51) (Acetates 50 and ,..,...,.,. (Acetate 5lf'J (Acetate '3'0) (Acetate SO) ,,...,,.. 23 (Keto acetate ~) 0 Chromatography of acetate mixture 4Q. and ,.a,.. Solvent Vol. Pentane 1:99 Ether-pentane 1:49 Ether-pentane 1:19 Ether-pentane 1:9 Ether-pentane 1:4 Ether-pentane 1:1 Ether-pentane Ether (ml.) 200 200 100 100 50 50 50 50 Wt. of residue (mg•) 0 0 ' 11 (Acetates 50 and 51) .IV' 21 (95% Acetate ~) 3 (99% Acetate 50) -... 0 The combined acetate 50 fractions from both ~ chromatograms were rechromatographed on Florisil (Table 3). The acetate ,..,...,.,. 50 of 99% purity obtained from the third chromatogram was molecularly distilled at 50° (5 mm.) to yield a colorless oil: ir. 6. 08 (C=C), and 8 .,04 (C-0) • Anal. Found: µ· (film) 3. 34 (=CH), 5. 74 (acetate), Calcd. for c12 H18 o2 : C, 74. 03; <H, 9 .,44. c, 74.19; H, 9.34. 108 Table 3. nechromatography of the acetate 2Q,. Vol. Solvent Pentane 1:99 Ether-pentane 1:99 Ether-pentane 1:99 Ether-pentane 1:49 Ether-pentane 1:49 Ether-pentane 1:19 Ether-pentane 1:9 Ether-pentane (ml.) 100 100 100 100 100 100 100 50 Wt. of residue {mg . ) 0 0 18 28 25 14 9 2 (93% Acetate 50) (97% Acetate (98% Acetate 50) (99% Acetate 56') (99% Acetate ~ ffi Reduc.tive Cleavaoe of Crude Acetate 50. ~~_...~~~ To an ether solution of 174 mg. {0.90 mmole) of crude acetate ,,...,... 50 obtained from the amine oxide elimination reaction, added, by way of w~s a soxhlet extractor, a 31-mg. (0.78 mmole) portion of 95% lithium aluminum hydride. After the reaction was heated under reflux for 2 hr . , the excess hydride was decomposed with wet ether and powered sodium sulfate decahydrate. The mixture was stirred for another 30 min. The solution was filtered and concentrated to yield 183 mg. of oil that was molecularly distilled at 90° (20 rrun.) to afford 128 mg. (94%) of oily alcohol .,..-... 45: ir. (film) 3.00 µ (OH) . The ~-nitrobenzoate derivative was prepared by 1 the addition of 75 mg. and o.063 ml. (0.40 mmole) of E-nitrobenzoyl chloride {0.80 mmole) of dry pyridine to a toluene solution of 30 mg. {0.20 mmole) of alcohol ,...,..,.... 48 e was heated to 100° for 5 min . The reaction The product was extracted 109 with pentane; the pentane solution was washed with water, dried over anhydrous magnesium sulfate, filtered, and was concentrated to give the ester~: 3.32 (=CH), 7.88 µ 5.78 (C-0). (C=O), 6.55 (N0 ), 2 m.p. 71-77°; ir. (CC1 4 ) 7.45 (N0 2 ), and The ester 52 was stirred in 1:1 acetone~ water at 25° for 24 hr. The product was worked up by extraction with pentane. The pentane solution was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated to give a solid that was identified as starting ester ;..,... 52 by its infrared spectrum. Ester .,__... 52 was then stirred in 3:2 dioxane-water at 70° for 80 min. After the workup described above and purification by thin-layer chromatography was performed, ester 52 was again isolated: ~ 0 m.p. 77-79 ; iru (CC1 4 ) same as the spectrum summarized above. Purification of Crude Alcohol 45. ~ ~ ~ ~""""""' A 300-mg. sample of crude alcohol 45 that was obtained from the reductive. cleavage of the crude acetate --. 50 was chromatographed on Florisil (Table 4). The composition of the fractions was monitored by v.p.c. (6 ft. of 5% qarbowax 20M, 180°). The 99% alcohol .,__... 45 fractions were combined and molecularly distilled at ao° C25 nun.) to yield a colorless, oily alcohol 45: ~ ir. (film) 3.oo (OH), 3.33 (=CH), and 6.07 n.m.r. (CHC1 ) 3 c~ 0H), 2 o 5 65 0 µ (C=C); (mo, 2, C.!!:=CH), 3.50 (d., 2, J and 2.83 p.p.m. (s., 1, OH). = 5 Hz., 110 Anal. Calcd. for c 10 H16o: c, 78.90; H, 10.59; c, 78.94; H, 10.80. Found: The crude alcohol 53 was rechromatographed on Florisil to give the purified alcohol 53: ~ 3.33 (=CH), and 6.07 µ C~=CH), 3.13 (m., 1, (d., 3, ~ (C=C); n.m.r. C~OH), (CHC13) 0 5.52 (m., 2, 2.78 (s., 1, = 6 Hz., CHCH ); v.p.c. 3 180°) 99% purity. Table 4. ir. (film} 3.00 (OH}, O~), and 0.92 p.p.m. (6 ft. of 5% Carbowax 20M, Chromatography of crude alcohol g. Solvent 1:19 Ether-pentane 1:9 Ether-pentane 1 :9 Ether-pentane 1:9 Ether-pentane 1:9 Ether-pentane 1:3 Ether-pentane 1:1 Ether-pentane Vol. (ml.) 100 100 200 100 100 200 100 Wt. of residue (mg•) 5 2 53 78 57 76 8 Alcohol 53) (95% Alcohol ~) (99% Alcohol 45) (99% Alcohol 45) (99% Alcohol ~) (95% ~ ~ 111 REFERENCES (l} P. Schleyer aria. R. Nicholas, !2:_. Arn. Che.."Il. Soc., 83, 182 (1961). ~ .-.... (2) P. Bartlett ands. (3) R. G. Lawton, ibid., 83, 2399 Bank,~., - ~' 2591 (1961}. (1961). A/V'. (4) s. Winstein and P. Carter, -ibid., ,,...,... 83, 4485 (5) D. (6) N. J. Leonard, L.A. Miller, and J. J. A.'11. Ch~'ll. Soc., 79, 1432 (1957). Prins,~·~·~' --- (7) (1961) .. 1.£ 1 1621 (1957). w. Berry, .-.... P. D. Gardner, G. R. Haynes, and R. L. Brandon, J. Org. CheJ1.1., - - 22, 1206 (1957) • """""" (8) P. Courtot, ~· ~· ~· ~., 1493 (1962). (9) L. N. Owen and P. A. Robins, J. Chem. ~., 320 (1949). (10) K. Bowden, I. M. Heilbron, E. R. H. Jones, and B. c. L. Weedon, ibid., 39 (1946). (11) A. Baeyer and w. A. Noyes, (12) s. Hunig, E. Lucke, and w. Brenninger, Org. syn., 41, 65 (1961) • ,,...,... (13) G. Stork and H. K. Landesman, J. 78, 5128 .,..,.. (14) Ch~'ll. Ber., 22, 2170 (1889) • .-.... ~Chem. ~., (1956) • c. s. Foote and R. B. Woodward, Tetrahedron, 637 20, .-.... (1964) • Ch~'ll. (15) Huang-11inlon, J. A.in. (16) ~·1. (17) 69, 2106 (1936). c. Mannich and H. Davidsen, Chem. ~., ,,..,.... (18) K. c. Brannock, R. D. Burpitt, v. w. Goodlett, and J . G. Thweatt, J. Orq. Chem., 29, 818 (1964) (19) Soc., 68, 2487 (1946). -----,,...,... Hartmann, z. Chem. / 7, 101 (1967) - ,,...,... ~ - ~ - .,....,.,. G w. s. Johnson, V. J . Bauer , and Ro W. Franck, Tetrahedron~., 72 (1961). 112 (20) R. A. Benkeser, R. F. Lambert, P. w. Ryan, and D. G. Stoffey, J. Am. Chem. Soc., 80, 6573 (1958). -----""""" (21) R. Greenwald, M. Chaykovsky, and E. J. Corey, J. Org. Ch~n., 28, 1128 (1963). - -- ~ (22) For a recent review of the 'Wittig reaction see A. Maercker in "Organic Reactions," Vol. XIV, John Wiley and Sons, New York, i~·. Y., 1965, pp. 270-490. (23) H. c. Brown and A. W. Moerikafer, J. Am. Che.rn. Soc., 83, 3417 (1961). - """" (24) P. Schleyer and R. Nicholas, ibid., 83, 182 (1961). (25) The comparison sample supplied by Professor Schleyer is gratefully acknowledged. (26) D. J. Cram, .M. R. V. Sahyun, and G. R. Knox, J. Am. Che.rn. Soc., 84, 1734 (1962). """" - (27) """" H. Brockmann and H. Schodder, Chem. (1941). ~., 74, 73 ......... PROPOSITIONS 114 Proposition 1 An investigation of the biogenesis of the iridoid, loganin (1), is proposed in order to determine if farnesol ,..,,.... is a precursor of this family of terpenoids. The iridoids (1) are a family of plant constituents with a cyclopentane monoterpenoid skeleton. A few represen- tative members of this family are iridodial (2) "'""' (2), asperuloside (3) ,....,.... (1) , loganin (1) (4). (5, 6, 7) is a nine-carbon iridoid and Aucubin (5) ,,..,.... unedoside {6) """' croside (7) ,,..-. (3), and nepetalactone (4) .,....,... (8) is an eight-carbon iridoid. (9) and swertiamarin (8) "'""' Skytanthir.e C.2J. (11) , actinidine C.1:,9) (11) Gentiopri- (10) are seco-iridoids. (12) and gentianine (13) are alkaloids that are related to the iridoids. ~ Fulvoplumierin (12) ... .,,....,,,,.... (1 4 ) (14), plumierid (13) """" (15), and plumericin (16) are thirteen- and fourteen-carbon compounds that are structurally related to the iridoids. Although the carbon skeleton of the ten-carbon iridoids can be divided into two isoprenoid units, the iridoids as a group possess several properties that are unique ai-nong the monoterpenes. The 1, 2-di~nethyl-3- isopropylcyclopentane-carbon skeleton is almost unknown to the monoterpenes. i·ilonoterp enes are usually hydrocarbons or mono-oxygenated compounds with three to five degrees of 115 OH 1 OCOCH3 2 0 3 4 OH 0-glu 5 6 7 9 10 11 OJ) 0-glu ___ A--orr CH3 :::: H 13 14 8 116 unsaturation, but the iridoids are usually poly-oxygenated substances with five to eleven degrees of unsaturation. Several iridoids exist as enol hemiacetal glucosides, an unusual linkage for a monoterpene. The existence of eight-, nine-, ten-, thirteen-, and fourteen-carbon homologues is also unique in terpene chemistry. The characteristics mentioned above do not exclude the iridoids from the realm of the monoterpenes, but these points do suggest that the biogenesis of the iridoids may differ from that of the regular monoterpenes and that the iridoids may be degradation products from higher terpenoids. Although geraniol has been shown to be a precursor of loganin (1) (17, 18) and loganic acid (19) as a result of """" labelling experiments, these experiments do not rule out the possibility that higher terpenoids derived from geraniol may actually be involved in the biogenesis of the iridoids. Therefore, the use of labelled [ 14 c]-farnesol in feeding experiments similar to those already carried out with geraniol (17, 18, 19) is proposed. Since farnesol is a precursor of all the higher terpenoids, incorporation of label from this precursor into loganin (1) would produce """ evidence for a degradative biogenesis, and negative results would support a monoterpene biogenesis. 117 Ref er enc es (1) L. H. Briggs, B. F. Cain, P . w. Le Quesne, and J. N. Schoolery, Tetrahedron Lett., 69 (1963). (2) G. 13 I (3) w. K. Cavill and D. L. Ford, ~· ~· ~·, 296 {1960) • K. Sheth, E. Ramstad, and J. Wolinsky, Tetrahedron ~., 394 (1961). (4) R. B. Bates, E. J. Eisenbraun, and s. M. McElvain, J. ~· Chem. ~·, ~ 3420 (1958). {5) s. Fujise , H. Obara, and H. Uda, ~· ~· 289 {London), (1960). (6) Wo Haegele, F. Kaplan, and H. Schmid, Tetrahedron ~., 110 (1961). (7} A. J. Birch, J. Gri.-rnshaw, and H. R. Juneja, J. Chem. Soc., 5194 (8) (1961) • T. Ao Geissman, Iv. F. Knaack, Jr., and J. o. Knight, Tetrahedron~., (9) 1245 (1966). L. Canonica , F. Pelizzoni, P. Manitto, and G. Jommi, 24, 7, (1960). ~.,No. Tomita,~. , (10) T . Kubata and Y. (11) c . Djerassi , J . P. Ku tney v J\l. Shani.ma, J. N. Schoolery, and L. F. Johnson , Chen. Ind. (12) 176 {1961). (London), 210 (1961). T. Sakan , A. Fujino , F. M.urai, Y. Butsugan, and A. Suzui, Bull. Chem. Soc. Jap., 32, 315 (1959). -----,,...,.,.. (13) T. R. Govindachari, I\. Nagarajan, and s. Rajappa, J. Chem. Soc., 551 (1957). (14) H. Schmid and w. Beneze, Helv. Chim •._.,...,... ?\eta, 36, 1468 (1 953). (15) o . Halpern and I-I. Schmid , ibid., 41, ,,...,.,.. 1109 (1958}. 118 (16) G. Albers-Schonberg and H. Schmid, ibid., 44, 1447 (1961). -""""" (17) A. R. Battersby, R. s. Kapil, and R. Southgate, Chem. Co~mun., 131, (1968). (18) s. Brechbuhler-Bader, c. J. Coscia, P. Loew, Ch. v. Szczepanski, and D. Arigoni, ibid., 136 (1968). (19) C. J. Coscia, R. Guarnaccia, ~·, 138 (1968) • 119 Proposition 2 ill A synthesis of the sesquiterpene, zizanoic acid (also known as khusenic acid) is proposed. The structure of zizanoic acid (1 ) (1) , knmm also as khusenic acid (2), has recently been elucidated. The synthesis of this unusual sesquiterpene is proposed starting from norboren-7-one (2). .rV""- Alkylation of the enone 2 with ,,....,.... the Grignard reagent ,,....,.... 3 should occur from the less hindered side of the carbonyl group to yield the unsaturated carbinol 4. If the carbinol 4, when solvolyzed in formic acid, gives """" "'"" the c -vclized fonnate 5-0CHO, reductive cleavage of the ~ formate 5-0CHO with lithium aluminum hydride followed by transformation of the resultant alcohol 5-0H with phosphorous tribromide should afford the corresponding bromide 5-Br. ~ The bromide 5-Br is converted to the Grignard reagent, which is carboxylated with carbon dioxide. The resultant acid 5-COOE is reduced with lithium aluminum hydride to the ~ alcohol 6-0H, which is then converted to the tosyiate 6-0Ts. ~ ~ 120 2 4 5-0GHO ~ 1) LAH 02N 2) PLr3 3) Hg, ether 4) C02 5) LAH 6) TsCl 7) NaN0 2 CHO 03 > ~ Et")N ..) CEO 6-N0 2 N02 CGH6 -H20 N02 > CHO 7 ,...,..... 8 ,...,..... ~ 1) DHP,TsOH 1) NaBH 4 ·- --:?;> --~ -->__..,,~ 2) NaH,HC02Et 2) Fe,HCl, H20,FeCl3 OTHP 9-0H 10 121 Li (CH 3 ) ..,cu --'3' OTHP OH 11 """"" 12 1) CF co H 3 3 13 1) Cro 3 CF 3 co~ 2) LAH OH 1) }?53P=CH'2 > 7 );> 2) CH 2 N2 Na OH 3) H30 ED 2) co 2cr-r 3 1~1 """"" 15-C02CH 3 ~ 1 ,,..,,... 122 Reaction of the tosylate 6-0Ts with sodiu,rn nitrite (3) ~ should procluce the nitroalkene 6-No 2 • After the nitro- alkene 6-N0 2 is converted upon ozonolysis (4) to the dialdehyde ,,.,,.._ 7, base-catalyzed condensation (5) should give the tricyclic nitro-olefin 8, whose aldehyde group will """ probably have the more stable beta orientation. Since the nitro group is stable to sodium borohydride (6), this reagent can be used to reduce the re.'TLaining aldehj:de group to an alcohol function. Then, reduction of the unsaturated nitro function with iron in aqueous hydrochloric acid (5) should give the ketol 9-0H. At this point it is necessary to protect the alcohol group of the ketol 9-0H with a tetrahydropyranyl ether linkage (7). The carbonyl group of the resulting ketone 9-0THP is converted into the hydroxymethylene derivative 10 with ~ sodium hydride and ethyl formate (8). The enol 10 is then treated with excess diazomethane (9) to give the ketone 11. """"'" Addition of methyllithimn to the ketone 11 follm·1ed by acidic workup (10) of the crude product is expected to give the enone 12. The enone 12 should undergo methylation with lithium dirnethylcopper (I) 13. {11) to yield the ketol If a Baeyer-Villiger oxidation (12, 13) of the ketone 13 is followed by reductive cleavage of the crude product with lithium aluminum hydride, the diol 14 should """" be obtained . Oxidation of the diol ,,..,...,.. 14 with excess chromic 123 acid reagent (14) to the keto acid 15-CDOH gives after methylation with diazomethane the keto ester 15-COOCH 3 • The keto ester 15-COOCH 3 is then converted into the unsaturated ester ,,...,...,.. 16 by reaction with methylenetriphenylphosphorane (15). Saponification of the ester 16 followed by acidification of the salt should give zizanoic acid (1). """"" 124 Ref er enc es (1) F. Kido, E. Uda, and A. Ysoshikoshi, 1247 (1968). (2) H. Komae and I. C. Nigam, J. Org. 1771 (1968). (3) Tetrahedron~., ~., 33, ~ N. Kornblum, H. o. Larson, R. K. Black\'lOOd, D. D • .t-looberry, E. P. Oliveto, and G. E. Graham, J. Am. Chem. Soc., 78, 1497 (1956). - - - .rv"V"- (4) J. J. Pappas, w. P. Keaveney, E. Gancher, and M. Berger, Tetrahedron Lett., 4273 (1966). (5) R. V. Heinzelman, Org. Syn., Coll. Vol. 4, 573 (1963). (6) -- -- H. Shechter, D. E. Ley, ~·, (7) ~ ,,,...,...,,... """' and L. Zeldin, J. Ai-n. Chern. 74' 3664 (1952). ,,....,..._ c. w. Greenhalgh, H. B. Henbest, and E. H. R. Jones, J. Chffiu. Soc., 2375 (1952). (8) c. Ainsworth, Org. Syn.,~· ~.~, 536 (1963). (9) D. Nasipuri and K. K. Biswas, Tetrahedron~., 2963 (1966). (10) 11. Stiles and A. Longroy, (11) H. o. House, W. L. Respess, and G. J. Org. Chem., 23::_, 3128 (1966). (12) w. D. Emrnons and G. B. Lucas, ~·Arn. Chem. Soc., 22..i 2287 (13) (1955). s. Mccallum, .rv"V"- I<. Bowden, B. (15) w. Whitesides, M. F. Hawthorne, \•l. D. Enunons, and K. ibid., 80, 6393 (1958). - (14) ibid., 337 (1961). c. I. M. Heilbron, E. R. H. Jones, and L. Weedon, J. ~· ~., 39 (1946). R. Greenwald, M. Chaykovsky, and E. J. Corey, J. Org. Che."TI.., 28, 1128 (1963). ,,...,..,... -- 125 Proposition 3 A synthesis of the quadricyclic hydrocarbon ,,.,_,....,... 1 is proposed. The synthetic scheme also yields intermediates that can be used in solvolytic routes to compounds related to birdcage hydrocarbon 2-H. ~ The quadricyclic hydrocarbonlis a homologue of the tricyclo (5.2.1.0 4110 Jdecane (3) ~ (1), which has been used as an intermediate in the synthesis of the triquinacene (2). The original purpose (1, 2) in preparing the tri- quinacene (4) was its use as a potential intermediate in ~ the synthesis of the dodecahedrane (5). ~ The interest in the hydrocarbon 1 st.e."ns from its relationship to the ""-" hvdrocarbons 3 and 5. ~ .l"V'V'. ~ 3 1 2-H 4 5 ill 126 The synthetic route proposed begins with the diketone 6 (3), which when converted to the bis-ena'Uine 7 and alkylated with methyl dibromoacetate is expected to yield the diketone ~by analogy to a series of reactions carried out by Stetter and Thomas (4) who prepared 4carbomethoxyadamantan-2,6-dione. The following conversion of the diketone 8 to the enone 9 is analogous to a series of reactions that were reported by Eaton (3). Mono- ketalization of the diketone 8 with ethylene ~lycol gives the ketone 10, which can be reduced with sodiu.i.11 borohydride ~ to the alcohol endo-11-0I·I . --~ The alcohol endo-11-0H after -~ treatment with hydrobromic acid is expected to yield the bromide exo-11-Br, which upon zinc-acetic acid reduction --~ leads to the enone 9. Catalytic hydrogenation of the enone 9 should give the ketone 12, which upon Wolff-Kishner reduction is """""'"' expected to afford the acid 13-COOI-I. The acid 13-COOH after ~ ~ chlorodecarboxylation is expected to give the chloride 13-Cl, ~ which can then be reduced with lithimn (6) to give the hydrocarbon 1. "-"'- The synthetic intermediates can also be used in other interesting studies. The enone 9 upon aluminum isopropoxide """" reduction can produce the alcohol 14-0I·I . ~ The solvolysis of the tosylate 13-0Ts can then be investigated as another ~ possible solvolytic route to compounds related to birdcage hydrocarbon 2-H. ~ 127 0-H> > M.eOOC 8 6 c: Ts OH 7 NaBH > 4 1) HBr ) > 2) Zn-HOAc MeOOC MeOOC endo-11-0H 10 -~ H2 -Pd W.K. > ODriie 12 9 > COOH 13-COOH ~ 1) P~{OAc) 4, I LiCl 2) Li, "1;t-Bu0H Al {O-i-Pr) 1 i-PrOH 1) TsCL 2) COOI•le HOAc > and/or 2-COOl1c ~ COOMe 14-0H ~ 128 Hef erences (1) (2) I. T. Jacobson, 1\cta Cher:l. Scand., 21, 2235 (1967). ---- ~ R. B~ Woodward, 'I'. J. Fukunaga, and R. J. hi:n. Chem. Soc., 86, 3162 (1964). c. Kelly, - (3) """"" P . E. Eaton, Abstracts, 155th National l"l eeting of the American Che:n ical Society, San Francisco, California, April 1968, No. Pl. ~·, ~' (4) H. Stetter and H. G. Thomas, Chem. (5) J. K. Kochi, J. A'll. Chem. Soc., 87, 2500 (1965). (6) P. Bruck, D. Thompson, and (London), 405 (1960). ----- 920 (1966). ~ s. Winstein, Chem. Ind. 129 Proposition 4 A synthesis of the sesquiterpene eremophilene 1 is """ proposecl. The sesquiterpene eremophilene 1 (1) has three """" asym...rnetric centers which are all common to one six-me..mbered 1 ring of a cis-octalin carbon skeleton. Since the olefinic cyclization procedure of Johnson and co-workers (2, 3) is ideally suited to establish this cis-fused octalin skeleton, a re la ti vely s:L-uple synthesis of eremophilene ( 1) is proposed. ""'" Chloromethylation (4) of the ether 2 should give the benzyl chloride 3-Cl, which is used to prepare the ~ corresponding Grignard reagent 3-IvlgCl. If the Gri,3nard ~ reagent 3-NgCl is coupled with allyl bromide, the ether ,,....,,. 4 ~ should be obtained. Birch reduction {5, 6) of the ether 4 is expected to give the dienone 5. Lithium aluminum hydride reduction to the allylic alcohol 6 followed by olef inic . """" cyclization in formic acid (2, 3) is expected to give the hydroxy olefin 7-0I-I after li thiu.'11 aluminum hydride reduction of the formate ester 7-0CHO. ~ After the alcohol 7-0H is ~ 130 2) CH2=CHCH2Br CE 2Cl 2 ,,...,.... 3-Cl 4 ~ LAH "=: . 1) > 5 HCOOH 2) LAH 6 l) HBr > + 9 """ 2) .i:1g, ether 7-a:-OH 3) AC 2o, -70° 8 ~ 9 ) 131 converted to the bromide 7-Dr with 48% hydrobromic acid, the corresponding Grignard reagent ~ can be prepared and converted to the ketones 8 and ,,..,,.._ 9 upon addition to acetic anhydride at -70° (7). The ketones 8 and 9 will probably require some type of chromatographic separation. If the mixture can be successfully separated , the undesired isomer ,,..,,.._ 9 can be re-equilibrated with acid to produce more of the desired ketone 8. The identity of the two ketones can be established by conversion of each isomer to the corresponding methylene derivatives with methylenetriphenylphosphorane (8); and the isomer ,,..,,.._ 8 ·will yield the desired eremophilene (1), ·w hich ,,...,... can be compared to an authentic sample. Although this synthetic scher.le suffers from a nonstereospecif ic introduction of the substituent at C7, the problem may be easily overcome by finding a suitable scherne to separate the k etones 8 and 9. The ketone 8 may serve also as a useful intermediate in the synthesis of derivatives of eremophilane. 132 References (1) Jo Hocr11-nannova and v. Herout, Coll. Czech. Che:n. COITLL"'11Un., 29, 2369 (1964). """""' (2) F. s. Johnson and K. E. Harding, J. Org. Chem., E' 478 (3) (1967). w. s. Johnson, P. J. Neustaedter, and K. K. Schmiegel, J. Am. Chem. Soc., - (4) - -- 87, 5148 ~ (1965). R. c. Fuson and c. H. McKeever, Org. Reactions, 1, 63 (1942). ~ (5) Ao J. Birch and H. Smith, Quart. Rev., (London), 14, 17 (1958); and references thereTn. (6) A. L. ·wilds and N. A. Nelson, J. 75, 5366 (1953). (7) I:,' i. 592 (8) ~· Che.."'11. §.££., s. Newman and A. s. Smith, J. Org. Che..rn., 13, (1948). ""'" R. Greenwald, i•1. Chaykovsky, and E. J. Corey, ibid., 23, 1128 (1963). ,..,.,... 133 Proposition 5 An investigation into the mechanism of the basecatalyzed rearrang·e.""1.ent of the half-cage ketone ,....,..., 1 is proposed. A study into the stereoche.~istry of the proton- ation of the birdcage alkoxide 2a should clarify the A.I' mechanism of the rearrangement. The half-cage ketone 1 undergoes base-catalyzed A.I' rearranga~ent to the half-cage ketone .rv-. 3 (1, 2). Further- more, since the birdcage alcohol 2 upon treatment with """'"' base ~lso has been transformed to the ketone 3, the anion """"' 2a has been established as an intermediate in the overall homoenolization-homoketonization, which begins by the formation of the homoenolate la, and continues by the ~ rearrangement of .rv-. la into the alkoxide ,...,....,.... 2a and then by the 2a into the homoenolate 3a, and finally rearrangement of -""' ,,.,,,.. concludes by the protona tion of ~ to yield the ketone _,1. Howe and Winstein (1) have suggested that the outside hydrogen Hx at C~ of ,...,.... 1 is abstracted by the base. If this mechanism is applicable, the protonation of the homoenolate 3a should also occur from the outside direction to give ketone ,. .3, . _ with the new hydrogen Hx at C v. u Hmqever, in another communication Winstein and co-workers (3) reveal that the chlorinated half-cage ketone ,,..,,.... 4 rearranges to the birdcage alcohol ,,....,.,. 5 upon heating with pyridine. Furthermore, 134 KOt-Bu, t-BuOH 1 3 2a la 2 3a Cl Py 1 !::,. > 1 Cl 4 5 """ """ D H KOt-Bu t-BuOD 2-0D > 3-Ca-D 135 when ketone 4 was treated with an equivalent of lithiu111 aluminum hydride, the birdcage alcohol 5 was also produced (4). In both cases the inside hydrogen at C 0 has been abstracted by the base. Therefore, either the mechanism of this homoenolization differs from that of the half-cage ketone 1 """"" or the mechanism of the latter rearrangement requires further examination. In order to remove the ambiguity in the mechanism of the homoketonization of alcohol 2, it is proposed that """ the alcohol 2-0D be prepared and rearranged in deuterated ~ t-butanol and potassi~~ t-butoxide. If the homoenolate 3a ~ is deuterated stereospecifically, then, nuclear magnetic resonance analysis of the deuterated ketone 3-C~D should reveal the orientation of the C 0 proton and, thereby, clarify the mechanisn of the homoketonization. 136 References (1) R. Howe and 915 (1965). s. Winstein, J. A.rrt . Chem. Soc., 87, """"' {2) T . Fukunaga, ibid., 87, 916 (1965). (3) P. Carter, R. Howe, ands. Winstein, i b id., 37, 914 {1965) . -""""' (4) s. B. Soloway, A. M. Damiana , J. w. Slins , H. Bluestone, and R. E. Lidov, ibid., 82, 5377 (1960). - ~